Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[O:10][CH3:11].[Li]CCCC.[C:17]([S:21]([N:23]=[CH:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:22])([CH3:20])([CH3:19])[CH3:18].[NH4+].[Cl-]>C1COCC1.CCOCC.O>[CH3:11][O:10][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[CH:24]([NH:23][S:21]([C:17]([CH3:18])([CH3:20])[CH3:19])=[O:22])[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC(=O)C=NS(=O)C(C)(C)C
Reactant: COc1cccc(OC)c1I
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C(NS(=O)C(C)(C)C)c1c(OC)cccc1OC
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A cooled (−78° C.) solution of 2-iodo-1,3-dimethoxybenzene (4.119 g; 15.13 mmol) in anh. THF (40 ml) was treated dropwise with a solution of 1.6 M n-BuLi in hexanes (10.40 ml; 16.64 mmol), and the resulting mixture was stirred at −78° C., under nitrogen, for 10 min. A solution of ethyl 2-((tert-butylsulfinyl)imino)acetate (3.106 g; 15.13 mmol) in anh. THF (20 ml) was added dropwise, and stirring at −78° C. was then continued for 25 min. The reaction mixture was treated with aq. sat. NH4Cl (30 ml), water (40 ml), and Et2O (60 ml). The separated aq. layer was extracted with Et2O (2×50 ml), and the mixed organic layers were washed with brine (40 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=20/1) afforded ethyl 2-(2,6-dimethoxyphenyl)-2-(1,1-dimethylethylsulfinamido)acetate as a yellow oil. LC-MS (conditions D): tR=0.91 min.; [M+H]+: 344.45 g/mol.
Reaction SMILES: [F:1][C:2]12[CH2:12][C:6]3([F:13])[CH2:7][C:8]([F:11])([CH2:10][C:4]([CH2:14][OH:15])([CH2:5]3)[CH2:3]1)[CH2:9]2.CC(C)([O-])C.[K+].[Cl:22][C:23]1[C:24](F)=[CH:25][C:26]([F:32])=[C:27]([CH:31]=1)[C:28]([OH:30])=[O:29]>CS(C)=O.C(OCC)(=O)C.O.Cl>[Cl:22][C:23]1[C:24]([O:15][CH2:14][C:4]23[CH2:10][C:8]4([F:11])[CH2:9][C:2]([F:1])([CH2:12][C:6]([F:13])([CH2:7]4)[CH2:5]2)[CH2:3]3)=[CH:25][C:26]([F:32])=[C:27]([CH:31]=1)[C:28]([OH:30])=[O:29]
Reactant: OCC12CC3(F)CC(F)(CC(F)(C3)C1)C2
Reactant: O=C(O)c1cc(Cl)c(F)cc1F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1cc(Cl)c(OCC23CC4(F)CC(F)(CC(F)(C4)C2)C3)cc1F
Reaction time: 0.33 h
Yield: 40.1 %

Procedure:
A mixture of (3,5,7-trifluoroadamantan-1-yl)methanol (1.37 g, 6.22 mmol) and potassium tert-butoxide (0.91 g, 8.09 mmol) in anhydrous dimethylsulfoxide (20 mL) was stirred under nitrogen for 20 minutes. The reaction mixture was treated with a mixture of 5-chloro-2,4-difluorobenzoic acid (1.20 g, 6.22 mmol) and potassium tert-butoxide (0.70 g, 6.22 mmol) in anhydrous dimethylsulfoxide (10 mL) that had been stirred for 10 min. The resulting mixture was stirred under nitrogen at ambient temperature for 20 hours, diluted with ethyl acetate (120 mL), water (20 mL) and 1 M aqueous hydrochloric acid solution (50 mL). The separated organic layer was washed with 1 M aqueous hydrochloric acid solution (50 mL) and brine; dried over anhydrous sodium sulfate; filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (2:1 hexanes:ethyl acetate (+0.2% acetic acid v/v)) to provide the title compound (0.98 g, 40%): 1H NMR (300 MHz, DMSO-d6) δ 13.13 (br s, 1H), 7.83 (d, J=7.6 Hz, 1H), 7.18 (d, J=12.6 Hz, 1H), 4.00 (s, 2H), 2.25-2.14 (m, 3H), 2.06-1.96 (m, 3H), 1.81-1.73 (m, 6H); MS (ES−) m/z 391.2, 393.2 (M−1).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][NH:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28]>>[CH3:23][N:24]([CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:18]([C:12]1[S:13][C:14]2[CH2:15][CH2:16][O:17][C:8]3[CH:7]=[C:6]([C:4]4[CH:3]=[N:2][NH:1][CH:5]=4)[CH:22]=[CH:21][C:9]=3[C:10]=2[N:11]=1)=[O:20]
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: CNCCC(C)C
Product: CC(C)CCN(C)C(=O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2

