Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:36]=[CH:35][C:11]([C:12]([C:14]2[CH:34]=[CH:33][C:17]([CH2:18][S:19][C:20]3[N:29]([CH3:30])[C:28](=[O:31])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[CH3:32])[N:21]=3)=[CH:16][CH:15]=2)=[O:13])=[CH:10][CH:9]=1)(=O)C.[OH-].[Na+].ClCCl>CO>[CH3:30][N:29]1[C:28](=[O:31])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2[CH3:32])[N:21]=[C:20]1[S:19][CH2:18][C:17]1[CH:33]=[CH:34][C:14]([C:12](=[O:13])[C:11]2[CH:10]=[CH:9][C:8]([O:7][CH2:6][CH2:5][OH:4])=[CH:36][CH:35]=2)=[CH:15][CH:16]=1
Reactant: CC(=O)OCCOc1ccc(C(=O)c2ccc(CSc3nc4cccc(C)c4c(=O)n3C)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(OCCO)cc4)cc3)n(C)c(=O)c12
Yield: 79.7 %

Procedure:
A solution of 2-[4-[4-(2-acetoxyethoxy)benzoyl]-benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (1.75 g) and 1N-aqueous sodium hydroxide solution (15 ml) in methanol (50 ml)-dichloromethane (25 ml) was stirred at room temperature for 3 hours. This reaction mixture was extracted with dichloromethane and the extract was dried and concentrated. The residue was recrystallized from ethyl acetate to provide the title compound as colorless solid (1.278 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH2:39][CH2:40][NH:41][CH2:42][CH2:43][OH:44])[N:11]=[C:12]3[C:21]4[C:16](=[C:17]([O:30]CC5C=CC=CC=5)[CH:18]=[CH:19][C:20]=4[O:22]CC4C=CC=CC=4)[C:15](=[O:38])[C:14]=1[C:13]=23.[ClH:45]>C(O)(=O)C.CC(O)C.[OH-].[OH-].[Pd+2]>[ClH:45].[NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH2:39][CH2:40][NH:41][CH2:42][CH2:43][OH:44])[N:11]=[C:12]3[C:21]4[C:16](=[C:17]([OH:30])[CH:18]=[CH:19][C:20]=4[OH:22])[C:15](=[O:38])[C:14]=1[C:13]=23
Reactant: NCCCNc1ccc2c3c(nn2CCNCCO)-c2c(OCc4ccccc4)ccc(OCc4ccccc4)c2C(=O)c13
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CC(C)O
Solvent: CC(=O)O
Product: NCCCNc1ccc2c3c(nn2CCNCCO)-c2c(O)ccc(O)c2C(=O)c13
Yield: 82 %

Procedure:
A mixture of 9.5 g (0.016 mol) of 5-[(3-aminopropyl)amino]-2-[2-(2-hydroxyethyl)amino]ethyl]-7,10-bis(phenylmethoxy)anthra[1,9-cd[pyrazol-6(2H)-one (3) in 300 ml of acetic acid was hydrogenated over 1.7 g of 20% palladium hydroxide on carbon at atmospheric pressure and at room temperature for two hours, filtered through celite, and concentrated under vacuum. The residue was dissolved in boiling methanol. The hot solution was treated with an excess (about 0.05 mol) of hydrogen chloride in 2-propanol, and chilled overnight. The red-orange precipitate was collected, washed with 2-propanol, dried at 65° C. under vacuum for 48 hours, and allowed to equilibrate in the air overnight to afford 6.4 g (82%) of 4, containing 0.6 mole of water, mp 267°-272° C. (dec) with prior sintering.
Reaction SMILES: Cl.[CH3:2][S:3]([NH:6][C:7]1[CH:20]=[CH:19][C:10]([C:11]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=1)(=[O:5])=[O:4].[C:21]([O-:24])([O-])=O.[K+].[K+]>C(O)C>[OH:12][CH:11]([CH2:13][N:16]1[CH2:17][CH2:18][CH:13]([C:11](=[O:12])[C:10]2[CH:9]=[CH:8][C:7]([NH:6][S:3]([CH3:2])(=[O:4])=[O:5])=[CH:20][CH:19]=2)[CH2:14][CH2:15]1)[CH2:10][O:24][C:21]1[CH:19]=[CH:20][C:7]([NH:6][S:3]([CH3:2])(=[O:5])=[O:4])=[CH:8][CH:9]=1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)C2CCNCC2)cc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc(OCC(O)CN2CCC(C(=O)c3ccc(NS(C)(=O)=O)cc3)CC2)cc1
Reaction time: 24 h
Yield: 155.8 %

