Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][S:4](Cl)(=[O:6])=[O:5].[CH:8]1([C@H:11]([NH2:33])[C:12]([N:14]2[CH2:18][C:17]([C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[F:26])=[CH:16][C@H:15]2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:13])[CH2:10][CH2:9]1.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:1][CH2:2][CH2:3][S:4]([NH:33][C@@H:11]([CH:8]1[CH2:10][CH2:9]1)[C:12]([N:14]1[CH2:18][C:17]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[F:26])=[CH:16][C@H:15]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:13])(=[O:6])=[O:5]
Reactant: N[C@H](C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1)C1CC1
Reactant: O=S(=O)(Cl)CCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C([C@@H](NS(=O)(=O)CCCl)C1CC1)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1
Temperature: 23 °C
Reaction time: 0.25 h

Procedure:
2-chloroethanesulfonyl chloride (81 μL, 0.78 mmol, 1.1 equiv) was added to a solution of (1S)-1-cyclopropyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethanamine (16-7, 250 mg, 0.705 mmol, 1 equiv) and N,N-diisopropylethylamine (160 μL, 0.917 mmol, 1.30 equiv) in dichloromethane (5 mL) at 0° C., and the resulting mixture was stirred for 15 minutes, then warmed to 23° C. and stirred for an additional 15 minutes. Additional 2-chloroethanesulfonyl chloride (1.2 equiv) and N,N-diisopropylethylamine (1.3 equiv) were added and the mixture was stirred for 30 minutes, then partitioned between water (75 mL) and dichloromethane (2×60 mL). The combined organic layers were dried over sodium sulfate and concentrated to give 2-chloro-N-{(1S)-1-cyclopropyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethyl}ethanesulfonamide (27-1) as a colorless oil. LRMS m/z (M+H—Cl) 445.4 found, 445.1 required.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([O-])([O-])=O.[K+].[K+].COS(OC)(=O)=O>CC(C)=O>[CH3:12][O:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1cc(I)ccc1O
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COc1ccc(I)cc1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 12 h

Procedure:
4-Hydroxy-3-nitroiodobenzene (3.2 g, 12.0 mmol) was dissolved in acetone (30 mL). K2CO3 (1.8 g, 1.1 equiv) and Me2SO4 (1.23 mL, 1.1 equiv) were added to the solution. The mixture was stirred at 65° C. for 12 h. The reaction was then cooled, concentrated, and diluted with H2O (100 mL) and CHCl3 (100 mL). The mixture was shaken in a separatory funnel. The organic layer was dried (Na2SO4), filtered, and concentrated to afford 4-methoxy-3-nitroiodobenzene as a beige solid (3.3 g, 12.0 mmol, quant.): mp: 92-93° C. 1H NMR (300 M Hz, CDCl3) δ 8.13 (d, 1H, J=2.4 Hz), 7.81 (dd, 1H, J=8.7, 2.4 Hz), 6.86 (d, 1H, J=8.7 Hz), 3.95 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=[C:4]([O:14][C:15]2[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([O:25]CC)=[O:24])=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2>C(Cl)(Cl)Cl.CO>[CH3:1][C:2]1[C:3]([C:28]2[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)=[C:4]([O:14][C:15]2[CH:16]=[CH:17][C:18](/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])=[CH:19][CH:20]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2
Reactant: CCOC(=O)/C=C/c1ccc(Oc2c(-c3ccc(OC)cc3)c(C)cc3ccc(OC)cc23)cc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc(-c2c(C)cc3ccc(OC)cc3c2Oc2ccc(/C=C/C(=O)O)cc2)cc1

