Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][NH:11][CH2:12][CH2:13][CH:14]=[C:15]2[C:21]3=[CH:22][CH:23]=[CH:24][NH:25][C:20]3=[CH:19][O:18][C:17]3[CH:26]=[CH:27][C:28]([C:30]([OH:33])([CH3:32])[CH3:31])=[CH:29][C:16]2=3)=[CH:4][CH:3]=1.[CH2:34]([N:36](CC)CC)C.Br[CH:42](CBr)[C:43]#N>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:43][CH2:42][N:11]([CH2:12][CH2:13][CH:14]=[C:15]3[C:21]4[CH:22]=[CH:23][CH:24]=[N:25][C:20]=4[CH2:19][O:18][C:17]4[CH:26]=[CH:27][C:28]([C:30]([OH:33])([CH3:31])[CH3:32])=[CH:29][C:16]3=4)[CH2:10][CH:9]2[C:34]#[N:36])=[CH:4][CH:3]=1
Reactant: N#CC(Br)CBr
Reactant: CCN(CC)CC
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCNCCNc1ccc(Cl)cc1)C1=CC=CNC1=CO2
Solvent: Cc1ccccc1
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCN(c3ccc(Cl)cc3)C(C#N)C1)c1cccnc1CO2
Temperature: 110 °C
Reaction time: 18 h

Procedure:
To a solution of 2-(5-{3-[2-(4-chloro-phenylamino)-ethylamino]-propylidene}-5,1-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl)-propan-2-ol (0.4 g, 0.86 mmol) in toluene (6 mL) was added triethylamine (0.48 mL, 3.44 mmol) and 2,3-dibromopropionitrile (0.19 mL, 1.72 mmol) and reaction mixture was heated to 110° C. (reflux) and stirred overnight for 18 h. The reaction mixture was concentrated in vacuo and the residue was diluted with ethyl acetate and extracted with 1.0N NaOH solution. The aqueous layer was back extracted twice with ethyl acetate. The combined organics were dried over sodium sulfate and concentrated. The crude product was purified using a short plug of silica gel using ethyl acetate to give the title compound. 1H-NMR (CDCl3) δ: 1.05 (6H, s), 2.20-2.70 (8H, 2×m), 3.00 (1H, m), 3.10-3.40 (3H, 2×m), 4.50 (1H, br, s), 5.30 (2H, br, s), 6.20 (1H, t), 6.70-6.90 (3H, 2×d), 7.10-7.35 (4H, m), 7.50 (2H, d), 8.50 (1H, dd). ESI-MS m/z: 515 (M+1), UV retention time: 2.36 min.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[O:25][C:26]2[CH:31]=[CH:30][C:29]([C:32](=[O:34])[NH2:33])=[CH:28][N:27]=2)[CH2:16]1)=O)(C)(C)C>ClCCl>[CH2:16]1[C:17]2[C:22](=[C:21]([O:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([NH2:33])=[O:34])=[CH:28][N:27]=3)[CH:20]=[CH:19][CH:18]=2)[CH2:23][CH2:24][NH:15]1
Reactant: CC(C)(C)OC(=O)N1CCc2c(cccc2Oc2ccc(C(N)=O)cn2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1ccc(Oc2cccc3c2CCNC3)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.2 %

Procedure:
Add drop wise via an addition funnel a solution of trifluoroacetic acid (5.7 mL) in dichloromethane (25 mL) to a stirred solution of 5-(5-carbamoyl-pyridin-2-yloxy)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (2.1 g, 5.7 mmol) in dichloromethane (75 mL) at 0° C. Warm to room temperature and stir for 18 hours. Evaporate on a rotary evaporator, dissolve the residue in methanol (50 mL) and dichloromethane (50 mL), and then add MP-carbonate resin (7.9 g @2.87 eq/g). Agitate for 2 hours, filter, concentrate on a rotary evaporator, and dry under vacuum to yield 6-(1,2,3,4-tetrahydro-isoquinolin-5-yloxy)-nicotinamide (1.5 g, 5.6 mmol): HPLC=85% (50/50 to 90/10 ACN/(0.1% TFA in water), Zorbax SB-Phenyl 4.6 mm×15 cm×5 micron, λ=254 nm). 1H NMR (DMSO-d6, 300.00 MHz): 8.55 (d, 1H), 8.23 (dd, 1H), 8.01 (s, 1H), 7.46 (s, 1H), 6.95 (m, 5H), 3.90 (s, 2H), 2.85 (m, 2H), 2.38 (m, 2H).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][OH:3].C([O-])([O-])=O.[K+].[K+].[CH2:13](O)[CH:14]=[CH:15]C>>[C:1]([O:5][CH2:6][CH:13]=[CH:14][CH3:15])(=[O:4])[CH2:2][OH:3]
Reactant: COC(=O)CO
Reactant: CC=CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC=CCOC(=O)CO