Procedure:
A stirred solution of 4-[4-methylsulfonylaminobenzoyl)piperidine hydrochloride (2.25 g, 7.06 mmol), 2-[(4-(methylsulfonyamino)phenoxy)-methyl]oxirane (U.S. Pat. No. 4,994,459, 1.73 g, 7.06 mmol) and K2CO3 (0.98 g, 7.06 mmol) in ethanol (40 mL) was heated at 90° C. for 24 hours and then at 25° C. for an additional 24 hours. The mixture was concentrated and the residue was partitioned between aqueous 10% NaHCO3 and 4:1 CH2Cl2 /isopropanol. The organic phase was dried and concentrated to afford 2.89 g (78%) of the title compound. A portion (1.60 g) was purified by HPLC (15% CH3OH/EtOAc) to give 0.92 g of product as a white solid: mp 179°-183° C. (dec); 1H NMR (DMSO-d6): δ 10.20 (brs, 1H), 9.33 (brs, 1H), 7.94 (d, J=8.72 Hz, 2H), 7.26 (d, J=8.92 Hz, 2H), 7.13 (d, J=9.13 Hz, 2H), 6.91 (d, J=8.92 Hz, 2H), 4.83 (m,1H), 3.93 (m, 2H), 3.85 (m, 1H), 3.09 (s, 3H), 2.96 (m, 2H), 2.87 (s, 3H), 2.45 (m, 2H), 2.20 (m, 2H), 1.75-1.50 (m, 4H); IR (KBr): 3420, 3300, 3250, 2910, 1675, 1610 cm-1 ; MS (m/z) 526 (MH+, 25%), 217 (40), 91 (100).
Reaction SMILES: Cl.Cl[C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[CH:4]=1.[CH2:17]([CH2:19][NH2:20])[OH:18].CCN(C(C)C)C(C)C>CCCCO>[Cl:16][C:12]1[CH:11]=[C:10]([NH:9][C:5]2[N:6]=[CH:7][N:8]=[C:3]([NH:20][CH2:19][CH2:17][OH:18])[CH:4]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: Clc1cccc(Nc2cc(Cl)ncn2)c1
Reactant: NCCO
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: OCCNc1cc(Nc2cccc(Cl)c2)ncn1
Temperature: 200 °C
Yield: 68 %

