Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:8]=2[CH2:7][N:6]([CH2:15][CH3:16])[CH2:5][CH2:4]1)[CH3:2].Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[O:27][CH2:28][C:29]#[N:30])[C:21]([Cl:35])=[CH:20][N:19]=1>>[Cl:35][C:21]1[C:22]([NH:24][C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[O:27][CH2:28][C:29]#[N:30])=[N:23][C:18]([NH:14][C:11]2[CH:12]=[CH:13][C:8]3[CH2:7][N:6]([CH2:15][CH3:16])[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[C:9]=3[CH:10]=2)=[N:19][CH:20]=1
Reactant: CCN1CCN(CC)c2cc(N)ccc2C1
Reactant: N#CCOc1ccccc1Nc1nc(Cl)ncc1Cl
Product: CCN1CCN(CC)c2cc(Nc3ncc(Cl)c(Nc4ccccc4OCC#N)n3)ccc2C1

Procedure:
The title compound was prepared from 1,4-Diethyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamine and [2-(2,5-Dichloro-pyrimidin-4-ylamino)-phenoxy]-acetonitrile in an analogous manner to example 730. Product was isolated as a tan solid (0.044 g, 31%). Mp 80-83° C.; LCMS (m/e) 478 (M+1); 1H-NMR (DMSO, 400 MHz) δ 9.17 (s, 1H), 8.23 (s, 1H), 8.14 (s, 1H), 7.99-7.97 (d, 1H, J=8.36 Hz), 7.28-7.22 (m, 2H), 7.16-7.07 (q, 2H, J=8.31 Hz), 7.05 (s, 1H), 6.95-6.87 (d, 1H, J=7.56 Hz), 5.21 (s, 2H), 3.76-3.57 (br, 1H), 3.09-2.97 (q, 2H, J=7.08 Hz), 2.93-2.85 (m, 2H), 2.83-2.70 (m, 2H), 2.48-2.35 (br, 2H), 1.15-1.08 (t, 3H, J=7.08 Hz), 1.07-0.99 (t, 3H, J=6.82 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][NH:12][C:13]([C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=1[Cl:25])[C:18]([O:20]C)=[O:19])=[O:14].[Li+].[OH-].Cl>CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][NH:12][C:13]([C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=1[Cl:25])[C:18]([OH:20])=[O:19])=[O:14]
Reactant: COC(=O)c1ccc(Cl)c(C(=O)NCc2ccc(OC)cc2OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(CNC(=O)c2cc(C(=O)O)ccc2Cl)c(OC)c1
Yield: 92.1 %