Procedure:
Synthesized in a manner similar to Example 46 (Step 7) using ethyl (2E)-3-[4-({3-methyl-7-(methyloxy)-2-[4-(methyloxy)phenyl]-1-naphthalenyl}oxy)phenyl]-2-propenoate (265). 1H NMR (CDCl3, 400 MHz) δ 7.74 (d, J=9.0 Hz, 1H), 7.64 (d, J=15.9 Hz, 1H), 7.60 (s, 1H), 7.29 (d, J=8.8 Hz, 2H), 7.14 (dd, J=8.7, 2.4 Hz, 1H), 7.06-7.04 (m, 3H), 6.81 (d, J=8.7 Hz, 2H), 6.63 (d, J=8.7 Hz, 2H), 6.24 (d, J=15.9 Hz, 1H), 3.78 (s, 3H), 3.74 (s, 3H), 2.24 (s, 3H). TLC (90:10; CHCl3/MeOH): Rf=0.26.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][O:8][C:9]2([C:13]3[S:14][CH:15]=[CH:16][N:17]=3)[CH2:12][O:11][CH2:10]2)=[CH:5][CH:4]=1.C([N-]C(C)C)(C)C.[Li+].[CH2:28]([Sn:32](Cl)([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH3:31]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2([C:13]3[S:14][C:15]([Sn:32]([CH2:33][CH2:34][CH2:35][CH3:36])([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:28][CH2:29][CH2:30][CH3:31])=[CH:16][N:17]=3)[CH2:12][O:11][CH2:10]2)=[CH:18][CH:19]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: COc1ccc(COC2(c3nccs3)COC2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnc(C2(OCc3ccc(OC)cc3)COC2)s1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a cold (−78° C.) solution of the 2-(3-(4-methoxybenzyloxy)oxetan-3-yl)thiazole (Example 11D) (1.8 g, 6.49 mmol) in tetrahydrofuran (11 mL) was added a solution of lithium diisopropylamide (7.79 mmol in 10 mL tetrahydrofuran) dropwise. The solution was stirred at −78° C. for 45 minutes, and tributyltin chloride (2.11 mL, 7.79 mmol) was added dropwise. The cold bath was removed, and the reaction slowly warmed to room temperature. The ambient reaction was then quenched by the addition of saturated aqueous ammonium chloride solution and diethyl ether. The layers were separated, and the aqueous layer was extracted with additional diethyl ether. The combined organics were washed with water, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound, which was used without further purification. MS ESI(+) m/z 568.7 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1.C1C(=O)N([Br:19])C(=O)C1>C(#N)C.O>[Br:19][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[F:1])[O:9][CH2:8][CH2:7][CH2:6]2
Reactant: Fc1ccc2c(c1)OCCC2
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC#N
Product: Fc1cc2c(cc1Br)CCCO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 7-fluorochroman (4.42 g, 29.0 mmol) in acetonitrile (40 mL) at 0° C. was treated with NBS ((5.16 g, 29 mmol)) and the mixture was stirred at ambient temperature for 2 hours. The reaction was diluted with water, stirred for 1 hour and then extracted with ethyl acetate, dried over sodium sulfte and concentrated under reduced pressure give a 6-bromo-7-fluorochroman as the major product in a 3:1 mixture of regioisomers as a colorless oil (4.05 g). This material was used in the next step without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm=7.19 (d, J=7.8 Hz, 1 H), 6.59 (d, J=10.0 Hz, 1 H), 4.19-4.16 (m, 2 H), 2.74 (t, J=6.5 Hz, 2 H), 2.04-1.95 (m, 2 H); LCMS (m/z) ES+=230 (M−1).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C@@H:11]([CH2:12][CH2:13][C:14]3[C:15]4[C@:26]([CH3:34])([CH2:27][CH2:28][C:29]=32)[C@@H:18]([C@H:19]([CH3:25])[CH2:20][CH2:21][C:22]([OH:24])=O)[CH2:17][CH:16]=4)[C:10]1([CH3:36])[CH3:35])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CN1CCOCC1.[NH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>ClCCl>[C:45]1([NH:44][C:22](=[O:24])[CH2:21][CH2:20][C@H:19]([C@@H:18]2[C@:26]3([CH3:34])[C:15]([C:14]4[CH2:13][CH2:12][C@@H:11]5[C@:30]([C:29]=4[CH2:28][CH2:27]3)([CH3:33])[CH2:31][CH2:32][C@H:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2])[C:10]5([CH3:36])[CH3:35])=[CH:16][CH2:17]2)[CH3:25])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: Nc1ccccc1
Reactant: C[C@H](CCC(=O)O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)[C@@H]1CC3
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H](CCC(=O)Nc1ccccc1)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)[C@@H]1CC3
Temperature: -15 °C
Reaction time: 8 h

