Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[CH:15]1[CH:16]=[CH:17][N:18]2[CH2:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[NH:21][CH2:20][C:19]=12.C(N(C(C)C)CC)(C)C>ClCCl>[N:1]1([C:6]2[CH:14]=[CH:13][C:9]([C:10]([N:21]3[C:22]4[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=4[CH2:24][N:18]4[CH:17]=[CH:16][CH:15]=[C:19]4[CH2:20]3)=[O:11])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: O=C(Cl)c1ccc(-n2cccn2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(-n2cccn2)cc1)N1Cc2cccn2Cc2ccccc21
Reaction time: 18 h
Yield: 76.7 %

Procedure:
The 4-(pyrazol-1-yl)benzoyl chloride (0.75 g) was added to a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.61 g) and diisopropylethylamine (0.47 g) in dichloromethane (25 ml). After 18 hours at room temperature, the reaction mixture was washed with water and a saturated aqueous sodium bicarbonate solution. The dichloromethane solution was dried over anhydrous sodium sulfate and filtered through a short column of hydrous sodium magnesium silicate and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated on a hot plate with the gradual addition of hexane until crystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (0.90 g), m.p. 179-181° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.[NH2:12][C:13]1[CH:14]=[C:15]([CH2:19][OH:20])[CH:16]=[CH:17][CH:18]=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][OH:20])[CH:14]=1)=[O:11]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Nc1cccc(CO)c1
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1ccccc1Br)Nc1cccc(CO)c1
Reaction time: 2 h

Procedure:
To a stirring solution of 2-(2-bromophenyl)acetic acid in dichloromethane (0.2 M) was added (3-aminophenyl) methan-1-ol (1.2 eq), triethylamine (1.5 eq), and EDAC (1.5 eq). After 2 hrs, the solution was washed with water, 10% HCl, 10% sodium carbonate, and water, dried over magnesium sulfate, filtered and concentrated in vacuo to afford a colorless solid. EI-MS m/z 320/322 (M+H)+
Reaction SMILES: Cl.[NH2:2][OH:3].[CH3:4][O:5][C:6]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17])=O>C(O)C.N1C=CC=CC=1>[CH3:4][O:5][C:6]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:7]=1[C:8](=[N:2][OH:3])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17]
Reactant: NO
Reactant: COc1ccc(C(=O)c2ccccc2OC)c(OC)c1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: COc1ccc(C(=NO)c2ccccc2OC)c(OC)c1

Procedure:
Hydroxylamine hydrochloride (4.98 g, 71.7 mmol) is added to a solution of 2,2′,4-tri-methoxybenzophenone (J. Org. Chem. 1996, 61, 6326; 6.5 g, 23.9 mmol) in ethanol (50 ml) and pyridine (10 ml). The mixture is heated at reflux for 2 hours and the solvent evaporated. The residue is partitioned between dichloromethane and 2 M aqueous HCl and the organic phase is washed with water, brine, dried (MgSO4) and evaporated to afford the title compound.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9](OC)=[O:10].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[CH2:9][OH:10]
Reactant: COC(=O)c1cccc(C2OCCO2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cccc(C2OCCO2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methyl 3-(1,3-dioxolan-2-yl)benzoate (11.0 g., 53 mmol) in tetrahydrofuran (50 ml) was added dropwise to a stirred suspension of lithium aluminium hydride (3.2 g) in tetrahydrofuran (100 ml). The temperature rose to ca. 45° C. The mixture was stirred for a further 1 hour cooling to room temperature, then was cooled in ice whilst water (3.2 ml) 2M sodium hydroxide (6.4 ml) and more water (6.4 ml) were added dropwise. The mixture was filtered through a pad of Celite filter acid and the filtrate was evaporated to a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:26][C:27]#[C:28][CH2:29][O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])(=O)=O.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[N:12]([CH2:26][C:27]#[C:28][CH2:29][O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[N:13]=2)=[N:6][CH:7]=1
Reactant: O=c1ccc(-c2ccc(Cl)cn2)n[nH]1
Reactant: CCCCCOCC#CCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCOCC#CCn1nc(-c2ccc(Cl)cn2)ccc1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.5 %