Procedure:
Methyl 3-[({[2,4-bis(methyloxy)phenyl]methyl}amino)carbonyl]-4-chlorobenzoate (600 mg, 1.65 mmol) dissolved in 17 mL CH3OH was treated with 16.5 mL 1N LiOH at ambient temperature for 16 h. The reaction mixture was concentrated to dryness, partitioned between EtOAc and water, the aqueous phase isolated and the pH adjusted to 2 with 6N HCl. The resultant precipitate was cooled in an ice bath with stirring, filtered, and washed with water to give 3-[({[2,4-bis(methyloxy)phenyl]methyl}amino)carbonyl]-4-chlorobenzoic acid (533 mg, 1.52 mmol) as a white crystalline solid. 1H NMR (300 MHz, DMSO-D6) d ppm 8.96 (m, 1H), 8.29 (d, J=2.2 Hz, 1H), 8.00 (dd, J=8.4, 2.3 Hz, 1H), 7.65 (d, J=8.3 Hz, 1H), 7.09 (d, J=8.3 Hz, 1H), 6.55 (d, J=2.3 Hz, 1H), 6.50 (dd, J=8.3, 2.3 Hz, 1H), 4.35 (d, J=5.6 Hz, 1H), 3.79 (s, 3H), 3.73 (s, 3H). LCMS ES+ 349.88, 351.91 (M+H).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]23[CH2:18][CH:16]([CH2:17]2)[C:15](=[O:19])[NH:14][C:13]3=[O:20])=[CH:8][CH:7]=1)([O-:5])=[O:4].[CH2:21](Br)[CH2:22][CH2:23][CH3:24]>CN(C)C=O>[CH2:21]([N:14]1[C:15](=[O:19])[CH:16]2[CH2:17][C:12]([C:9]3[CH:8]=[CH:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:11][CH:10]=3)([CH2:18]2)[C:13]1=[O:20])[CH2:22][CH2:23][CH3:24]
Reactant: CCCCBr
Reactant: O=C1NC(=O)C2(c3ccc([N+](=O)[O-])cc3)CC1C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCN1C(=O)C2CC(c3ccc([N+](=O)[O-])cc3)(C2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.36 g of sodium hydride is added to a solution of 2.46 g of 1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione in 25 ml of N,N-dimethylformamide and the whole is stirred at room temperature for 30 minutes. 1.6 ml of n-butyl bromide dissolved in 10 ml of N,N-dimethylformamide are then added dropwise thereto. When the reaction is complete, the reaction mixture is freed of N,N-dimethylformamide. The residue is partitioned between ethyl acetate and water, and the organic phase is dried over magnesium sulphate and, after concentration by evaporation and subsequent recrystallisation from ethyl acetate/petroleum ether, the product is obtained having a melting point of 120°-123°.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.CN(C)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(Cl)Cl>[Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([NH:8][S:15]([CH3:14])(=[O:17])=[O:16])=[N:6][CH:7]=1
Reactant: Cc1cc(N)ncc1Br
Reactant: CS(=O)(=O)Cl
Agent: CN(C)C
Solvent: ClCCl
Product: Cc1cc(NS(C)(=O)=O)ncc1Br
Reaction time: 0.33 h

Procedure:
5-Bromo-4-methylpyridin-2-amine (1.56 g) was dissolved in DCM (40 ml), trimethylamine (1.4 ml) added, followed by methanesulfonyl chloride (1.9 g) and the mixture stirred for 20 min. The solution was washed with water, dried (MgSO4) and evaporated. The residue was dissolved in THF, treated with TBAF, stirred for 16 h and evaporated. The residue was purified by chromatography on silica eluting with 27% EtOAc/isohexane. Yield 1.3 g. Carried forward to step (ii) without characterisation.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C@@H:5]1[C:28](=[O:29])[N:7]2[C:8]([C:25]([O-:27])=[O:26])=[C:9]([CH2:12][N+:13]3[N:14]([CH3:24])[C:15]([NH:18][CH2:19][C:20]([O:22]C)=[O:21])=[CH:16][CH:17]=3)[CH2:10][S:11][C@H:6]12.C[Si](C)(C)NC(=O)C.Cl.[NH2:39][C:40]1[S:44][N:43]=[C:42](/[C:45](=[N:49]/[O:50][CH3:51])/[C:46](Cl)=[O:47])[N:41]=1.C(OCC)(=O)C>O1CCCC1>[NH2:39][C:40]1[S:44][N:43]=[C:42]([C:45](=[N:49][O:50][CH3:51])[C:46]([NH:4][C@@H:5]2[C:28](=[O:29])[N:7]3[C:8]([C:25]([O-:27])=[O:26])=[C:9]([CH2:12][N+:13]4[N:14]([CH3:24])[C:15]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:16][CH:17]=4)[CH2:10][S:11][C@H:6]23)=[O:47])[N:41]=1
Reactant: COC(=O)CNc1cc[n+](CC2=C(C(=O)[O-])N3C(=O)[C@@H](N)[C@H]3SC2)n1C
Reactant: CO/N=C(\C(=O)Cl)c1nsc(N)n1
Agent: CC(=O)N[Si](C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccc(NCC(=O)O)n3C)CS[C@H]12)c1nsc(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.5 %