Procedure:
75 mg of 6-chloro-N-(3-chlorophenyl)pyrimidin-4-amine hydrochloride, 24 mg of ethanolamine and 87 mg of DIPEA were dissolved in 1 mL of n-BuOH and charged into a microwave vial and the vial obtained was heated to 200° C. for 45 minutes under microwave irradiation. The reaction was monitored by TLC. The crude product was obtained by evaporating n-BuOH. Purification was carried out by column chromatography using EtOAc: MeOH 10:1. 2-(6-(3-Chlorophenylamino)pyrimidin-4-ylamino)ethan-1-ol in the form of a colorless solid was obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:6]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:7][CH2:8][CH2:9][N:10]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:11]/[CH:12]=[CH:13]/[CH2:14][N:15]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:4][CH3:5].[CH2:48](Br)[CH3:49]>CN(C=O)C>[CH2:48]([N:19]([C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH2:18][CH2:17][CH2:16][N:15]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH2:14]/[CH:13]=[CH:12]/[CH2:11][N:10]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:9][CH2:8][CH2:7][N:6]([CH2:3][CH2:4][CH3:5])[C:41]([O:43][C:44]([CH3:46])([CH3:45])[CH3:47])=[O:42])[CH3:49]
Reactant: CCBr
Reactant: CCCN(CCCN(C/C=C/CN(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN(CCCN(C/C=C/CN(CCCN(CC)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
0.05 g (1.25 mmol) of sodium hydride dispersion (approx. 60%) is added, with stirring, to a solution of 0.40 g (0.622 mmol) of (E)-1-propyl-1,5,10,14-tetra-BOC-1,5,10,14-tetraazatetradec-7-ene (see Example 1a) in 6 ml of DMF. The mixture is stirred for 5 min. at room temperature; 0.093 ml (1.25 mmol) of ethyl bromide is added, and the reaction mixture is stirred for a further 36 h at 20° C. and is then concentrated by evaporation in vacuo. Working up analogously to Example 1a) yields the title compound, Rf value=0.55 (silica gel/ethyl acetate:hexane (1:1)).
Reaction SMILES: [NH2:1][CH2:2][C:3](=[CH2:27])[C:4]([NH:6][C:7]1[CH:8]=[C:9]([C:13]2[C:14]3[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][NH:19][C:15]=3[N:16]=[CH:17][N:18]=2)[CH:10]=[CH:11][CH:12]=1)=[O:5].C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[CH3:35][S:36]([NH:1][CH2:2][C:3](=[CH2:27])[C:4]([NH:6][C:7]1[CH:8]=[C:9]([C:13]2[C:14]3[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][NH:19][C:15]=3[N:16]=[CH:17][N:18]=2)[CH:10]=[CH:11][CH:12]=1)=[O:5])(=[O:38])=[O:37]
Reactant: CS(=O)(=O)Cl
Reactant: C=C(CN)C(=O)Nc1cccc(-c2ncnc3[nH]cc(C(=O)OCC)c23)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(CNS(C)(=O)=O)C(=O)Nc1cccc(-c2ncnc3[nH]cc(C(=O)OCC)c23)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 4-(3-(2-(aminomethyl)acrylamido)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (32 mg, 0.088 mmol) in DCM (438 μL) was added triethylamine (12 μL, 0.088 mmol) and methanesulfonyl chloride (7.5 μL, 0.096 mmol) at 0° C. The reaction mixture was allowed to stir at 0° C. for 1 hour and then gradually warmed up to room temperature over 1 hour. The resulting mixture was diluted with DCM (2 mL) and washed with saturated aqueous sodium bicarbonate solution (2 mL). The aqueous layer was extracted with DCM (×3) and the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC using an acetonitrile gradient in water with 0.1% TFA modifier to give ethyl 4-(3-(2-(methylsulfonamidomethyl)acrylamido)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate. LRMS (ESI) calc'd for C20H22N5O5S [M+H]+: 444, found 444. 1H NMR (600 MHz, DMSO-D6) δ 12.99 (bs, 1H), 10.11 (s, 1H), 8.90 (s, 1H), 8.30 (s, 1H), 8.05 (s, 1H), 7.84 (d, J=8.21 Hz, 1H), 7.42 (t, J=8.21 Hz, 1H), 7.38 (t, J=6.45 Hz, 1H), 7.33 (d, J=7.63 Hz, 1H), 6.01 (s, 1H), 5.75 (s, 1H), 3.89 (d, J=6.45 Hz, 2H), 3.86 (q, J=7.04 Hz, 2H), 2.94 (s, 3H), 0.86 (t, J=7.04 Hz, 3H).