Procedure:
Following Example 216, to a well stirred solution of 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid and N,3-dimethylbutan-1-amine to give 255. MS: (ESI+)=397.1
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:20](O)[CH3:21].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([O:17][CH2:20][CH3:21])=[O:16])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CCO
Reactant: Cn1c(CC(=O)O)ccc1C(=O)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)Cc1ccc(C(=O)c2ccc(Cl)cc2)n1C

Procedure:
A suspension of 55.4 g. of 5-(p-chlorobenzoyl)-1-methyl-pyrrole-2-acetic acid, 44 ml. of absolute ethanol, 1g. of p-toluenesulfonic acid and 650 ml. of benzene is heated under reflux with azeotropic removal of water for 7 hours. The reaction mixture is filtered, washed with sodium bicarbonate solution, dried over anhyrous magnesium sulfate and the solvent evaporated in vacuo. The crystalline residue is recrystallized twice from cyclohexane to give ethyl 5-(p-chlorobenzoyl)-1-methyl-pyrrole-2-acetate as a yellow solid, m.p. 74°-76°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][C@@H:11]2[CH2:16][CH2:15][N:14](C(OC)=O)[CH2:13][C@@H:12]2[CH3:21])=[O:9])[NH:5][C:6]=1[CH3:7].[OH-].[K+].O.NN.O>C(O)CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][C@@H:11]2[CH2:16][CH2:15][NH:14][CH2:13][C@@H:12]2[CH3:21])=[O:9])[NH:5][C:6]=1[CH3:7]
Reactant: COC(=O)N1CC[C@@H](NC(=O)c2cc(Cl)c(C)[nH]2)[C@@H](C)C1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: Cc1[nH]c(C(=O)N[C@@H]2CCNC[C@@H]2C)cc1Cl
Yield: 52.7 %

Procedure:
A solution of methyl (3S,4R)-4-{[(4-chloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methylpiperidine-1-carboxylate (Intermediate 38, 2.2 g, 7.05 mmol), potassium hydroxide (2.76 g, 49.35 mmol), and hydrazine hydrate (2.5 mL, 49.35 mmol) in ethylene glycol (150 mL) was stirred for 40 h at 120° C. The reaction mixture was poured in to water (120 mL) and extracted with ethyl acetate (2×150 mL). The combined organic extracts were dried over anhydrous sodium sulphate, filtered, concentrated in vacuo to yield the crude product which was triturated with water (30 mL) to afford 4-chloro-5-methyl-N-[(3S,4R)-3-methylpiperidin-4-yl]-1H-pyrrole-2-carboxamide 950 mg (52%) as brown solid.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]2[C:11](=[O:12])[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[N:7]([CH2:17][C:18]#[CH:19])[C:6]=12.C=O.[C:22]1([CH2:28][N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[CH:35](OC(C)C)([CH3:37])[CH3:36].C(#N)C>[Cu]Cl>[CH3:1][C:2]1[S:3][CH:4]=[C:5]2[C:11](=[O:12])[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[N:7]([CH2:17][CH2:18][CH2:19][C:36]#[C:35][CH2:37][N:32]3[CH2:31][CH2:30][N:29]([CH2:28][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:34][CH2:33]3)[C:6]=12
Reactant: C#CCN1c2ccccc2NC(=O)c2csc(C)c21
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CC(C)OC(C)C
Agent: Cl[Cu]
Agent: C=O
Solvent: CC#N
Product: Cc1scc2c1N(CCCC#CCN1CCN(Cc3ccccc3)CC1)c1ccccc1NC2=O
Yield: 12 %

