Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1>CS(C)=O>[C:11]([C:7]1[CH:8]=[C:9]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)c1cc(-c2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c1O
Temperature: 25 °C

Procedure:
8.40 g (40.7 mmol) 2,6-di-tert-butylphenol was dissolved in 100 ml dried DMSO. 8 g (58 mmol) potassium carbonate and 8.5 g (54 mmol) p-chloronitrobenzene were added into the DMSO solution. The DMSO solution was heated to 100˜120° C. for 12 hrs with stirring. Then the reaction mixture was allowed to cool to room temperature and poured into distilled water. The aqueous solution was acidified to pH 2˜4 and yellow precipitate was collected by filtration. The yellow precipitate was washed with water and dried. The crude yield was 92%. The yellow precipitate was purified by recrystallizing in cyanomethane, mp 157˜160° C. Elemental Anal. Calcd.: C, 73.40; H, 7.64; N, 4.28. Found: C, 73.25; H, 7.58; N, 4.25%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].CCN(CC)CC.[S:23](Cl)([C:26]1[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=1)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:30][C:29]1[CH:31]=[CH:32][C:26]([S:23]([O:1][CH2:2][CH2:3][CH2:4][N:5]2[C:13](=[O:14])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:15])(=[O:25])=[O:24])=[CH:27][CH:28]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCN2C(=O)c3ccccc3C2=O)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 0.1 %

Procedure:
To a solution of 2-(3-hydroxypropyl) isoindoline-1,3-dione (1.8 g, 8.77 mmol) in CH2Cl2 (30 mL, 3 mL/mmol) was added Et3N (2 mL, 13.1 mmol). After stirring for 10 min at 0° C., tosylchloride (2 g, 10.5 mmol) was added and the reaction was stirred for 12 h at RT. The reaction was quenched with water and extracted with CH2Cl2 (2×50 mL). The organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Purification by silica gel column chromatography provided 3-(1,3-dioxoisoindolin-2-yl)propyl 4-methylbenzenesulfonate (3 mg, 96%). Observed mass (M+1): 360.1.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13]Br)=[N:5]1)(=[O:3])[CH3:2].Cl.[CH2:16]([CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][N:27]2[CH2:28][CH2:29][CH:24]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:25][CH2:26]2)=[N:5]1)(=[O:3])[CH3:2]
Reactant: c1ccc(CCC2CCNCC2)cc1
Reactant: CC(=O)n1nc(CBr)c2ccccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)n1nc(CN2CCC(CCc3ccccc3)CC2)c2ccccc21
Temperature: 20 °C
Reaction time: 16 h
Yield: 13.7 %

Procedure:
1-Acetyl-3-bromomethyl-1H-indazole (0.50 g, 1.98 mmol) in CH2Cl2 (25 mL) was treated with 4-phenethylpiperidine hydrochloride (0.893 g, 3.96 mmol) and Hunig's base (0.78 g, 5.94 mmol) and the mixture stirred at 20° C. for 16 h. The mixture was poured into saturated aqueous sodium bicarbonate solution (25 mL) and extracted with CH2Cl2 (3×25 mL). The combined organic extracts were dried (MgSO4), concentrated and the residue purified by flash chromatography (0%→10% EtOAc in hexane) to give 1-acetyl-3-(4-phenethylpiperidin-1-ylmethyl)-1H-indazole as a colourless oil (98 mg, 14%). This was dissolved in CH2Cl2 /methanol (1:1, 10 mL), treated with NaOMe (2 mg) and stirred for 15 min at 20° C. The mixture was poured into saturated aqueous sodium bicarbonate solution (25 mL) and extracted with CH2Cl2 (3×25 mL). The combined organic extracts were dried (MgSO4), concentrated and the residue recrystallised from EtOAc/hexane to give the title compound (55 mg, 69%) as colourless crystals; mp 153°-155° C. (from EtOAc/hexane); 1H NMR (360 MHz, d6 -DMSO) δ 12.75 (bs, 1H, NH), 7.84 (d, J=8.1 Hz, 1H, indazole), 7.46 (d, J=8.4 Hz, 1H, indazole), 7.31 (t, J=6.7 Hz, 1H, indazole), 7.27-7.12 (m, 5H, Ph), 7.07 (t, J=7.1 Hz, 1H, indazole), 3.78 (s, 2 H, Ar--CH2N), 2.85 (m, 2 H, aliphatic), 2.56 (m, 2 H, aliphatic), 1.94 (m, 2H, aliphatic), 1.65 (m, 2H, aliphatic), 1.47 (m, 2H, aliphatic), 1.16 (m, 3H, aliphatic); MS (CI+) m/e 320 (M+H+); Anal. calcd for C21H25N3 : C, 78.96; H, 7.89; N, 13.15. Found: C, 78.94; H, 7.96; N, 12.89.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([O:20]C)=O)[CH:16]=3)[CH:11]=[CH:10]2)=[CH:5][CH:4]=1.O.[NH2:23][NH2:24]>C(O)C>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([NH:23][NH2:24])=[O:20])[CH:16]=3)[CH:11]=[CH:10]2)=[CH:5][CH:4]=1
Reactant: NN
Reactant: COC(=O)c1ccc2ccn(-c3ccc(SC)cc3)c2c1
Solvent: CCO
Solvent: O
Product: CSc1ccc(-n2ccc3ccc(C(=O)NN)cc32)cc1