Procedure:
3β-tert-Butyldimethylsilyloxy-4,4-dimethyl-5α-chola-8,14-dien-24 oic acid (0.50 g) is dissolved in 15 ml of dry dichloromethane. After cooling to −15° C., 0.188 ml of N-methylmorpholine and 0.153 ml of isobutylchloroformiate is added and the mixture is stirred at −15° C. for 20 minutes, whereupon 0.44 ml of aniline is added. The mixture is stirred overnight and the temperature is slowly elevated to room temperature. After aqueous work-up and crystallization from methanol, 3β-tert-butyldimethylsilyloxy-4,4-dimethyl-5α-chola-8,14-dien-24-oic acid-N-phenyl amide (0.431 g) is obtained. H-NMR (CDCl3, 400 MHz): δ=7.53 (2H, d); 7.34 (2H, t); 7.17 (1H, s); 7.12 (1H, t); 5.35 (1H, s); 3.21 (1H, m); 0.9 (9H, s); 0.04 (6H, m).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:14][C:15]2[C:20]([CH3:21])=[C:19]([O:22][CH3:23])[C:18]([CH3:24])=[CH:17][N:16]=2)[CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:5]([N+:25]([O-:27])=[O:26])=[C:4]([CH3:28])[N:3]=1.[NH3:29]>C1COCC1>[NH2:29][C:2]1[N:7]=[C:6]([N:8]([CH2:14][C:15]2[C:20]([CH3:21])=[C:19]([O:22][CH3:23])[C:18]([CH3:24])=[CH:17][N:16]=2)[CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:5]([N+:25]([O-:27])=[O:26])=[C:4]([CH3:28])[N:3]=1
Reactant: COC(=O)CN(Cc1ncc(C)c(OC)c1C)c1nc(Cl)nc(C)c1[N+](=O)[O-]
Reactant: N
Solvent: C1CCOC1
Product: COC(=O)CN(Cc1ncc(C)c(OC)c1C)c1nc(N)nc(C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 2-[(2-chloro-6-methyl-5-nitro-pyrimidin-4-yl)-[(4-methoxy-3,5-dimethyl-pyridin-2-yl)methyl]amino]acetate (Intermediate 28)(465 mg, 1.13 mmol) was stirred in THF (50 mL) and ammonia (28% in water, 10 mL) was added and the mixture stirred at room temperature overnight. The mixtures were concentrated in vacuo and water (200 mL) was added and extracted with DCM (3×100 mL) and concentration in vacuo yielded Intermediate 27 an orange solid (437 mg, 99%); 1H NMR spectrum (400 MHz, DMSO-d6) δ 2.21 (9H, m), 3.63 (3H, d), 3.73 (3H, s), 4.39 (2H, d), 4.98 (2H, d), 7.90 (2H, s), 8.14 (1H, s); Mass spectrum: (M+H)+ 391.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[CH2:23]([N:31]=[C:32]=[O:33])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:32]([NH:31][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:33])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CCCCCCCCN=C=O
Solvent: Cc1ccccc1
Product: CCCCCCCCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Yield: 41 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (51 mg) was dissolved in toluene (5 ml) with heat, octyl isocyanate (0.2 ml) was added, and the admixture was refluxed with heat for 2 hours. The resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 32 mg of the title compound (yield: 41%).
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[CH2:14]([O:16][C:17](=[O:30])[CH2:18][S:19][C:20]1[N:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[N:21]=1)[CH3:15].[CH3:31][C:32]([CH2:34][CH3:35])=[O:33]>CCCCCC.O1CCCC1>[CH2:14]([O:16][C:17](=[O:30])[CH:18]([S:19][C:20]1[N:21]=[C:22]([O:28][CH3:29])[CH:23]=[C:24]([O:26][CH3:27])[N:25]=1)[C:32]([OH:33])([CH3:31])[CH2:34][CH3:35])[CH3:15]
Reactant: CCOC(=O)CSc1nc(OC)cc(OC)n1
Reactant: CCC(C)=O
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C(Sc1nc(OC)cc(OC)n1)C(C)(O)CC
Temperature: -65 °C
Reaction time: 0.33 h