Procedure:
Prepared analogously to Example lb) from 4,9-dihydro-3-methyl-4-(prop-2-ynyl)-10H-thieno[3,4-b][1,5]benzodiazepin-10-one, paraformaldehyde and N-(phenylmethyl)piperazine in the presence of copper(I)chloride in a yield of 12% of theory. RF 0.5 (Merck, readymade TLC plates, silica gel 60F-254; eluant: dichloromethane/ethanol 9/1 v/v).
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Cl:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[C:3](=[O:13])[N:20]([CH2:19][C:18]1[CH:21]=[CH:22][C:15]([Cl:14])=[CH:16][CH:17]=1)[CH2:11]2
Reactant: NCc1ccc(Cl)cc1
Reactant: COC(=O)c1c(Cl)cccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1c2c(Cl)cccc2CN1Cc1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
A mixture of 2-bromomethyl-6-chloro-benzoic acid methyl ester (0.132 g, 0.5 mmol), 4-chloro-benzylamine (0.073 g, 0.6 mmol), and K2CO3 (0.207 g, 1.5 mmol) in toluene (4 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 7-chloro-2-(4-chloro-benzyl)-2,3-dihydro-isoindol-1-one (0.116 g, 79%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.24 (s, 2H), 4.74 (s, 2H) 7.24-7.46 (m, 7H). GC-MS: m/z 291 (M)+.
Reaction SMILES: [CH2:1]([N:3]([C:18]1[CH:23]=[CH:22][C:21]([C:24]([O:26]C)=[O:25])=[CH:20][N:19]=1)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2].[OH-].[Na+]>C1COCC1.CO>[CH2:1]([N:3]([C:18]1[CH:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[CH:20][N:19]=1)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2]
Reactant: CCN(Cc1ccccc1Oc1ccccc1)c1ccc(C(=O)OC)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCN(Cc1ccccc1Oc1ccccc1)c1ccc(C(=O)O)cn1
Reaction time: 60 h

Procedure:
A solution of methyl 2-(N-ethyl-N-(2-phenoxybenzyl)amino)pyridine-5-carboxylate (0.65 g, 1.74 mmol) in THF (3 ml) and methanol (3 ml) was treated with aqueous sodium hydroxide (1N, 4 ml). The reaction mixture was heated at reflux for 3 hours cooled to ambient and allowed to stand for 60 hours, then heated at reflux for 3 hours. The organic solvent was evaporated, the residue diluted with water and acidified (pHi) with HCl (conc.). The aqueous suspension was extracted with ethyl acetate, the organic phase was dried (MgSO4) and evaporated and the solid was recrystallized from ethyl acetate/water and dried under reduced pressure to give the title product.
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:14]([CH2:15][CH3:16])=[N:13][NH:12][C:11]=2[NH2:17])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18](OCC)(=[O:23])[CH2:19][C:20]([CH3:22])=O>C(O)(=O)C>[C:1]1([S:7]([C:10]2[C:14]([CH2:15][CH3:16])=[N:13][N:12]3[C:18]([OH:23])=[CH:19][C:20]([CH3:22])=[N:17][C:11]=23)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCc1n[nH]c(N)c1S(=O)(=O)c1ccccc1
Reactant: CCOC(=O)CC(C)=O
Solvent: CC(=O)O
Product: CCc1nn2c(O)cc(C)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 71.2 %