Procedure:
A mixture of methyl 1-[4-(methylthio)phenyl]-1H-indole-6-carboxylate (2.50 g, 8.41 mmol), hydrazine monohydrate (4.08 mL, 84.1 mmol) and ethanol (40 mL) was heated under reflux overnight. After cooling, the precipitate was collected by filtration and washed with ethanol to give crude 1-[4-(methylthio)phenyl]-1H-indole-6-carbohydrazide.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH:10]([SiH2:12][CH2:13][Cl:14])Cl>>[CH3:10][Si:12]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:13][Cl:14]
Reactant: ClC[SiH2]C(Cl)Cl
Reactant: Br[Mg]c1ccccc1
Product: C[Si](CCl)(c1ccccc1)c1ccccc1

Procedure:
When R5 and R7 are both phenyl, about two molar equivalents of phenyl magnesium bromide is reacted with about one molar equivalent of dichloromethyl chloromethyl silane to give methyl diphenylchloromethyl silane.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4](Cl)[N:3]=1.O.[NH2:19][NH2:20]>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([NH:19][NH2:20])[N:3]=1
Reactant: NN
Reactant: Clc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Solvent: O
Solvent: CCCCO
Product: NNc1nc(Cl)nc2c1ncn2C1CCCCO1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a suspension of 2,6-dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (5 g, 20 mmol) in 1-butanol (75 mL) was added hydrazine hydrate (2.0 ml, 40 mmol) at room temperature. The mixture was stirred at 80° C. for 4 hours. The reaction mixture was concentrated under reduced pressure to give the desired product. LCMS calculated for C10H14ClN6O (M+H): 269.1; found: 269.0.
Reaction SMILES: [CH2:1]([C:8]1([N:15]([CH3:17])[CH3:16])[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([NH2:21])[CH2:19][CH3:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>O1CCCC1.C(O)(=O)C>[CH2:1]([C:8]1([N:15]([CH3:17])[CH3:16])[CH2:13][CH2:12][CH:11]([NH:21][CH2:18][CH2:19][CH3:20])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C1(Cc2ccccc2)CCC(=O)CC1
Reactant: CCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCNC1CCC(Cc2ccccc2)(N(C)C)CC1