Procedure:
To a 100 mL 3 neck flask equipped with magnetic stirrer, addition funnel, and nitrogen inlet was charged 2.13 grams (g) of 6-(5-chloropyridin-2-yl)pyridazin-3(2H)-one (10.3 mmol), 2.20 g of potassium carbonate (16 mmol), and 50 mL of dry DMF. The reaction mixture was stirred for about 30 minutes at ambient temperature followed by the dropwise addition of 2.54 g of 4-(pentyloxy)but-2-ynyl methanesulfonate (10.8 mmol) in about 5 mL of dry DMF. The reaction was stirred overnight at ambient temperature, and checked by TLC and GC the next morning. No starting material remained, and one new product was formed. The reaction was poured into about 100 mL of water, and extracted with 3×50 mL of ethyl ether. The combined ether extract was washed with 100 mL of water, 100 mL of saturated aqueous sodium chloride solution, dried, and stripped to the crude product which was purified by silica gel column chromatography. The pure fractions were combined and concentrated under vacuum on a rotary evaporator to afford 1.3 g of a white solid. The NMR data is as follows: 300 MHz 1H NMR (CDCl3, TMS=0 ppm) 0.90 (m 3H); 1.30 (m, 4H); 1.55 (m, 2H); 3.45 (t, 2H); 4.15 (s, 2H); 5.05 (s, 2H); 7.05 (d, 1H); 7.75 (d, 1H); 8.15 (d, 1H); 8.30 (d, 1H); 8.55 (s, 1H).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:10])[C@@H:3]([C:5]1[S:6][CH:7]=[CH:8][N:9]=1)[OH:4].N[C@@H](C)[C@H:13](C1SC=CN=1)[OH:14].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH3:10][C@H:2]1[C@@H:3]([C:5]2[S:6][CH:7]=[CH:8][N:9]=2)[O:4][C:13](=[O:14])[NH:1]1
Reactant: C[C@H](N)[C@H](O)c1nccs1
Reactant: C[C@H](N)[C@@H](O)c1nccs1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: C[C@@H]1NC(=O)O[C@@H]1c1nccs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 13 %