Procedure:
A solution of 2.9 g (11.5 mmol) of 4-benzenesulphonyl-5-ethyl-2H-pyrazol-3-ylamine and 1.8 ml (13.8 mmol) of ethyl acetoacetate in 10 ml of acetic acid was heated at reflux for 3 hrs. The reaction solution was cooled to RT and evaporated. The residue was partitioned between CH2Cl2 and H2O and the aqueous phase was washed three times with 150 ml of CH2Cl2. The combined organic phases were dried (MgSO4), filtered and evaporated. Crystallization from ethyl acetate yielded 2.6 g (71%) of 3-benzenesulphonyl-2-ethyl-5-methyl-pyrazolo[1,5-a]pyrimidin-7-ol as colorless crystals.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:19][N:14]4[CH2:15][CH2:16][NH:17][CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](O)=[O:29])=[CH:23][CH:22]=1.C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1.C(N(C(C)C)CC)(C)C>ClCCl>[CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:19][N:14]4[CH2:15][CH2:16][N:17]([C:28](=[O:29])[CH2:27][C:24]5[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=5)[CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: c1nc(C2CC2)cnc1O[C@@H]1C[C@H]2CNCCN2C1
Reactant: O=C(O)Cc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: O=C(Cc1ccc(F)cc1)N1CCN2C[C@H](Oc3cnc(C4CC4)cn3)C[C@H]2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of the product from Example 54F (30 mg, 0.115 mmol) and 2-(4-fluorophenyl)acetic acid (21.3 mg, 0.138 mmol) was added a solution of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (33.1 mg, 0.173 mmol) in dichloromethane (1.0 mL). To the resulting solution was added hydroxybenzotriazole hydrate (26.5 mg, 0.173 mmol) and diisopropylethylamine (0.040 mL, 0.230 mmol), and the mixture was stirred at room temperature for 16 hours. The mixture was partitioned between water and ethyl acetate, and the organic extract was dried over Na2SO4. The mixture was filtered and concentrated in vacuo, and the crude product was purified by column chromatography on silica gel using a solvent gradient of 0-100% ethyl acetate in hexanes. The title compound was obtained as a colorless solid (16 mg, 35%). 1H NMR (300 MHz, CDCl3) δ ppm 0.85-1.03 (m, 4 H), 1.78-2.06 (m, 3 H), 2.11-2.48 (m, 3 H), 2.63-3.27 (m, 3 H), 3.61-4.00 (m, 4 H), 4.55-4.85 (m, 1 H), 5.25-5.40 (m, 1 H), 6.96-7.06 (m, 2 H), 7.15-7.25 (m, 2 H), 7.93 (d, J=1.36 Hz, 1 H), 8.01 (d, J=1.36 Hz, 1 H); MS (ESI) m/z 397 (M+H)+.
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)[C:5]#[N:6].O.[NH2:19]N.C(O)(=O)C>C(O)C>[F:14][C:13]([F:16])([F:15])[C:9]1[CH:8]=[C:7]([C:4]2[CH:3]=[N:2][NH:6][C:5]=2[NH2:19])[CH:12]=[CH:11][CH:10]=1
Reactant: NN
Reactant: CN(C)C=C(C#N)c1cccc(C(F)(F)F)c1
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1[nH]ncc1-c1cccc(C(F)(F)F)c1
Reaction time: 5 h
Yield: 97.4 %

Procedure:
To a mixture of 3-(dimethylamino)-2-(3-(trifluoromethyl)phenyl)acrylonitrile (2.93 g, 12.20 mmol) in ethanol (35 ml) was added hydrazine hydrate (3.80 ml, 122 mmol) and acetic acid (6.98 ml, 122 mmol). Upon to reflux; a solution formed. After 5 hours, 0.25 mL of hydrazine hydrate was added and the reaction refluxed an additional 15 hours. The volatiles were removed in vacuo, and the residue partitioned between EtOAc and water. After extracting three times with EtOAc, the combined organics were washed twice with saturated aqueous NaHCO3, dried over Na2SO4, and concentrated in vacuo to cleanly give 4-(3-(trifluoromethyl)phenyl)-1H-pyrazol-5-amine (2.7 g, 97% yield) as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[CH:5]=[C:4]([CH3:12])[N:3]=1.CN(C)C=O.[CH3:18][CH:19]([CH3:22])[CH2:20][NH2:21]>C(N(CC)CC)C>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:21][CH2:20][CH:19]([CH3:22])[CH3:18])[CH:5]=[C:4]([CH3:12])[N:3]=1
Reactant: CC(C)CN
Reactant: Cc1cc(Cl)c([N+](=O)[O-])c(Cl)n1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(NCC(C)C)c([N+](=O)[O-])c(Cl)n1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
2,4-Dichloro-6-methyl-3-nitropyridine (28.75 g) and anhydrous dimethylformamide (300 ml) were combined and cooled to 0° C. Triethylamine (19.4 ml) and then 2-methylpropylamine (13.8 ml) were added to the resulting mixture. The reaction was not complete as determined by HPLC and TLC after 16 hours. An additional 1.38 ml of 2-methylpropylamino was added to the reaction mixture, and after another hour the reaction was complete. The dimethylformamide was removed from the resulting reaction mixture under reduced pressure, and the resulting dark yellow oil was dissolved in ethyl acetate. The ethyl acetate solution was washed with water (3×), dried with magnesium sulfate, and the solvent was removed under reduced pressure. The resulting yellow oil was dissolved in hexane and cooled to below 0° C. overnight. A yellow solid formed. The yellow solid was washed with cold (<0° C.) hexane and filtered. The remaining crystals (22.02 g) were found to be pure by NMR analysis and used in the next step.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH:17]([OH:22])[CH2:18][NH:19][CH2:20][CH3:21])=[CH:16][C:3]1=2.[BH4-].[Na+]>CO>[OH:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH:17]([OH:22])[CH2:18][NH:19][CH2:20][CH3:21])=[CH:16][C:3]1=2
Reactant: CCNCC(O)c1ccc2c(c1)C(=O)c1ccccc1CO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCNCC(O)c1ccc2c(c1)C(O)c1ccccc1CO2
Reaction time: 2 h
Yield: 65.4 %