Procedure:
6.00 g 4-benzyl-4-dimethylamino-cyclohexanone (see example 3) were dissolved in 90 ml analytical grade tetrahydrofuran, and 1.53 g n-propylamine followed by 3.36 ml glacial acetic acid were added, while stirring in an ice-bath. 7.68 g sodium triacetoxyborohydride were then added in portions in the course of 15 minutes and the mixture was subsequently stirred for approx. 65 hours. For working up, 45 ml two molar sodium hydroxide solution were added dropwise (pH>10) and the mixture was extracted three times with 50 ml diethyl ether each time. The combined organic phases were washed twice with 50 ml water each time, dried over sodium sulfate and filtered and the filtrate was concentrated. The crude product obtained (6.43 g) was chromatographed over silica gel with diethyl ether with the addition of five percent by volume of aqueous ammonia solution (25 wt. %). 707 mg of the nonpolar diastereoisomer of 1-benzyl-N,N-dimethyl-N′-propyl-cyclohexane-1,4-diamine were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:8]=2[C:9]2[C:10]([CH2:22][O:23][CH3:24])=[C:11]([CH:20]=O)[N:12]=[CH:13][C:14]=2[NH:15]3)=[CH:4][CH:3]=1.Cl.[NH2:28][OH:29]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:8]=2[C:9]2[C:10]([CH2:22][O:23][CH3:24])=[C:11]([CH:20]=[N:28][OH:29])[N:12]=[CH:13][C:14]=2[NH:15]3)=[CH:25][CH:26]=1
Reactant: COCc1c(C=O)ncc2[nH]c3cccc(Cc4ccc(Cl)cc4)c3c12
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: COCc1c(C=NO)ncc2[nH]c3cccc(Cc4ccc(Cl)cc4)c3c12
Yield: 63.2 %

Procedure:
0.75 g (0.002 mol) of 5-(4-chlorobenzyl)-4-methoxymethyl-β-carboline-3-carbaldehyde is heated one hour to 105° C. with 0.18 g (0.0026 mol) of hydroxylaminehydrochloride in 19 ml of pyridine. 0.48 g (61% of theory) of 5-(4-chlorobenzyl)-4-methoxymethyl-β-carboline-3-carbaldehyde-oxime is obtained from the evaporation residue after recrystallization from ethanol, melting point 224°-228° C.
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][CH2:5][CH2:6][OH:7].C1OCCOCCOCCOCCOC1.[Cl:23][C:24]1[CH:25]=[C:26]([NH:38][C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][C:47]=3F)[N:42]=[CH:41][N:40]=2)[CH:27]=[CH:28][C:29]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1>CC(N(C)C)=O>[Cl:23][C:24]1[CH:25]=[C:26]([NH:38][C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][C:47]=3[O:7][CH2:6][CH2:5][NH:4][CH3:3])[N:42]=[CH:41][N:40]=2)[CH:27]=[CH:28][C:29]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1
Reactant: CNCCO
Reactant: Fc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CNCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Temperature: 100 °C
Yield: 45 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.63 g) was added to 2-(methylamino)ethanol (0.95 ml), 15-crown-5 (100 μl) and N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-fluoroquinazolin-4-amine (1.5 g) in DMA (25 ml) and the reaction heated at 100° C. for 2 hours. The reaction was cooled, quenched with saturated aqueous ammonium chloride solution to pH 7-8. Addition of a small amount of saturated aqueous sodium hydrogen carbonate solution resulted in the formation of a precipitate, which was filtered, washed with water and dried. The solid was purified by chromatography using DCM-5% methanol/7N ammonia as eluent to give N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[2-(methylamino)ethoxy]quinazolin-4-amine as a yellow solid (0.27 g, 45%); NMR spectrum (DMSO-d6) 2.40 (s, 3H), 3.02 (t, 2H), 4.35 (t, 2H), 5.28 (s, 2H), 7.12 (d, 1H), 7.25 (d, 1H), 7.31 (d, 1H), 7.37 (m, 1H), 7.57 (d, 1H), 7.71 (dd, 1H), 7.85 (m, 2H), 8.10 (d, 1H), 8.51 (s, 1H), 8.58 (m, 1H), 10.57 (bs, 1H); Mass spectrum MH+ 436.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][N:4]=1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19]Br)=[C:15]([Cl:21])[CH:14]=1>>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:7]([C:6]2[CH:5]=[N:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)=[O:9])=[C:15]([Cl:21])[CH:14]=1
Reactant: Clc1cc(Br)ccc1CBr
Reactant: COc1ccc(C(=O)O)cn1
Product: COc1ccc(C(=O)Cc2ccc(Br)cc2Cl)cn1