Procedure:
To a mixture of (1S,2S)-2-amino-1-thiazol-2-yl-propan-1-ol and (1R,2S)-2-amino-1-thiazol-2-yl-propan-1-ol (2.9 g, 12.5 mmol) in CH2Cl2 (40 mL) was added under argon NEt3 (10.5 mL, 75 mmol) at 0° C. Then, triphosgene (1.86 g, 6.27 mmol) dissolved in 40 mL of CH2Cl2 was added slowly, and the temperature was allowed to warm from 0° C. to room temperature. The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was then quenched by addition of aqueous NaHCO3. The organic layers were separated, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography using EtOAc in heptane from 0% to 100% in order to give the desired product (330 mg, 13%). LC-MS: [M+H] 185.0; Rt 0.48 min; (LCMS method 1). 1H NMR (400 MHz, CHCl3-d): 7.79 (d, 1H), 7.34 (d, 1H), 5.91 (d, 1H), 5.71 (br s, 1H), 4.48-4.38 (m, 1H), 0.89 (d, 3H).
Reaction SMILES: [AlH](CC(C)C)CC(C)C.[F:10][C:11]1[CH:12]=[CH:13][C:14]2[C:15]3[CH2:24][CH2:23][NH:22][C:21](=O)[C@H:20]([CH3:26])[C:16]=3[NH:17][C:18]=2[CH:19]=1>C(Cl)Cl.C1COCC1>[F:10][C:11]1[CH:12]=[CH:13][C:14]2[C:15]3[CH2:24][CH2:23][NH:22][CH2:21][C@@H:20]([CH3:26])[C:16]=3[NH:17][C:18]=2[CH:19]=1
Reactant: C[C@H]1C(=O)NCCc2c1[nH]c1cc(F)ccc21
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@@H]1CNCCc2c1[nH]c1cc(F)ccc21
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To an oven-dried flask containing dry THF (10 mL) under argon at −78° C. was added a 1 M solution of (iBu)2AlH in CH2Cl2 (16.3 mL). This mixture was stirred at −78° C. for 5 min. To this was (R)-8-fluoro-5-methyl-2,3,5,6-tetrahydroazepino[4,5-b]indol-4(1H)-one (0.236 g, 1.02 mmol) in dry THF (16 mL). The reaction mixture was stirred at rt for 72 h, cooled to 0° C., then quenched by the addition of MeOH (4.5 mL). The mixture was partitioned between CH2Cl2 and 1 M aq NaO2CCH(OH)CH(OH)CO2K. The CH2Cl2 extracts were washed with brine, and dried, filtered and concentrated to give an oil. The oil was purified by silica chromatography to give the amine. To a solution of this amine (0.105 g, 0.48 mmol) in dry MeOH (4 mL) was added fumaric acid (0.028 g, 0.24 mmol) in MeOH (2.2 mL). The mixture was stirred overnight, concentrated, and the residue was dissolved in hot MeOH from which crystalline product was recovered: mp 256-258° C.; MS (ESI+) m/z 219.1; 1H NMR (CD3SOCD3, 300 MHz) δ 10.83 (1H), 9.3-8.5 (2H), 7.35 (1H), 7.01 (1H), 6.78 (1H), 6.43 (1H), 3.22-2.70 (8H), 1.30 (3H); Anal. C, 64.94; H, 6.27; N, 10.07.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:34][CH:35]=[CH2:36])=[C:5]([CH:27]=[CH:28][C:29]=1[C:30]([NH:32][CH3:33])=[O:31])[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[C:12]([CH2:24][CH2:25][CH3:26])=[C:13]([CH:21]=[CH:22][CH:23]=1)[O:14][CH2:15][C:16]([O:18]CC)=[O:17].[OH-].[Li+].CO.Cl>O>[CH3:1][O:2][C:3]1[C:4]([CH2:34][CH:35]=[CH2:36])=[C:5]([CH:27]=[CH:28][C:29]=1[C:30]([NH:32][CH3:33])=[O:31])[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[C:12]([CH2:24][CH2:25][CH3:26])=[C:13]([CH:21]=[CH:22][CH:23]=1)[O:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: C=CCc1c(OCCCOc2cccc(OCC(=O)OCC)c2CCC)ccc(C(=O)NC)c1OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=CCc1c(OCCCOc2cccc(OCC(=O)O)c2CCC)ccc(C(=O)NC)c1OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The compound of Example 52 (95 mg, 0.19 mmol) and 380 μl (0.38 mmol) of 1M lithium hydroxide were added to 2.0 ml of methanol, and the reaction mixture was stirred for four hours at room temperature. The solvent was removed under vacuum to give a white solid which was suspended in 5.0 ml of water. The mixture was acidified with 10% hydrochloric acid, stirred and filtered to remove the resultant solid which was then dried at 40° C. overnight in a vacuum oven to give the product.
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:9]([C:11]2[CH:33]=[CH:32][C:14]3[N:15]([CH3:31])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][C:21]=4[O:29][CH3:30])=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:42]([O:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[O:43]>ClCCl.C(O)C>[C:2]1([N:8]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:9]([C:11]2[CH:33]=[CH:32][C:14]3[N:15]([CH3:31])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:42]([O:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[O:43])=[CH:22][C:21]=4[O:29][CH3:30])=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCOC(=O)Cl
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1OC)n2C)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccc4)ccc3n2C)c(OC)c1
Yield: 68 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidino-2-methoxyphenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide hydrochloride and n-heptyl chloroformate. Yield: 68% of theory, C37H46N6O6 (670.8); Rf value: 0.56 (silica gel; dichloromethane/ethanol=9:1); EKA mass spectrum: (M+H)+=671; (M+H+Na)++=347.4.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[CH2:6][NH:7][CH:8]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:13]=1)[C:9]([OH:11])=[O:10].[OH-].[Na+:34]>CO>[F:32][C:2]([F:1])([F:31])[C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[CH2:6][NH:7][CH:8]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:13]=1)[C:9]([O-:11])=[O:10].[Na+:34]
Reactant: O=C(O)C(NCc1cccc(C(F)(F)F)c1)c1cn(Cc2ccccc2)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])C(NCc1cccc(C(F)(F)F)c1)c1cn(Cc2ccccc2)c2ccccc12