Procedure:
At -50° C., 16.6 ml of a 1.6 molar n-butyllithium solution in hexane are introduced into a prepared mixture of 3.1 g of N,N,N',N'-tetramethylethylenediamine and 25 ml of absolute tetrahydrofuran. 6.2 g of 2-[(4,6-dimethoxy-pyrimidin-2-yl)thio]-acetic acid ethyl ester dissolved in 15 ml of tetrahydrofuran are then added dropwise thereto at a temperature of -65° C. and the mixture is stirred for 20 minutes. 2.4 ml of ethyl methyl ketone are added at a temperature below -60° C. and the reaction mixture is heated to room temperature in the course of 1 hour. Ice-water is then added to the reaction mixture which is then extracted twice with ethyl acetate, washed with saturated sodium chloride solution, dried and concentrated by evaporation. Column chromatography on silica gel, eluant ethyl acetate/hexane 1:4 yields pure 2-[(4,6-dimethoxy-pyrimidin-2-yl)thio]-3-hydroxy-3-methylpentanoic acid ethyl ester in the form of a yellow oil; 1H-NMR(CDCl3): 1.36/1.40, 2s, CH3 ; 3.17/3.31, OH; 3.93, s, OCH3 ; 4.2, m, OCH2CH3 ; 4.79/4.80, 2s, CH; 5.76, s, CH; 70/30 isomeric mixture.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:7][C:6]=2[C:5]([Cl:23])=[CH:4][C:3]=1[CH2:24][OH:25].O[N:27]1[C:31](=[O:32])[C:30]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]2[C:28]1=[O:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:1][C:2]1[C:10]2[O:9][C:8]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[O:7][C:6]=2[C:5]([Cl:23])=[CH:4][C:3]=1[CH2:24][O:25][N:27]1[C:28](=[O:37])[C:29]2=[CH:36][CH:35]=[CH:34][CH:33]=[C:30]2[C:31]1=[O:32]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: OCc1cc(Cl)c2c(c1Cl)OC(c1ccccc1)(c1ccccc1)O2
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OCc1cc(Cl)c2c(c1Cl)OC(c1ccccc1)(c1ccccc1)O2
Yield: 66.2 %

Procedure:
4,7-Dichloro-2,2-diphenyl-1,3-benzodioxol-5-methanol (250 mg) (0.67 mmol), 108 mg (0.67 mmol) of N-hydroxyphthalimide and 175 mg (0.67 mmol) of triphenylphosphine are suspended in 20 ml of absolute tetrahydrofuran. 128 mg (0.73 mmol) of diethyl azodicarboxylate are added dropwise at 0° C. while stirring. The mixture is stirred at 0° C. for 1 hour and at room temperature for 24 hours. Subsequently, the solvent is removed in a high vacuum. The residue is crystallized and recrystallized from ethanol/diethyl ether. There are obtained 230 mg of N-[(4,7-dichloro-2,2-diphenyl-1,3-benzodioxol-5-yl)methoxy]phthalimide as white crystals of m.p. 127°-129° C.
Reaction SMILES: Br[C:2]1[C:3]([F:33])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:19]([OH:31])[C:20]4[N:24]([CH:25]5[CH2:30][CH2:29][CH2:28][CH2:27][O:26]5)[N:23]=[CH:22][CH:21]=4)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:32]=1.[CH3:34][C:35]([OH:39])([CH3:38])[C:36]#[CH:37].C(NC(C)C)(C)C>CN(C=O)C>[F:33][C:3]1[C:2]([C:37]#[C:36][C:35]([OH:39])([CH3:38])[CH3:34])=[CH:32][C:6]2[C:7]3[N:8]([C:13]([CH:19]([OH:31])[C:20]4[N:24]([CH:25]5[CH2:30][CH2:29][CH2:28][CH2:27][O:26]5)[N:23]=[CH:22][CH:21]=4)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=3)[CH:9]3[CH2:12][CH:11]([C:5]=2[CH:4]=1)[CH2:10]3
Reactant: NC(=O)c1nc2n(c1C(O)c1ccnn1C1CCCCO1)C1CC(C1)c1cc(F)c(Br)cc1-2
Reactant: C#CC(C)(C)O
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CC(C)(O)C#Cc1cc2c(cc1F)C1CC(C1)n1c-2nc(C(N)=O)c1C(O)c1ccnn1C1CCCCO1