Reaction SMILES: [C:1]([N:5]1[C:9]([NH:10][C:11]2[N:16]=[C:15]([CH2:17][C:18]3([C:37]([NH:39][NH:40]C(OC(C)(C)C)=O)=[O:38])[CH2:23][CH2:22][N:21]([C:24](=[O:36])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[C:26]=4[F:35])[CH2:20][CH2:19]3)[CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[C:1]([N:5]1[C:9]([NH:10][C:11]2[N:16]=[C:15]([CH2:17][C:18]3([C:37]([NH:39][NH2:40])=[O:38])[CH2:19][CH2:20][N:21]([C:24](=[O:36])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:32])([F:34])[F:33])[C:26]=4[F:35])[CH2:22][CH2:23]3)[CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NNC(=O)C1(Cc2cccc(Nc3ccnn3C(C)(C)C)n2)CCN(C(=O)c2cccc(C(F)(F)F)c2F)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CC(C)(C)n1nccc1Nc1cccc(CC2(C(=O)NN)CCN(C(=O)c3cccc(C(F)(F)F)c3F)CC2)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 195 mg of tert-butyl 2-((4-((6-((1-tert-butyl-1H-pyrazol-5-yl)amino)pyridin-2-yl)methyl)-1-(2-fluoro-3-(trifluoromethyl)benzoyl)piperidin-4-yl)carbonyl)hydrazinecarboxylate in 4 ml of chloroform was added 2 ml of trifluoroacetic acid at 0° C. The reaction mixture was stirred at 0° C. for 2 hours and at room temperature for 2 hours, followed by concentrating in vacuo. The resulting residue was basified with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The ethyl acetate solution was dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (eluent: chloroform to chloroform/methanol=10/1) to give the title compound as a colorless oil.
Reaction SMILES: Cl.Cl.[CH3:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH2:20][NH:19][CH2:18][CH2:17]2.[CH3:24][C:25]([CH3:27])=O.[BH3-]C#N.[Na+]>CO.O>[CH:25]([N:19]1[CH2:18][CH2:17][C:16]2[C:21](=[CH:22][CH:23]=[C:14]([O:13][CH2:12][CH2:11][CH2:10][N:5]3[CH2:6][CH2:7][CH2:8][CH2:9][CH:4]3[CH3:3])[CH:15]=2)[CH2:20]1)([CH3:27])[CH3:24]
Reactant: CC(C)=O
Reactant: CC1CCCCN1CCCOc1ccc2c(c1)CCNC2
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)N1CCc2cc(OCCCN3CCCCC3C)ccc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a flask equipped with a stir bar is placed 6-[3-(2-Methyl-piperidin-1-yl)-propoxy]-1,2,3,4-tetrahydro-isoquinoline dihydrochloride (300 mg, 0.83 mmol), acetone (excess), NaCNBH3 (155 mg, 2.5 mmol) in MeOH (8 mL) and the mixture stirred at room temperature for 2 h. The reaction mixture is diluted with water, and extracted with CH2Cl2. The organic phase is dried over Na2SO4 and concentrated. M+1 331, LCMS >98% @ 230 nm and ELSD.
Reaction SMILES: C([O-])(=O)C.[Na+].[Cl-].[CH2:7]([O:9][NH3+:10])[CH3:8].[C:11]([CH:16]1[C:21](=[O:22])[CH2:20][CH:19]([CH:23]2[CH:28]([CH3:29])[CH2:27][CH2:26][O:25][CH2:24]2)[CH2:18][C:17]1=[O:30])(=O)[CH2:12][CH2:13][CH3:14]>C(O)C>[CH2:7]([O:9][NH:10][C:11](=[C:16]1[C:17](=[O:30])[CH2:18][CH:19]([CH:23]2[CH:28]([CH3:29])[CH2:27][CH2:26][O:25][CH2:24]2)[CH2:20][C:21]1=[O:22])[CH2:12][CH2:13][CH3:14])[CH3:8]
Reactant: CCO[NH3+]
Reactant: CCCC(=O)C1C(=O)CC(C2COCCC2C)CC1=O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: CCCC(NOCC)=C1C(=O)CC(C2COCCC2C)CC1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
3.69 parts by weight of sodium acetate and 3.51 parts by weight of ethoxyammonium chloride were added to 10.0 parts by weight of 2-butyryl-5-(4-methyltetrahydropyran-3-yl)-cyclohexane-1,3-dione in 100 ml of ethanol, and the mixture was stirred for 20 hours at room temperature. To work up the mixture, it was poured into ice water and extracted with methylene chloride, and the organic phase was washed with water, dried and evaporated down to give 10.7 parts by weight of 2-(1-ethoxyaminobutylidene)-5-(4-methyltetrahydropyran-3-yl)-cyclohexane-1,3-dione (active ingredient No. 1); nD22 =1.5235.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].[F:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1>>[F:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([C:13]2[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=2[F:11])[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(F)cccc1Br
Reactant: CC1(C)OB(c2cc([N+](=O)[O-])ccc2F)OC1(C)C
Product: N#Cc1c(F)cccc1-c1cc([N+](=O)[O-])ccc1F