Procedure:
To a solution of 7β-amino-3-[2-methyl-3-methoxycarbonylmethylamino-1-pyrazolio]methyl-3-cephem-4-carboxylate trihydrochloride (0.7 g) and N-(trimethylsilyl)acetamide (1.87 g) in tetrahydrofuran (14 ml) was added (Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetyl chloride hydrochloride (0.37 g) under ice-cooling and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ethyl acetate (140 ml) and the resultant powder was collected by filtration. The powder was dissolved in ice-water and adjusted to pH 13 with 1N aqueous sodium hydroxide. After stirring for 20 minutes under ice-cooling, the solution was adjusted to pH 2 with 3N hydrochloric acid and subjected to column chromatography on "Diaion HP-20" using 5% aqueous isopropyl alcohol as an eluent. Fractions containing the object compound were combined, evaporated in vacuo to remove isopropyl alcohol and lyophilized to give 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-(3-carboxymethylamino-2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate (syn isomer) (0.24 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].BrC1C=CC(Cl)=CC=1[CH2:20][O:21][CH2:22]OC>>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[CH2:4][O:5][CH2:20][O:21][CH3:22]
Reactant: O=C(O)c1ccc(F)cc1Br
Reactant: COCOCc1cc(Cl)ccc1Br
Product: COCOCc1ccc(F)cc1Br

Procedure:
This compound was made from 2-bromo-4-fluorobenzoic acid in the same manner as compound 18d and was used for the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[C:5]([O:12][CH3:13])[CH:4]=1.[Br:14]Br>C(Cl)(Cl)Cl>[Br:14][C:8]1[CH:7]=[C:6]([N+:9]([O-:11])=[O:10])[C:5]([O:12][CH3:13])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: BrBr
Reactant: COc1ccc([N+](=O)[O-])c(OC)c1
Solvent: ClC(Cl)Cl
Product: COc1cc(OC)c([N+](=O)[O-])cc1Br
Temperature: 25 °C

Procedure:
1,3-Dimethoxy-4-nitrobenzene (5.0 g, 27 mmol) in chloroform (50 ml) at 0° C., was treated with a solution of bromine (1.68 ml, 33 mmol) in chloroform (50 ml). The solution was stirred with warming to room temperature for 4 hours, washed with 10% sodium thiosulfate solution and brine then dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude product was used without further purification (D17). MS (ES+) m/e 262/264 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:18]=[C:19]([C:21]3[CH2:25][C@@H:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[O:23][N:22]=3)[CH:20]=2)[C:11]([O:13]C(C)(C)C)=[O:12])=[N:6][CH:7]=1.Cl>ClCCl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:18]=[C:19]([C:21]3[CH2:25][C@@H:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[O:23][N:22]=3)[CH:20]=2)[C:11]([OH:13])=[O:12])=[N:6][CH:7]=1
Reactant: Cc1ccc(-c2cc(C(=O)OC(C)(C)C)cc(C3=NO[C@H](c4ccccn4)C3)c2)nc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(-c2cc(C(=O)O)cc(C3=NO[C@H](c4ccccn4)C3)c2)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 123 %

Procedure:
To a solution of tert-butyl 3-(5-methylpyridin-2-yl)-5-[(5S)-5-pyridin-2-yl-4,5-dihydroisoxazol-3-yl]benzoate (18.6 g, 44.8 mmol) in dichloromethane (100 mL) was added hydrogen chloride (4.0 M in dioxane; 56.0 mL, 224 mmol). The reaction mixture was stirred at ambient temperature. After 18 h, the mixture was concentrated. Dichloromethane was added the suspension was filtered. The solid cake was washed with dihchloromethane and dried under reduced pressure gave the hydrochloride salt of the title compound (19.8 g). MS 359.8 (M+1).
Reaction SMILES: [C:1]([C:3]1([CH2:18][CH2:19]Br)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2)#[N:2].[CH3:21][NH:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:3]1([CH2:18][CH2:19][N:22]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH3:21])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2)#[N:2]
Reactant: CNCCc1ccc(F)cc1
Reactant: N#CC1(CCBr)c2ccccc2CCc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCc1ccc(F)cc1)CCC1(C#N)c2ccccc2CCc2ccccc21