Procedure:
9-Fluoro-3-(hydroxy(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)methyl)-10-(3-hydroxy-3-methylbut-1-yn-1-yl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was prepared similarly according to General Procedure E with slight modification. 10-bromo-9-fluoro-3-(hydroxy(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was reacted with 3-methyl-1-butyne-3-ol in a solution of DMF (1.3 mL/mmol) and diisopropylamine (2.6 mL/mmol) to afford the title compound which was carried forward to the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][CH2:16][CH2:17][C:18]#[N:19])[C:10]([CH:20]=[O:21])=[CH:9]2.C([O-])([O-])=O.[K+].[K+].S([CH2:43][N+:44]#[C-:45])(C1C=CC(C)=CC=1)(=O)=O>CO>[Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][CH2:16][CH2:17][C:18]#[N:19])[C:10]([C:20]1[O:21][CH:45]=[N:44][CH:43]=1)=[CH:9]2
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: N#CCCCn1c(C=O)cc2cc(OCc3c(Cl)cccc3Cl)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: N#CCCCn1c(-c2cnco2)cc2cc(OCc3c(Cl)cccc3Cl)ccc21
Yield: 94.7 %

Procedure:
A mixture of 4-[5-(2,6-dichlorobenzyloxy)-2-formyl-indol-1-yl]butyronitrile (0.2 g, 0.52 mmol), from Example 9(b), K2CO3 (0.14 g, 1.03 mmol) and tosylmethyl isocyanide (0.11 g, 0.57 mmol) in MeOH (15 mL) was stirred at room temperature for 5 min followed by reflux for 3 h to give a clear yellow solution. The solvent was removed under reduced pressure and the resulting solid was partitioned between chloroform and water. The aqueous layer was washed with chloroform twice and the combined organic layers were washed with water, brine and dried over Na2SO4. After filtration, the yellow filtrate was concentrated to yield the desired oxazol (0.21 g, 95%) as a yellow oil. MS(ES) m/e 426.0 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[S:28])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2Br)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(C(=S)Nc2ccccc2Br)cc1

Procedure:
To a solution of EXAMPLE 1A (15 g) in toluene (55 mL) was added Lawesson's reagent (11.49 g) and the mixture heated at reflux for 4 hours. The mixture was cooled and concentrated and the residue was dissolved in ethyl acetate and washed with 1N hydrochloric acid and brine. The organic layers were concentrated and the crude material was triturated with ethyl acetate and filtered to afford title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=2)[C@H:11]([C:20]([O:22]C)=[O:21])[O:10][C:9]1([CH3:25])[CH3:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>C(O)C.O>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=2)[C@H:11]([C:20]([OH:22])=[O:21])[O:10][C:9]1([CH3:25])[CH3:24])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1c1ccc(I)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@@H](c2ccc(I)cc2)[C@H](C(=O)O)OC1(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 103.1 %