Procedure:
In analogy to Example 203, step 1, 6-methoxynicotinic acid was converted to the acid chloride and subsequently reacted with 4-bromo-1-bromomethyl-2-chloro-benzene to give the title compound (not completely pure) as a light yellow solid.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].[O:6]=[P:7](Cl)([Cl:9])[Cl:8]>C(Cl)Cl>[P:7]([Cl:9])([Cl:8])([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:6]
Reactant: CCCCO
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCCCOP(=O)(Cl)Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of butanol (0.98 mL, 10.0 mmol) in anhydrous CH2Cl2 (10 mL) was added dropwise POCl3 (3.0 mL, 32.0 mmol) at 0° C. After stirring at 0° C. for 1 h, the mixture was refluxed for 5 h and then followed by vacuum distillation to afford butyl dichlorophosphate.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]([O:12][C:13]([NH:15][C@@H:16]([C:24](O)=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)=[O:14])([CH3:11])[CH3:10].ClC(OCC(C)C)=O>O1CCCC1>[N:21]1[CH:20]=[CH:19][C:18]([CH2:17][C@@H:16]([NH:15][C:13](=[O:14])[O:12][C:9]([CH3:10])([CH3:8])[CH3:11])[CH2:24][OH:25])=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccncc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CO)Cc1ccncc1
Temperature: -18 °C
Reaction time: 0.5 h
Yield: 10.6 %

Procedure:
0.52 cm3 of triethylamine is added to a stirred mixture of 1 g of Boc-D-4-pyridylalanine in 10 cm3 of tetrahydrofuran, under an inert atmosphere, and the mixture is then cooled to a temperature in the region of −18° C. After addition of 0.47 cm3 of isobutyl chloroformate, stirring is continued for 30 minutes at a temperature of between −18° C. and −10° C. The mixture is rapidly filtered, followed by addition to the filtrate of 0.28 g of sodium borohydride predissolved in 2 cm3 of water. The mixture is stirred for 1 hour at a temperature in the region of 0° C. and then for 16 hours at a temperature in the region of 20° C. The mixture is made alkaline by addition of aqueous potassium carbonate solution and then stirred in the presence of ethyl acetate. The organic phase is separated out after settling has taken place and then washed with water, dried over magnesium sulphate, filtered and concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained is purified by chromatography under an argon pressure of 50 kPa on a column of silica gel (particle size 40-63μ: diameter 2.2 cm; height of silica 30 cm), eluting first with ethyl acetate alone and collecting 30-cm3 fractions. Fractions 1 to 18 are discarded and the column is then eluted with a mixture of ethyl acetate/methanol (90/10 by volume). Fractions 23 to 26 are collected and then combined. After concentration under reduced pressure (5 kPa) at a temperature in the region of 40° C., 0.10 g of tert-butyl (1R)-1-(4-pyridylmethyl)-2-hydroxy-ethylcarbamate is obtained in the form of an oil. Infrared spectrum (CH2Cl2): 3618; 3434; 2981; 1708; 1501; 1367; 1168 and 1057 cm−1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[N:7]([C:9]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)([CH2:13][NH:14][CH3:15])[CH2:10][CH:11]=[CH2:12])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:32](Cl)(=[O:36])[CH:33]([CH3:35])[CH3:34]>C(#N)C>[C:1]([O:5][C:6](=[O:24])[N:7]([C:9]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)([CH2:13][N:14]([C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH3:15])[CH2:10][CH:11]=[CH2:12])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCC(CNC)(c1ccc(Cl)c(Cl)c1)N(C)C(=O)OC(C)(C)C
Reactant: CC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=CCC(CN(C)C(=O)C(C)C)(c1ccc(Cl)c(Cl)c1)N(C)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 64 %

Procedure:
tert-Butyl[1-(3,4-dichlorophenyl)-1-methylaminomethyl-3-butenyl]methylcarbamate (2.0 g) produced in Example 4 was dissolved in acetonitrile (40 mL). Under cooling with ice, triethylamine (1.49 mL) and isobutyryl chloride (1.12 mL) was added thereto. Under cooling with ice, the mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and water was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate anhydrate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (n-hexane:ethyl acetate=3:1), to thereby give the title compound (1.53 g, 64%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[CH:9]=[C:10]([CH:15]2[NH:20][C:19](=O)[CH2:18][O:17][CH2:16]2)[CH:11]=[CH:12][C:13]=1[F:14]>CCOCC.C1COCC1>[F:7][C:8]1[CH:9]=[C:10]([CH:15]2[NH:20][CH2:19][CH2:18][O:17][CH2:16]2)[CH:11]=[CH:12][C:13]=1[F:14]
Reactant: O=C1COCC(c2ccc(F)c(F)c2)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Fc1ccc(C2COCCN2)cc1F