Procedure:
A solution of 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)-N-ethyl-N-hydroxyethylamine (4.1 g) in 100 ml methanol at 0° C. was treated with sodium borohydride (1.04 g) in two portions and stirred under a nitrogen blanket for 2 hours. The solution was evaporated and taken up in chloroform and washed with saturated bicarbonate. This solution was evaporated again and the residue purified by flash chromatography (silica gel, 19:1 Chloroform-methanol) to give an oil. This oil crystallized from ether to give 2.7 g of 2-(6,11-dihydro-1 l-hydroxydibenz[b,e]oxepin-2-yl)-N-ethyl-N-hydroxyethylamine as crystals, m.p. 116-118° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.C([Li])CCC.[CH2:17]([N:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1.C(OCC)(=O)C>[CH2:17]([N:24]1[CH2:29][CH2:28][C:27]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=2)([OH:30])[CH2:26][CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC1(c2ccc(C(F)(F)F)cc2)CCN(Cc2ccccc2)CC1
Reaction time: 2 h
Yield: 46 %

Procedure:
4-Bromobenzotrifluoride (1 g, 4.44 mmol) was dissolved in THF (15 ml), to which n-butyllithium (1.5 M) hexane solution (3.1 ml, 4.67 mmol) was added dropwise at −70° C. Then a solution of 1-benzyl-4-piperidone in THF (15 ml) was added dropwise to the mixture, and the resulting mixture was stirred for 2 hours and then at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/acetone=2/1) to afford 1-benzyl-4-(4-trifluoromethylphenyl)piperidin-4-ol (692 mg, yield 46%) as a colorless crystalline powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].N1(C(N2C=CN=C2)=S)C=CN=[CH:10]1.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[C:29]1[NH:30][C:31]2[CH:37]=[C:36]([C:38]([NH:40][NH2:41])=[O:39])[CH:35]=[CH:34][C:32]=2[N:33]=1.CCN=C=NCCCN(C)C>CN(C=O)C.CCOC(C)=O>[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[C:29]1[NH:30][C:31]2[CH:37]=[C:36]([C:38]3[O:39][C:10]([NH:1][C:2]4[CH:3]=[N:4][CH:5]=[CH:6][C:7]=4[CH3:8])=[N:41][N:40]=3)[CH:35]=[CH:34][C:32]=2[N:33]=1
Reactant: Cc1ccncc1N
Reactant: NNC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccncc1Nc1nnc(-c2ccc3nc(-c4c(Cl)cccc4Cl)[nH]c3c2)o1
Reaction time: 72 h