Procedure:
2-Bromo-6-fluorobenzonitrile and 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane were coupled following the procedure in Example 2 to afford 3,2′-difluoro-5′-nitrobiphenyl-2-carbonitrile as a black solid: δH (360 MHz, CDCl3) 7.32-7.44 (3H, m), 7.71-7.77 (1H, m), 8.35-8.41 (2H, m).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[CH3:26][S:27]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])=[CH:17][CH:18]=1)(=[O:29])=[O:28]
Reactant: CC(C)(C)OC(=O)COc1ccc(CCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)COc1ccc(CCOS(C)(=O)=O)cc1
Temperature: -10 °C
Reaction time: 16 h
Yield: 95.5 %

Procedure:
Tert-butyl [4-(2-hydroxyethyl)phenoxy]acetate (6.000 g, 23.781 mmol) and triethylamine (9.9 ml, 71.341 mmol) were dissolved in DCM. The mixture was cooled to −10° C. and methanesulfonyl chloride (2.8 ml, 35.671 mmol) was added dropwise to the mixture. The reaction mixture was allowed to reach room temperature and was stirred for 16 hours. The mixture was diluted with DCM. The organic layer was washed with water, brine and 0.3M KHSO4, dried with MgSO4, and evaporated under reduced pressure. Obtained 7.5 g of light-yellow crystals (yield 95.5%).
Reaction SMILES: [ClH:1].[CH:2]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH2:9])=[NH:8])=O.[NH2:13][NH:14][C:15]([NH2:17])=[S:16]>CO.O.Cl>[ClH:1].[CH:2](=[N:13][NH:14][C:15]([NH2:17])=[S:16])[C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH2:9])=[NH:8]
Reactant: N=C(N)c1cccc(C=O)c1
Reactant: NNC(N)=S
Agent: Cl
Solvent: CO
Solvent: O
Product: N=C(N)c1cccc(C=NNC(N)=S)c1

Procedure:
A solution of 1.84 g (~0.01 mol) of crude 3-formylbenzamidine hydrochloride (prepared analogously to Example 1b) in 10 ml of methanol is added dropwise to a solution of 0.91 g (0.01 mol) of thiosemicarbazide in 5 ml of water and 10 ml of 2N hydrochloric acid. This mixture is heated under reflux for 1 hour, cooled, filtered and concentrated to dryness by evaporation. The residue is recrystallised from methanol; m.p. 210° (with decomposition). The product contains 0.5 mol of water.
Reaction SMILES: [CH3:1][N:2]([CH3:33])[CH2:3][C:4]([N:6]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[NH:19][C:20]2[C:21]3[C:28]([CH3:29])=[C:27]([C:30]([OH:32])=O)[S:26][C:22]=3[N:23]=[CH:24][N:25]=2)[CH2:7]1)=[O:5].[NH3:34]>CO>[CH3:33][N:2]([CH3:1])[CH2:3][C:4]([N:6]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[NH:19][C:20]2[C:21]3[C:28]([CH3:29])=[C:27]([C:30]([NH2:34])=[O:32])[S:26][C:22]=3[N:23]=[CH:24][N:25]=2)[CH2:7]1)=[O:5]
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3OC3CCN(C(=O)CN(C)C)C3)c12
Reactant: N
Solvent: CO
Product: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3OC3CCN(C(=O)CN(C)C)C3)c12