Procedure:
A mixture of 3 g (6.84 mmoles) of α-[3-(trifluoromethyl)benzylamino]-1-benzylindole 3-acetic acid, 3.4 ml (6.80 mmoles) of 2N NaOH, and 100 ml of MeOH was warmed until a solution was obtained (one to two hours). The solvent was evaporated. The residue was dried in a vacuum oven at 66° for 70 hours giving 2.70 (86%) of the title compound as an orange solid, m.p. 210°-215°.
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[ClH:15].Cl.[C:17]1([NH:23][C:24]([NH:26][C:27]([NH2:29])=[NH:28])=[NH:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[ClH:15].[CH2:3]([C:2]1([CH3:1])[N:23]([C:17]2[CH:18]=[CH:19][C:20]([Cl:15])=[CH:21][CH:22]=2)[C:24]([NH2:25])=[N:26][C:27]([NH2:29])=[N:28]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCC(C)=O
Reactant: N=C(N)NC(=N)Nc1ccccc1
Agent: Cl
Solvent: CCO
Product: CCCCCCCCCCCC1(C)N=C(N)N=C(N)N1c1ccc(Cl)cc1

Procedure:
200 ml of ethanol, 10.1 g (50.9 mmol) of 2-tridecanone and 2.0 ml of concentrated hydrochloric acid were added to 12.0 g (48.4 mmol) of N1-phenyl-biguanide hydrochloride, and the mixture was refluxed for 40 hours. The solvent was distilled off under reduced pressure, and the residue was purified two times by silica gel column chromatography (elution with a mixture of chloroform and methanol (8:1.5) and subsequently with a mixture of chloroform/methanol/acetic acid (8:0.5:0.5→8:1:1)). The eluate was dissolved in 80% aqueous ethanol, and the solvent was distilled off under reduced pressure. The residue was dried well under reduced pressure to obtain 6.6 g of a pale yellow resinous solid.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:11][C:12]1[CH:13]=[C:14]([CH2:19][C:20]#[N:21])[CH:15]=[CH:16][C:17]=1[Cl:18].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>C1COCC1>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][C:19]([C:20]#[N:21])([C:14]1[CH:15]=[CH:16][C:17]([Cl:18])=[C:12]([Cl:11])[CH:13]=1)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:28]
Reactant: CCOC(=O)CBr
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sodium bis-(trimethylsilyl)amide (7910 mL, 1M, 7910 mmol) was cooled to 0° C. A solution of 3,4-dichlorophenylacetonitrile (700 g, 3763 mmol) in THF (2.50 L) was added maintaining the temperature of the reaction mixture between 0° and 20° C. After 1 hour, the above solution is added by candula to a solution of ethyl bromoacetate (910 mL) in THF (1.40 L) cooled to 0° C. The addition is carried out at such a rate that the temperature of the reaction mixture does not rise above 20° C. After 15 minutes, the reaction was quenched by the addition of t-butyl methyl ether (7.0 L) and water (3.5 L). The organic layer was separated and was extracted with water, 5% NaHCO3, and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to obtain a residue. The residue was recrystallized from diethyl ether to give the title compound: mp=69°-71° C.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[O:32]1[C:36]2[CH2:37][NH:38][CH2:39][CH2:40][C:35]=2[C:34]([OH:41])=[N:33]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:38]5[CH2:39][CH2:40][C:35]6[C:34]([OH:41])=[N:33][O:32][C:36]=6[CH2:37]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:29])([F:30])[F:31])[CH:3]=1
Reactant: Oc1noc2c1CCNC2
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C1N=C(N2CCc3c(O)noc3C2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(3-hydroxy-4,7-dihydroisoxazolo[5,4-c]pyridin-6(5H)-yl)-1,3-thiazol-4(5H)-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 4,5,6,7-Tetrahydro-isoxazolo[5,4-c]pyridin-3-ol following general procedure C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7]C)=O.[CH3:12][C:13]([CH3:15])=[O:14].C[O-].[Na+]>C1COCC1>[NH2:1][C:2]1[CH:3]=[C:4]([C:5](=[O:7])[CH2:12][C:13](=[O:14])[CH3:15])[CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)=O
Reactant: COC(=O)c1cccc(N)c1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)CC(=O)c1cccc(N)c1
Reaction time: 0.5 h
Yield: 37.7 %