Procedure:
To a suspension of LiAlH4 (6.0 mmol, 0.23 g) in 25.0 mL of Et2O was added a solution of 5-(3,4-difluoro-phenyl)-morpholin-3-one (2.0 mmol, 0.42 g) in 20.0 mL Et2O and 5.0 mL THF at room temperature. The resulting suspension was heated to reflux for 2 hours and was then quenched with water and aq. NaOH solution. The solid was filtered off and the filtrate was dried over Na2SO4. The filtrate was then decanted and the solvent was removed in vacuo to obtain 5-(3,4-difluoro-phenyl)-morpholine as a viscous oil. It was converted to its hydrochloride salt for its analysis. Yellow powder. M.P.=171-173° C.; Mass spec. 200 (M+1, 100%). Analysis calculated for C10H12NOF2Cl.0.5 acetone: C, 51.96; H, 5.61; N, 5.41. Found: C, 51.98; H, 5.70; N, 5.34.
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.[Cl:5][C:6]1[CH:7]=[N:8][N:9]([C:11]2([C:14]3[NH:31][C:17]4=[N:18][C:19]([N:22]5[CH2:27][CH2:26][CH2:25][C@@H:24]([C:28](O)=[O:29])[CH2:23]5)=[CH:20][CH:21]=[C:16]4[N:15]=3)[CH2:13][CH2:12]2)[CH:10]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>ClCCl>[N:1]1([C:28]([C@@H:24]2[CH2:25][CH2:26][CH2:27][N:22]([C:19]3[N:18]=[C:17]4[NH:31][C:14]([C:11]5([N:9]6[CH:10]=[C:6]([Cl:5])[CH:7]=[N:8]6)[CH2:12][CH2:13]5)=[N:15][C:16]4=[CH:21][CH:20]=3)[CH2:23]2)=[O:29])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)[C@@H]1CCCN(c2ccc3nc(C4(n5cc(Cl)cn5)CC4)[nH]c3n2)C1
Reactant: C1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C([C@@H]1CCCN(c2ccc3nc(C4(n5cc(Cl)cn5)CC4)[nH]c3n2)C1)N1CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 6.4 %