Procedure:
A mixture containing 1-[(5-cyano-10,11-dihydrodibenzo[a,d]cyclohepten-5-yl]-2-bromoethane (3.26 g -- see Preparation 26), N-methyl-4-fluorophenethylamine (1.53 g -- see C.A. 80:P120985y), anhydrous potassium carbonate (2.76 g) and acetonitrile (50 ml) was heated under reflux for 24 hours then concentrated in vacuo. Water (50 ml) was added to the residue and the resulting mixture was extracted with dichloromethane (3×60 ml). The combined dichloromethane extracts were dried (Na2SO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with hexane containing dichloromethane (25% up to 100%) and then with dichloromethane containing methanol (0% up to 5%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a viscous oil, yield, 1.7 g.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[C:12]([CH:16]=[O:17])[CH:11]=[C:10]([S:18]([NH2:21])(=[O:20])=[O:19])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:22]([NH:21][S:18]([C:10]1[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH2:1])[CH:3]=2)[C:13]([O:14][CH3:15])=[C:12]([CH:16]=[O:17])[CH:11]=1)(=[O:19])=[O:20])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1c(C=O)cc(S(N)(=O)=O)cc1-c1cccc(N)c1
Reactant: O=C(Cl)c1ccccc1
Product: COc1c(C=O)cc(S(=O)(=O)NC(=O)c2ccccc2)cc1-c1cccc(N)c1

Procedure:
Proceeding as in Reference 21, but substituting 3′-amino-5-formyl-6-methoxy-biphenyl-3-sulfonamide and benzoyl chloride, gave N-benzoyl-3′-amino-5-formyl-6-methoxy-biphenyl-3-sulfonamide.
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:36][CH2:35][N:10]2[C:11]3[C:16]([C:17]([C:18]4[C:19](=[O:34])[NH:20][C:21](=[O:33])[C:22]=4[C:23]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:25]([CH3:32])[CH:24]=4)=[C:9]2[CH2:8]1)=[CH:15][CH:14]=[CH:13][CH:12]=3)(=O)=O.O.C[N:39](C)[CH:40]=[O:41]>N>[CH:40]([NH:39][CH2:6][CH:7]1[CH2:36][CH2:35][N:10]2[C:11]3[C:16]([C:17]([C:18]4[C:19](=[O:34])[NH:20][C:21](=[O:33])[C:22]=4[C:23]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:25]([CH3:32])[CH:24]=4)=[C:9]2[CH2:8]1)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:41]
Reactant: CN(C)C=O
Reactant: Cn1cc(C2=C(c3c4n(c5ccccc35)CCC(COS(C)(=O)=O)C4)C(=O)NC2=O)c2ccccc21
Agent: N
Solvent: O
Product: Cn1cc(C2=C(c3c4n(c5ccccc35)CCC(CNC=O)C4)C(=O)NC2=O)c2ccccc21