Procedure:
To a solution of methyl 3-aminobenzoate (7 g, 46.36 mmol) in THF (150 mL) was added acetone (7.5 g, 102 mmol). The solution was warmed to 35° C. where sodium methoxide (3 g, 55.63 mmol) was added sequentially over 20 minutes. The mixture was stirred for 30 minutes, and then brought to reflux for 3 hours. The solvent was removed under reduced pressure and the residue taken up in ethyl acetate. The resulting solution was washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 1-(3-aminophenyl)-1,3-butanedione as a brown oil (3.1 g, 37%). This oil was used in the next step without further purification.
Reaction SMILES: [CH3:1][Si:2]([CH3:30])([CH3:29])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[C:12]1[S:16][C:15]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[CH:18]=2)=[N:14][C:13]=1[CH:27]=C.O.I([O-])(=O)(=O)=[O:33].[Na+]>O1CCCC1.[Os](=O)(=O)(=O)=O.O>[CH:27]([C:13]1[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[CH:18]=2)[S:16][C:12]=1[C:8]1[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:29])[CH3:30])[CH:11]=[CH:10][N:9]=1)=[O:33]
Reactant: C=Cc1nc(-c2ccnc(NC(C)=O)c2)sc1-c1nccn1COCC[Si](C)(C)C
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(-c2nc(C=O)c(-c3nccn3COCC[Si](C)(C)C)s2)ccn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 38.3 %

Procedure:
N-{4-[5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-4-vinyl-1,3-thiazol-2-yl]pyridin-2-yl}acetamide (0.650 g, 1.47 mmol) was dissolved in tetrahydrofuran (20 mL) and water (10 mL) at ambient temperature and 0.157 M osmium tetraoxide in water (93 uL, 0.014 mmol) was added. The mixture was stirred at room temperature for 5 minutes. Sodium metaperiodate (0.661 g, 3.09 mmol) was then added in portions over 20 minutes and the mixture was stirred at room temperature overnight. Solids were removed by filtration and washed with THF (2×50 mL) and ethyl acetate (2×5 mL). The filtrate was extracted with ethyl acetate (3×100 mL). The extracts were combined, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Crude material was purified by silica gel chromatography (0 to 30% ethyl acetate in hexanes) to afford the title compound (0.25 g, 38%). LCMS: (FA) ES+, 444. 1H NMR (400 MHz, CDCl3) δ: 8.75 (s, 1H), 10.21 (s, 1H), 8.41 (d, J=5.18 Hz, 1H), 8.20-8.07 (m, 1H), 7.76 (dd, J=5.21, 1.58 Hz, 1H), 7.30 (dd, J=2.87, 1.21 Hz, 2H), 5.32 (s, 2H), 3.50-3.33 (m, 2H), 2.26 (s, 3H), 0.93-0.78 (m, 2H), −0.04 (s, 9H).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:16])[CH:14]=2)[NH:9][CH:8]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[Cl:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:6][CH2:5][CH2:4][NH2:1]
Reactant: [N-]=[N+]=NCCCc1c[nH]c2ccc(Cl)cc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCCCc1c[nH]c2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 22 h
Yield: 33.6 %