Procedure:
Prepared analogously to example 1.4 from 4-{2-[1-(2-Dimethylamino-acetyl)-pyrrolidin-3-yloxy]-4-fluoro-phenylamino}-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid and ammonia in methanol.
Reaction SMILES: [C:1]([NH:6][C:7](=[S:15])[O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)([O:3]CC)=O.CC[O-].[K+].Cl[CH2:21][C:22]#[N:23]>CO>[CH:9]1([O:8][C:7]2[S:15][C:21]([C:22]#[N:23])=[C:1]([OH:3])[N:6]=2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: N#CCCl
Reactant: CCOC(=O)NC(=S)OC1CCCCC1
Agent: CC[O-]
Agent: [K+]
Solvent: CO
Product: N#Cc1sc(OC2CCCCC2)nc1O
Reaction time: 2 h
Yield: 40.6 %

Procedure:
A suspension of 38.3 g of cyclohexyl N-carbethoxy-thiocarbamate and 11.56 g of potassium ethylate in 400 ml of methanol was stirred for 2 hours and 12.45 g of chloroacetonitrile were added thereto. The mixture was stirred for 48 hours at room temperature and was then concentrated to dryness. The residue was added to water and the aqueous phase was acidified with hydrochloric acid. The aqueous phase was extracted with ether and the ether phase was dried and concentrated to dryness to obtain 15 g of 2-cyclohexyloxy-4-hydroxy-5-cyanothiazole in the form of white crystals melting at 138° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[N:4]=[CH:3]1.C([Li])CCC.C=O.[OH:15][CH2:16]C1N2CCCCC2=CN=1>>[CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[N:4]=[C:3]1[CH2:16][OH:15]
Reactant: OCc1ncc2n1CCCC2
Reactant: Cc1cn(C)cn1
Agent: C=O
Agent: [Li]CCCC
Product: Cc1cn(C)c(CO)n1

Procedure:
The reaction of 1,4-dimethylimidazole (5.65 g.) with n-butyl lithium followed by treatment with formaldehyde according to the method described for the preparation of 3-hydroxymethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine (used for Example 224) gave 1,4-dimethyl-2-hydroxymethylimidazole (2.71 g.), m.p. 125°-126° (ethyl acetate-petroleum ether).
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([NH:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:3][CH:2]=1.[CH2:15]1[C:20]2([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:19][CH2:18][O:17][CH:16]1O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl.C(N(CC)CC)C>[C:1]1([CH3:14])[CH:2]=[CH:3][C:4]([NH:7][CH:8]2[CH2:13][CH2:12][N:11]([CH2:18][CH2:19][C:20]3([CH2:15][CH2:16][OH:17])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)[CH2:10][CH2:9]2)=[CH:5][CH:6]=1
Reactant: Cc1ccc(NC2CCNCC2)cc1
Reactant: OC1CC2(CCCCCCC2)CCO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NC2CCN(CCC3(CCO)CCCCCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 45.5 %