Procedure:
A solution of 120 mg of the pyrroledione product of Example 6 in 6 ml of dimethylformamide and 6 ml of 33% aqueous ammonia was heated to 140° C. for 6 hours. The cooled mixture was poured into water and the precipitate was filtered off. The product was purified by chromatography on silica gel with dichloromethane/acetic acid/methanol/water (60:18:2:3). Trituration with ethyl acetate gave 50 mg of 3-[8-(formamidomethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione of melting point 332°-334° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:6][CH:5]([C:7]2[N:11]3[CH:12]=[CH:13][N:14]=[C:15]([NH2:16])[C:10]3=[C:9]([C:17]3[CH:26]=[C:25]4[C:20]([CH:21]=[CH:22][C:23]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[N:24]4)=[CH:19][CH:18]=3)[N:8]=2)[CH2:4]1.CCN(C(C)C)C(C)C.[CH3:42][C:43](OC(C)=O)=[O:44]>C(Cl)Cl>[NH2:16][C:15]1[C:10]2[N:11]([C:7]([C@@H:5]3[CH2:4][C@H:3]([CH2:2][NH:1][C:43](=[O:44])[CH3:42])[CH2:6]3)=[N:8][C:9]=2[C:17]2[CH:26]=[C:25]3[C:20]([CH:21]=[CH:22][C:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[N:24]3)=[CH:19][CH:18]=2)[CH:12]=[CH:13][N:14]=1
Reactant: NCC1CC(c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(N)nccn23)C1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)NC[C@H]1C[C@@H](c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(N)nccn32)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A suspension of 3-[3-(aminomethyl)cyclobutyl]-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-8-amine (0.237 mmol, 100 mg) in DCM (6 mL) was charged with DIEA (0.475 mmol, 83 μL) and Ac2O (0.237 mmol, 22.43 μL) at −40° C. The reaction solution was warmed to rt slowly and stirred under N2 for 1.5 h. The reaction was quenched with water (3 mL), diluted with methylene chloride (20 mL), washed with water (30 mL) and brine (30 mL), and dried (Na2SO4). The filtrate was concentrated under reduced pressure, and the crude material was purified by silica gel flush column chromatography (Jones Flashmaster, 10 g/70 mL cartridge), eluting with 3% MeOH (7 N NH3) in DCM, yielding the title compound as a light yellow solid. The sample was recrystallized from DCM (minimal amount) and EtOAc. The final product was obtained as an off-white solid; 1H NMR (400 MHz, CDCl3) δ 8.43-8.42 (m, 1H), 8.28 (dd, J=8.0 Hz, 0.4 Hz, 1H), 8.20-8.18 (m, 2H), 7.97-7.92 (m, 3H), 7.57-7.48 (m, 3H), 7.15 (d, J=4.8 Hz, 1H), 7.12 (d, J=5.2 Hz, 1H), 5.19 (b, 2H), 3.78-3.70 (m, 1H), 3.38 (t, J=5.6 Hz, 2H), 2.77-2.66 (m, 3H), 2.42-2.34 (m, 2H), 1.87 (s, 3H); MS (ES+): m/z 463 (100) [MH+]; HPLC: tR=2.06 min (OpenLynx, polar 5 min).
Reaction SMILES: [C:1]1([C@:7]23[CH2:15][NH:14][CH2:13][C@H:12]2[CH2:11][S:10][C:9]([NH:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:25][C:26]1[CH:27]=[N:28][C:29](Cl)=[N:30][CH:31]=1.O1CCOCC1.C(N(CC)CC)C>O>[F:25][C:26]1[CH:27]=[N:28][C:29]([N:14]2[CH2:13][C@@H:12]3[C@@:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)([N:8]=[C:9]([NH:16][C:17](=[O:24])[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[S:10][CH2:11]3)[CH2:15]2)=[N:30][CH:31]=1
Reactant: O=C(NC1=N[C@@]2(c3ccccc3)CNC[C@H]2CS1)c1ccccc1
Reactant: Fc1cnc(Cl)nc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(NC1=N[C@@]2(c3ccccc3)CN(c3ncc(F)cn3)C[C@H]2CS1)c1ccccc1
Yield: 79.6 %

Procedure:
A solution of N-[(4aR,7aS)-7a-phenyl-4a,5,6,7-tetrahydro-4H-pyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (250 mg, 0.629 mmol), 5-fluoro-2-chloropyrimidine (167 mg, 1.26 mmol), 1,4-dioxane (10 mL), and triethylamine (318 mg, 3.14 mmol) is stirred at 110° C. for 4 hours. The reaction is cooled, diluted with water and extracted with dichloromethane. The organic layers are combined, dried, filtered, and concentrated under reduced pressure to give a residue. The residue is purified by silica gel flash chromatography, eluting with hexane/ethyl acetate (1:0) to hexane/ethyl acetate (0:1) to give the title compound (0.217 g, 80%). ES/MS (m/e): 434 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@@H:9]([O:13][C:14]1[NH:15][C:16]([NH2:25])=[C:17]2[C:21]([N:22]=1)=[N:20][C:19]([O:23][CH3:24])=[N:18]2)[CH2:10][CH2:11][CH3:12].Br[CH2:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[CH3:8][C@@H:9]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]2[CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCC[C@@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: BrCCCC1CCOCC1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@@H](C)Oc1nc(N)c2nc(OC)n(CCCC3CCOCC3)c2n1