Procedure:
Azetidine (0.1 mL, 1.42 mmol) was added to a solution of (R)-1-(2-(1-(4-chloro-1H-pyrazol-1-yl)cyclopropyl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidine-3-carboxylic acid (50 mg, 1.29 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′,-tetramethyluronium hexafluorophosphate (HATU) (49 mg, 1.29 mmol) and diisopropylethylamine (0.1 mL, 3.88 mmol) in anhydrous dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 2 h, then was partitioned between dichloromethane and water. The organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via preparative TLC to afford the title compound (35 mg). MS (ES+APCI) (M+H) 426.1; LCMS retention time: 3.440 min (Method S1).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]1([N:16]=[C:17]=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl.Cl.[N:21]1[C:29]2[CH2:28][CH2:27][NH:26][CH2:25][C:24]=2[S:23][C:22]=1[NH:30][C:31]([NH2:33])=[NH:32].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:10]1([NH:16][C:17]([N:26]2[CH2:27][CH2:28][C:29]3[N:21]=[C:22]([NH:30][C:31]([NH2:33])=[NH:32])[S:23][C:24]=3[CH2:25]2)=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N=C(N)Nc1nc2c(s1)CNCC2
Reactant: O=C=Nc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N=C(N)Nc1nc2c(s1)CN(C(=O)Nc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Diisopropylethylamine (0.2 mmol) and, after 5 min, phenyl isocyanate (0.11 mmol) are added to a suspension of N-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine-2-yl)-guanidine dihydrochloride (0.1 mmol) in dimethylformamide (0.5 ml). The reaction mixture is stirred for another 3 hours at room temperature. Then saturated aqueous sodium carbonate solution is added and extraction is carried out with ethyl acetate. The pure title compound is obtained after drying of the combined organic phases over sodium sulphate and removal of the solvent in a vacuum.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12](F)[C:11]([C:15]#[N:16])=[CH:10][C:9]=1[N+:17]([O-:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[NH:21]1[CH2:26][CH2:25][S:24][CH2:23][CH2:22]1>CS(C)=O>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([N:21]2[CH2:26][CH2:25][S:24][CH2:23][CH2:22]2)[C:11]([C:15]#[N:16])=[CH:10][C:9]=1[N+:17]([O-:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(C#N)cc1[N+](=O)[O-]
Reactant: C1CSCCN1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Nc1cc(N2CCSCC2)c(C#N)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (4-cyano-5-fluoro-2-nitro-phenyl)-carbamic acid tert-butyl ester (Example A10) (2.00 g, 7.11 mmol) and thiomorpholine (3.38 ml, 35.6 mmol) in DMSO (30 mL) at RT according to the general procedure C. Obtained as a light yellow solid (2.20 g, 85%).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][C:17]([O:23][CH:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)=[CH:18][CH:19]=4)[C:14]3=[O:30])[CH:7]=2)[CH2:3][CH2:2]1.I[CH2:33][CH3:34].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][C:17]([O:23][CH:24]5[CH2:29][CH2:28][N:27]([CH2:33][CH3:34])[CH2:26][CH2:25]5)=[CH:18][CH:19]=4)[C:14]3=[O:30])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccc2ccc(OC3CCNCC3)cc2c1=O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN1CCC(Oc2ccc3ccn(-c4cc(C(=O)NC5CC5)ccc4C)c(=O)c3c2)CC1

Procedure:
N-Cyclopropyl-4-methyl-3-[1-oxo-7-(piperidin-4-yloxy)isoquinolin-2(1H)-yl]benzamide (50 mg), iodoethane (0.105 ml) and potassium carbonate (66 mg) were stirred in DMF (0.5 ml) at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with water (5×), brine, dried (magnesium sulfate) and concentrated to give N-cyclopropyl-3-[7-[(1-ethylpiperidin-4-yl)oxy]-1-oxoisoquinolin-2(1H)-yl]-4-methylbenzamide as a cream coloured foam solid (44 mg); NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.69 (m, 2H), 1.00 (t, 3H), 1.69 (m, 2H), 1.99 (m, 2H), 2.10 (s, 3H), 2.25 (m, 2H), 2.38 (m, 2H), 2.71 (m, 2H), 2.85 (m, 1H), 4.53 (m, 1H), 6.70 (d, 1H), 7.20 (d, 1H), 7.41 (d, 1H), 7.49 (d, 1H), 7.67 (s, 1H), 7.70 (d, 1H), 7.72 (s, 1H), 7.88 (d, 1H), 8.42 (d, 1H); Mass Spectrum: M+H+ 446.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11]([S:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=1)=[O:12])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:28][C:29]1[N:30]=[C:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:32][C:33]=1[CH3:34]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11]([S:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:28][C:29]2[N:30]=[C:31]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[O:32][C:33]=2[CH3:34])[CH:15]=1)=[O:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCCN1C(=O)Sc1cccc(O)c1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H]1CCCN1C(=O)Sc1cccc(OCc2nc(-c3ccccc3)oc2C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of the title C compound, 1-(3-hydroxy-phenylsulfanylcarbonyl)-pyrrolidine-2-carboxylic acid ethyl ester (1.1 g, 3.73 mmol) and potassium carbonate (0.78 g, 5.59 mmol) in DMF (25 mL) is added 4-chloromethyl-5-methyl-2-phenyl-oxazole (0.78 g, 3.73 mmol) at RT. The reaction mixture is stirred for 16 h. The stirring is continued for another 3 h at 40° C. The reaction mixture is cooled to RT, diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated at reduced pressure. The crude product is purified on a Biotage 40M column using 25% ethyl acetate in hexane to yield (R)-1-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenylsulfanylcarbonyl]-pyrrolidine-2-carboxylic acid ethyl ester as a clear, heavy oil.