Procedure:
To a solution of 3-(3-Azidopropyl)-5-chloro-1H-indole (0.299 g; 1.27 mmol) in THF (9 mL) were added triphenylphosphine (0.354 g; 1.34 mmol) and water (0.6 mL). The reaction mixture was stirred at room temperature for 22 hours and was then concentrated under reduced pressure. The residue was dissolved in dichloromethane (10 mL) and 10 mL of 6N hydrochloric acid were added. After separation, the aqueous layer was further extracted with dichloromethane (2×10 mL) and the pH was adjusted to 14 with an aqueous solution of sodium hydroxide 6N. This basic solution was extracted dichloromethane (3×20 mL) and the combined organic layer was dried over magnesium sulphate, and evaporated to afford 0.089 g (34%) of 3-(5-Chloro-1H-indol-3-yl)propan-1-amine as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([N:21]1[CH2:31][CH2:30][C:24]2[N:25]=[CH:26][N:27]=[C:28](Cl)[C:23]=2[CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:28]2[C:23]3[CH2:22][N:21]([CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:31][CH2:30][C:24]=3[N:25]=[CH:26][N:27]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ncnc2c1CN(Cc1ccccc1)CC2
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2ncnc3c2CN(Cc2ccccc2)CC3)C1
Temperature: 120 °C
Yield: 97 %

Procedure:
(S)-tert-Butyl-3-aminopyrrolidine-1-carboxylate (50 g, 192.5 mmol) was added to 6-benzyl-4-chloro-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (39.440 g, 211.8 mmol) in NMP (200 mL) solution followed by the addition of K2CO3 (39.9 g, 288.8 mmol). The mixture was heated to 120° C. for 20 h. The mixture was allowed to cool, partitioned between water (300 mL) and ethylacetate (500 mL). the bottom aqueous phase was discarded and the upper organic phase was washed with brine (150 mL) and concentrated in vacuo to provide crude (S)-3-(6-benzyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester as a pale yellow foam (76.44 g, 97% yield).
Reaction SMILES: [C:1]([C:3]1[C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[ClH:16]>C(O)C.[Pd]>[ClH:16].[ClH:16].[NH2:2][CH2:1][C:3]1[C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CCOC(=O)COc1cccnc1C#N
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)COc1cccnc1CN
Reaction time: 4 h

Procedure:
To a solution of 2-cyano-3-(ethoxycarbonylmethoxy)pyridine (3.2 g, 15.52 mmol) in 180 ml of ethanol is added concentrated aqueous HCl (2.92 ml, 35 mmol) and 10% palladium on charcoal (1.5 g). After stirring for 4 hours under a hydrogen pressure of 4 bar, the mixture is filtered through celite, rinsed with ethanol and evaporated. The 2-aminomethyl-3-(ethoxycarbonylmethoxy)pyridine dihydrochloride thus obtained is sufficiently pure and used in the next step without further purification. Yield: 3.82 g (100%).
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].[CH3:14][N:15]1[CH:19]2[CH2:20][C:21]([CH2:23][CH:16]1[CH2:17][CH2:18]2)=O>O1CCOCC1>[C:1]([CH:3]=[C:21]1[CH2:23][CH:16]2[N:15]([CH3:14])[CH:19]([CH2:18][CH2:17]2)[CH2:20]1)#[N:2]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CN1C2CCC1CC(=O)C2
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CN1C2CCC1CC(=CC#N)C2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 102.5 %

Procedure:
A solution of 1.95 g of diethyl cyanomethylphosphonate in 40 ml of dioxane was cooled to 10° C., followed by the addition of 0.44 g of sodium hydride (60%) in an argon gas atmosphere. A solution of 1.39 g of tropinone in 25 ml of dioxane was added dropwise to the resulting mixture at the same temperature, followed by stirring at room temperature for 1.5 hours. After the solvent was evaporated, water was added to the residue. The resulting mixture was extracted with chloroform, followed by drying over anhydrous potassium carbonate. The solvent was then evaporated, whereby 1.66 g of 3-cyanomethylene-8-methyl-8-azabicyclo[3.2.1]octane was obtained as the oily form.