Procedure:
Prepared similarly to Intermediate 216 from 2-{[(1R)-1-methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 4-(3-bromopropyl)tetrahydro-2H-pyran.
Reaction SMILES: [N:1]([CH2:4][C@H:5]([O:12]C(=O)CCCCC)[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N+]=[N-].C([O:23][CH2:24][CH3:25])(=O)C>[Pd]>[C:24]([NH:1][CH2:4][C@H:5]([OH:12])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:23])[CH2:25][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCC(=O)O[C@@H](CN=[N+]=[N-])CC(=O)OCC
Reactant: CCOC(C)=O
Agent: [Pd]
Product: CCCCCC(=O)NC[C@H](O)CC(=O)OCC
Temperature: 25 °C
Reaction time: 7 h
Yield: 87 %

Procedure:
In a 200 ml autoclave were charged 8.50 g (29.5 mmol) of ethyl (R)-4-azido-3-hexanoyloxybutyrate, 0.20 g of 5% Pd—C, and 16 ml of ethyl acetate, and the mixture was stirred at room temperature under a hydrogen pressure of 1000 KPa. for 7 hours. The catalyst was removed for concentration to give 7.07 g (87%) of the title compound.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][CH:14]([CH:17]3[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][CH3:25])[CH2:19][CH2:18]3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1.C([O-])([O-])=O.[K+].[K+].O>CO.CC(OC)(C)C.Cl>[C:4]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[CH2:16][CH2:15][CH:14]([CH:17]3[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][CH3:25])[CH2:19][CH2:18]3)[CH2:13][CH2:12]2)=[CH:9][CH:10]=1)#[CH:3]
Reactant: CCCC1CCC(C2CCC(c3ccc(C#C[Si](C)(C)C)cc3)CC2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: COC(C)(C)C
Product: C#Cc1ccc(C2CCC(C3CCC(CCC)CC3)CC2)cc1

Procedure:
20.0 g (52.5 mmol) of trimethyl-[4-(4′-propylbicyclohexyl-4-yl)phenylethynyl]silane are stirred for 48 h together with 8.71 g (63.0 mmol) of K2CO3 and 1.5 ml of water in 250 ml of methanol. The mixture is diluted with MTBE and neutralised using dil. hydrochloric acid. The aqueous phase is extracted with MTBE, and the combined organic phases are washed with water and sat. sodium chloride solution. The solution is dried using sodium sulfate and concentrated to completion. The crude product is recrystallised from n-heptane. 4′-(4-Ethynylphenyl)-4-propylbicyclohexyl is obtained as a colourless solid having an m.p. of 71° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6](F)=[C:7]([CH:12]=1)[C:8]([O:10]C)=[O:9])#[N:2].[F:14][C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([F:14])[CH:16]=2)=[C:7]([CH:12]=1)[C:8]([OH:10])=[O:9])#[N:2]
Reactant: COC(=O)c1cc(C#N)ccc1F
Reactant: Oc1cccc(F)c1
Product: N#Cc1ccc(Oc2cccc(F)c2)c(C(=O)O)c1