Procedure:
Combine 3-amino-4-methyl-pyridine (66 mg, 0.606 mmol) and di-imidazol -1-yl-methanethione (108 mg, 0.606 mmol) in DMF (1.5 mL) and stir for 7.5 hr. Add 2-(2,6-dichloro-phenyl)-3H-benzoimidazole-5-carboxylic acid hydrazide (150 mg, 0.466 mmol) and DMF (1 mL). Stir for 3 days. Add EDCI (179 mg, 0.932 mmol) and heat to 80° C. for 1 hr. Upon cooling, dilute the reaction with EtOAc (75 mL) and extract with water (15 mL). Dry the organic phase over Na2SO4 and evaporate the solvent. Purify the residue by reverse phase HPLC (30-45% ACN/H2O+5 mM NH4OH) to afford the title compound as a light yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 2.35 (s, 3 H) 7.30 (d, J=4.80 Hz, 1 H) 7.62-7.68 (m, 1 H) 7.72 (d, J=2.02 Hz, 1 H) 7.70 (s, 1 H) 7.83 (br. s., 2 H) 7.98-8.19 (m, 1 H) 8.24 (d, J=4.80 Hz, 1 H) 8.98 (s, 1 H) 9.95 (br. s., 1 H) 13.28 (br. s., 1 H); MS m/z=436.9 (M+1).
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].C(OC(=O)C)(=O)C.[Cl:14][C:15]1[CH:25]=[CH:24][C:18]([CH2:19][NH:20][C:21]([NH2:23])=[O:22])=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:25]=[CH:24][C:18]([CH2:19][NH:20][C:21]([NH:23][C:4](=[O:6])[CH2:3][C:1]#[N:2])=[O:22])=[CH:17][CH:16]=1
Reactant: N#CCC(=O)O
Reactant: NC(=O)NCc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: N#CCC(=O)NC(=O)NCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
68.7 g of 98% cyanoacetic acid and 155 ml of acetic anhydride were kept at 65° C. for 30 minutes. 4-chlorobenzylurea (132.9 g) was added in portions over 10 minutes. After 2 hrs. at 70-75° C., further acetic anhydride (25 ml) was added. After a further 15 minutes,90 ml of toluene was added, cooled to room temperature, the solid collected and washed with toluene to give the title compound (155.60 g) as a white-solid mp 203-6° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:32]=[CH:31][C:30]5[C:25](=[CH:26][CH:27]=[C:28]([OH:33])[CH:29]=5)[C:24]4=[O:34])=[CH:19][C:18]=3[F:35])[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:37][CH:38]1[CH2:40][CH2:39]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN1C(=O)CCC1>O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:32]=[CH:31][C:30]5[C:25](=[CH:26][CH:27]=[C:28]([O:33][CH2:37][CH:38]6[CH2:40][CH2:39]6)[CH:29]=5)[C:24]4=[O:34])=[CH:19][C:18]=3[F:35])[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCC1CC1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCN(c3ccc(-n4ccc5cc(O)ccc5c4=O)cc3F)C2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CCN(c3ccc(-n4ccc5cc(OCC6CC6)ccc5c4=O)cc3F)C2)C1
Temperature: 60 °C

Procedure:
A mixture of 7-[2-fluoro-4-(6-hydroxy-1-oxo-1H-isoquinolin-2-yl)-phenyl]-2,7-diaza-spiro[4.4]nonane-2-carboxylic acid tert-butyl ester (250 mg), bromomethyl-cyclopropane (70 mg), cesium carbonate (170 mg) and NMP (5 mL) was heated for 4 hours at 60° C. The cooled reaction mixture was distributed between ethyl acetate and water. The organic phase was dried over magnesium sulfate and concentrated. The raw product was purified by preparative HPLC.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:36][CH3:37])=[CH:4][C:5]([C:10]2[CH:31]=[CH:30][C:13]([O:14][CH2:15][CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)=[C:12]([C:32]([F:35])([F:34])[F:33])[CH:11]=2)=[N:6][C:7]=1[C:8]#[N:9].Cl.[N:39]([O-])=O.[Na+].C(OCC)(=O)C>CN1C(=O)CCC1.O>[C:8]([C:7]1[C:2]2[N:1]=[N:39][N:36]([CH3:37])[C:3]=2[CH:4]=[C:5]([C:10]2[CH:31]=[CH:30][C:13]([O:14][CH2:15][CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)=[C:12]([C:32]([F:35])([F:33])[F:34])[CH:11]=2)[N:6]=1)#[N:9]
Reactant: CNc1cc(-c2ccc(OCCC3CCN(C(=O)OC(C)(C)C)CC3)c(C(F)(F)F)c2)nc(C#N)c1N
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: Cn1nnc2c(C#N)nc(-c3ccc(OCCC4CCN(C(=O)OC(C)(C)C)CC4)c(C(F)(F)F)c3)cc21
Temperature: 7.5 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
To tert-butyl 4-(2-(4-(5-amino-6-cyano-4-(methylamino)pyridin-2-yl)-2-(trifluoromethyl)phenoxy)ethyl)piperidine-1-carboxylate (1.8 g) in NMP (20 ml) was added 1M hydrochloric acid (15 ml) and cooled to 5-10° C. with an ice bath. To above solution was then added dropwise a solution of sodium nitrite (0.335 g) in water (3 ml) during 2 minutes. The mixture was stirred further at room temperature for another 1 hour. After adding ethyl acetate (200 ml), the mixture washed with water (4×100 ml), brine (50 ml), solvent removed under reduced pressure and residue was columned on silica gel using 2:1 EtOAc:Heptane as eluant to give tert-butyl 4-(2-(4-(4-cyano-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)ethyl)-piperidine-1-carboxylate (1.55 g) as a white solid.