Procedure:
To a suspension of 4-(p-toluidino)piperidine ditrifluoroacetate (synthesized in Preparation Example 4-5) (1.31 g) in 1,2-dichloroethane (6 mL) was added triethylamine (0.96 mL). The suspension was stirred at room temperature for 5 minutes. Then, a solution of 3-oxaspiro[5.7]tridecan-2-ol (synthesized in Example 72) (0.62 g) in 1,2-dichloroethane (3 mL) was added to the suspension, and it was stirred at room temperature for additional 10 minutes. The reaction solution was ice-cooled and sodium triacetoxyborohydride (0.70 g) was added thereto. The reaction solution was then allowed for its temperature to rise to room temperature, and the solution was stirred for additional 4.5 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction solution and it was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by chromatography [silica gel, methanol-chloroform (3:97 to 1:9)] to give the title compound (0.53 g).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[C:8]([CH2:16]O)=[N:9][C:10]([S:14][CH3:15])=[N:11][C:12]=1[CH3:13].CCN(CC)CC>C(Cl)Cl>[Cl:6][C:7]1[C:12]([CH3:13])=[N:11][C:10]([S:14][CH3:15])=[N:9][C:8]=1[CH2:16][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: CSc1nc(C)c(Cl)c(CO)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSc1nc(C)c(Cl)c(CS(C)(=O)=O)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
MsCl (248 mg, 2.169 mmol) was added to a stirred, cooled 0° C. mixture of the title compound from Step D (370 mg, 1.808 mmol) in CH2Cl2 (10 mL), followed by addition of Et3N (274 mg, 2.71 mmol). The mixture was stirred at 0° C. for 30 min. TLC showed no starting material left. The mixture was quenched with water (5 mL) and the mixture was washed with more water (10 mL). The organic fraction were washed with brine (saturated, 10 mL), dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel Biotage 40S, eluting with EtOAc/hexane (2/8) to give the title compound as a colorless solid. 1H NMR (CDCl3, 500 MHz) δ 5.40 (s, 2H), 3.20 (s, 3H), 2.61 (s, 3H), 2.59 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:10]2[CH:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=[N:11]2)[CH:6]=[CH:7][C:8]=1[OH:9])#[N:2].[CH:20]1(Br)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[C:1]([C:3]1[CH:4]=[C:5]([N:10]2[CH:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=[N:11]2)[CH:6]=[CH:7][C:8]=1[O:9][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)#[N:2]
Reactant: BrC1CCCCC1
Reactant: CCOC(=O)c1cnn(-c2ccc(O)c(C#N)c2)c1
Product: CCOC(=O)c1cnn(-c2ccc(OC3CCCCC3)c(C#N)c2)c1

Procedure:
The same reaction and treatment as in Example 5 using ethyl 1-(3-cyano-4-hydroxyphenyl)pyrazole-4-carboxylate and cyclohexyl bromide gives ethyl 1-(3-cyano-4-cyclohexyloxyphenyl)pyrazole-4-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[NH2:27][CH2:28][CH2:29][CH2:30][NH:31]C(=O)OC(C)(C)C>>[NH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:3]1[C:4]2[CH2:10][CH2:9][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:7][CH2:6][C:5]=2[CH:17]=[CH:18][C:2]=1[Cl:1]
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NCCCN
Product: NCCCNc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Yield: 34 %

Procedure:
Use a method similar to the Preparation 20, using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (600 mg, 1.41 mmol) and tert-butyl N-(3-aminopropyl)-carbamate (1.11 g, 6.34 mmol) to give the title compound (34% overall).
Reaction SMILES: [CH3:1]OS(OC)(=O)=O.[OH:8][C:9]1[CH:17]=[CH:16][C:12]2[CH2:13][CH2:14][O:15][C:11]=2[CH:10]=1>[OH-].[Na+]>[CH3:1][O:8][C:9]1[CH:17]=[CH:16][C:12]2[CH2:13][CH2:14][O:15][C:11]=2[CH:10]=1
Reactant: Oc1ccc2c(c1)OCC2
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2c(c1)OCC2
Reaction time: 3 h

Procedure:
Dimethylsulfate (35 ml) was added over a period of 3 hours to a stirred solution of 6-hydroxy-2,3-dihydrobenzofuran (12.0 g) dissolved in 200 ml of 10% sodium hydroxide. The solution was stirred for an additional 3 hours after dimethylsulfate addition was completed. The solution was then extracted with ether, the ether extracts combined, dried, and evaporated to give a residue which was distilled (140° C. at 0.5 mm) to yield 6-methoxy-2,3-dihydrobenzofuran.