Procedure:
The title compound was prepared according to the procedure described in step 1 and 2 of Example 67 from methyl 5-cyano-2-fluorobenzoate and 3-fluorophenol: 1H-NMR (CDCl3) δ 8.36 (1H, s), 7.73 (1H, m), 7.39 (1H, m), 7.00–6.78 (4H, m).
Reaction SMILES: Cl.C([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:20][C:21]3[CH:29]=[C:28]4[C:24]([CH:25]=[CH:26][NH:27]4)=[CH:23][CH:22]=3)=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:30][CH3:31])C1C=CC=CC=1.C([O-])=O.[NH4+]>>[OH:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:20][C:21]3[CH:29]=[C:28]4[C:24]([CH:25]=[CH:26][NH:27]4)=[CH:23][CH:22]=3)=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:30][CH3:31]
Reactant: COc1cc2c(Nc3ccc4cc[nH]c4c3)ncnc2cc1OCc1ccccc1
Agent: Cl
Agent: O=C[O-]
Agent: [NH4+]
Product: COc1cc2c(Nc3ccc4cc[nH]c4c3)ncnc2cc1O
Yield: 76 %

Procedure:
Using an analogous procedure to that described for the preparation of the starting material in Example 201, 7-benzyloxy-4-(indol-6-ylamino)-6-methoxyquinazoline hydrochloride was treated with ammonium formate (655 mg, 10.4 mmol) to give 7-hydroxy-4-(indol-6-ylamino)-6-methoxyquinazoline (162 mg, 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][OH:11])[CH:5]=[N:6][C:7]=1[O:8][CH3:9].[H-].[Na+].[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1F)[C:18]#[N:19]>CN(C=O)C>[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[O:11][CH2:10][C:4]1[CH:5]=[N:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[CH:3]=1)[C:18]#[N:19]
Reactant: COc1ncc(CO)cc1Cl
Reactant: N#Cc1ccc(F)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ncc(COc2ccc(C#N)cc2Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of 5-chloro-3-hydroxymethyl-6-methoxypyridine (50 mg, 0.29 mmol) in DMF (3 mL) was added sodium hydride dispersion in oil (60%, 13.8 mg, 0.576 mmol) and the reaction stirred at 0° C. for 30 minutes. 3-Chloro-4-fluorobenzonitrile (45 mg, 0.288 mmol) was then added and the reaction stirred, warming to room temperature for 2 hours. The reaction was poured onto water (10 mL) and extracted with EtOAc (10 mL), dried over sodium sulfate and concentrated in vacuo to afford the title compound (89 mg, 72%).
Reaction SMILES: [CH:1]1([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][NH:17][CH:18]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1>CCCCCC>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:34])[N:17]([CH2:16][C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][N:8]([CH:1]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:33]([NH:32][C:29]3[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=3)=[O:34])[CH:11]=2)[CH:18]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:28][CH:27]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: c1cc(CNC2CCCCCC2)cc(CNC2CCCCCC2)c1
Solvent: CCCCCC
Product: O=C(Nc1ccc(Cl)cc1)N(Cc1cccc(CN(C(=O)Nc2ccc(Cl)cc2)C2CCCCCC2)c1)C1CCCCCC1
Reaction time: 2 h
Yield: 173.9 %

Procedure:
To a solution of 0.5 g N,N'-dicycloheptyl-m-xylylenediamine in 50 ml n-hexane, was added dropwise with stirring 5 ml of a n-hexane solution containing 0.25 g 4-chlorophenyl isocyanate under ice cooling, and stirring was continued at room temperature for two hours. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography, giving 0.9 g of 1,3-bis[[3-(p-chlorophenyl)-1-cycloheptylureido]methyl]benzene as amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=2[CH:19]=O)[CH:8]=[CH:9][CH:10]=1.[NH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][C:27]1=[O:31]>>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:19][NH:22][CH2:23][CH2:24][CH2:25][N:26]2[CH2:30][CH2:29][CH2:28][C:27]2=[O:31])[CH:8]=[CH:9][CH:10]=1
Reactant: NCCCN1CCCC1=O
Reactant: COC(=O)Cc1cccc(-c2c(C=O)cccc2OC)c1
Product: COC(=O)Cc1cccc(-c2c(CNCCCN3CCCC3=O)cccc2OC)c1

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using the following starting materials: (2′-formyl-6′-methoxy-biphenyl-3-yl)-acetic acid methyl ester and 1-(3-aminopropyl)-2-pyrrolidinone.