Procedure:
To a solution of 1.3 g of methyl (4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4-(4-iodophenyl)-5-oxazolidinecarboxylate in 25 cm3 of ethanol is added, at a temperature in the region of 25° C., a solution of 0.35 g of lithium hydroxide hydrate in 8 cm3 of distilled water. The reaction medium is stirred for 30 minutes at a temperature in the region of 25° C. and then concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40° C. The evaporation residue is dissolved in 20 cm3 of distilled water and the solution obtained is washed with twice 15 cm3 of diethyl ether, acidified to a pH in the region of 2 by addition of aqueous 1N hydrochloric acid solution and extracted with twice 40 cm3 of ethyl acetate. The organic phases are combined, washed with twice 10 cm3 of distilled water, dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40° C. 1.3 g of (4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4-(4-iodophenyl)-5-oxazolidinecarboxylic acid are thus obtained in the form of a yellow oil.
Reaction SMILES: O.O.[Sn](Cl)Cl.[C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[N+:21]([O-])=O)=[CH:10][CH:9]=1)#[N:7]>Cl.O.C(O)C>[NH2:21][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:15]=1[NH:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]#[N:7])=[CH:9][CH:10]=1
Reactant: N#Cc1ccc(Nc2ccncc2[N+](=O)[O-])cc1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(Nc2ccncc2N)cc1
Temperature: 0 °C
Yield: 88.6 %

Procedure:
According to a modification of the method of Pharm. Helv. Acta, 50, 188 (1975), tin(II) dichloride dihydrate (56.4 g, 250 mmol) was added to a suspension of 4-[N-(4-cyanophenyl)amino]-3-nitropyridine (see part (a)) (12.0 g, 50 mmol) in 2N aqueous hydrochloric acid (35 ml), water (150 ml) and ethanol (75 ml) and the resulting mixture was heated under reflux for 10 minutes under nitrogen. The mixture was cooled in ice, poured into ice-cold 2N aqueous sodium hydroxide (400 ml) and filtered The creamy-coloured solid was washed with 2N aqueous sodium hydroxide and water, and then dried in a vacuum desiccator to provide the title compound, (9.31 g), which gradually turns reddish brown on exposure to light and air.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([I:23])[CH:15]=[C:16]([CH2:21]O)[CH:17]=3)[N:12]([CH3:24])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.N1C(C)=CC(C)=CC=1C.CS([Cl:40])(=O)=O>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([I:23])[CH:15]=[C:16]([CH2:21][Cl:40])[CH:17]=3)[N:12]([CH3:24])[CH:11]=2)=[O:9])=[CH:25][CH:26]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CO)cc(I)c21
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: Cc1cc(C)nc(C)c1
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)cc(I)c21
Temperature: 65 °C
Yield: 93 %

Procedure:
A solution of N-(4-chlorobenzyl)-6-(hydroxymethyl)-8-iodo-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide (4.89 g), DMAP (209 mg) and collidine (1.59 mL) in 173 mL anhydrous DMF is heated to 65° C. to solubilize the starting material. To this solution is added methanesulfonyl chloride (2.77 mL) at room temperature. The reaction is heated at 65° C. for 2 h, then allowed to cool to room temperature. The reaction is poured into H20 (300 mL) to precipitate the product. The solid is filtered and recrystallized from CH2Cl2/hexanes to afford 4.74 g (93%) of the desired product as a white solid.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][CH:27]4[CH2:28][CH2:29][N:30]([C:36](=[O:37])[CH2:35][O:34][CH3:33])[CH2:31][CH2:32]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)NC1CCNCC1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f6) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[CH2:17]([O:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:14][O:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[O:15][CH3:16])[N:3]=[C:2]([NH:29][C:28]1[CH:27]=[CH:26][C:25]([O:24][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:31][CH:30]=1)[N:11]=[C:10]2[NH2:12]
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Product: COc1cc2nc(Nc3ccc(OCc4ccccc4)cc3)nc(N)c2cc1OC
Reaction time: 16 h

Procedure:
2-chloro-6,7-dimethoxy-4-quinazolinamine (1.73 g, 7 mmol) and 4-benzyloxyaniline (2.5 g, 12 mmol) were heated in an s.s. bomb at 145° C. for 16 hrs. Upon cooling the resultant solid was washed well with ether to afford the product. 1H NMR DMSO 3.86 (d, 6H , OCH3), 5.14 (s, 2H, CH2), 6.9-7.5 (m, 11H, ArH)