Procedure:
Methyl glycolate (10.4 g, 114 mmol), crotyl alcohol (100 ml, excess), was refluxed in the presence of K2CO3 (0.8 g) for 1 hr, during which time about 10 ml of the condensate was removed through a Dean-Stock trap. After diluting with hexane (100 ml), the solid was filtered through a short silica gel column (50 g), washed with 1:5 ethylacetate:hexane (250 ml). The combined filtrate and washings was concentrated to 100 ml, and was diluted again with hexane (100 ml), passed through silica gel column and washed. The solution was concentrated to ˜12.5 g of oil, which was vacuum distilled to give crotyl glycolate: 9.3 g (97° C./20 mmHg) as a mixture of cis:trans (1:10). NMR (500 MHz, CDCl3) δ: 1.3 (m, 3H), 4.15 (s, 2H), 4.62 (d, 2H), 5.6 (m, 1H), 5.84 (m, 1H). cis isomer: 1.71 (m, 3H), the rest peaks overlaps with trans isomer.
Reaction SMILES: [F:1][C:2]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([N:16]2[CH2:19][CH:18]([NH:20]C(=O)OC(C)(C)C)[CH2:17]2)(=[O:15])=[O:14])[CH:9]=[C:8]([O:28][CH3:29])[N:7]=1.C(O)(C(F)(F)F)=O>CO>[NH2:20][CH:18]1[CH2:19][N:16]([S:13]([NH:12][C:10]2[CH:9]=[C:8]([O:28][CH3:29])[N:7]=[C:6]([S:5][CH2:4][C:3]3[CH:30]=[CH:31][CH:32]=[C:33]([F:34])[C:2]=3[F:1])[N:11]=2)(=[O:14])=[O:15])[CH2:17]1
Reactant: COc1cc(NS(=O)(=O)N2CC(NC(=O)OC(C)(C)C)C2)nc(SCc2cccc(F)c2F)n1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1cc(NS(=O)(=O)N2CC(N)C2)nc(SCc2cccc(F)c2F)n1
Reaction time: 2 h

Procedure:
A solution of tert-butyl {1-[({2-[(2,3-difluorobenzyl)thio]-6-methoxypyrimidin-4-yl}amino)sulfonyl]azetidin-3-yl}carbamate (the product of step ii, 0.48 g) and TFA (2 ml) in methanol (6 ml) was stirred at room temperature for 1.5 h then the volatiles evaporated and 7M ammonia in methanol (6 ml) added to the residue. The solution was stirred for 2 h then the volatiles evaporated and the residue purified by column chromatography on silica using a 2-8% mixture of methanol in DCM and then further purified by reverse phase HPLC (gradient 5-95% acetonitrile in 0.1% aqueous ammonium acetate) to afford the title compound as a white solid. Yield: 73 mg
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[N:7][O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH2:3][CH2:2]1.Cl[C:22]1[N:27]=[CH:26][C:25]([CH:28]=[O:29])=[CH:24][C:23]=1[F:30].C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>CS(C)=O>[CH:18]([O:17][C:15]([N:12]1[CH2:11][CH2:10][CH:9]([O:8][N:7]=[C:4]2[CH2:3][CH2:2][N:1]([C:22]3[C:23]([F:30])=[CH:24][C:25]([CH:28]=[O:29])=[CH:26][N:27]=3)[CH2:6][CH2:5]2)[CH2:14][CH2:13]1)=[O:16])([CH3:20])[CH3:19]
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCNCC2)CC1
Reactant: O=Cc1cnc(Cl)c(F)c1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)OC(=O)N1CCC(ON=C2CCN(c3ncc(C=O)cc3F)CC2)CC1
Temperature: 60 °C

Procedure:
2d (0.45 g, 1.6 mmol), 6-chloro-5-fluoro-pyridine-3-carbaldehyde 53a (0.6 g, 3.76 mmol) and diisopropylethylamine (0.75 mL, 4.5 mmol) were combined in 5 mL of DMSO and heated at 60° C. for 18 h. The mixture was poured into ethyl acetate (30 mL), washed with water (2×20 mL) and brine (2×20 mL) and concentrated to give the crude 53b.
Reaction SMILES: [C:1]([C:3]1[O:4][C:5]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:6]=2[CH:7]=1)#[CH:2].C#CCCCCCC.[C:22]([O:26][C:27](=[O:46])[NH:28][C:29]1([C:37]#[C:38][C:39]2[CH:44]=[CH:43][C:42](I)=[CH:41][CH:40]=2)[CH2:34][O:33][C:32]([CH3:36])([CH3:35])[O:31][CH2:30]1)([CH3:25])([CH3:24])[CH3:23].IC1C=C2C(=CC=1)CN(C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C2>>[CH3:13][O:12][C:10]1[CH:9]=[CH:8][C:6]2[CH:7]=[C:3]([C:1]#[C:2][C:42]3[CH:43]=[CH:44][C:39]([C:38]#[C:37][C:29]4([NH:28][C:27](=[O:46])[O:26][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:34][O:33][C:32]([CH3:36])([CH3:35])[O:31][CH2:30]4)=[CH:40][CH:41]=3)[O:4][C:5]=2[CH:11]=1
Reactant: CC(C)(C)OC(=O)NC1(C#Cc2ccc(I)cc2)COC(C)(C)OC1
Reactant: C#Cc1cc2ccc(OC)cc2o1
Agent: C#CCCCCCC
Agent: Ic1ccc2c(c1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Product: COc1ccc2cc(C#Cc3ccc(C#CC4(NC(=O)OC(C)(C)C)COC(C)(C)OC4)cc3)oc2c1
Yield: 90 %

Procedure:
When the product of Step D was substituted for 1-octyne and tert-butyl-5-((4-iodophenyl)ethynyl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate was substituted for 5-iodo-2-tritylisoindoline in Example 2, Step D, the similar process afforded the title compound in 90% yield, as a light yellow paste. 1H-NMR (CDCl3) 1.44 (s, 3H); 1.47 (s, 9H); 1.49 (s, 3H); 3.85 (s, 3H); 4.02 (d, 2H, J=11.34 Hz); 4.09 (d, 2H, J=11.38 Hz); 5.20 (s, 1H); 6.88 (dd, 1H, J=2.24, 8.6 Hz); 6.93 (s, 1H); 6.96 (d, 1H, J=1.97 Hz); 7.38-7.41 (m, 3H); 7.46 (d, 2H, J=8.44 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([C:6]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[O:18]1[CH2:20][C@H:19]1[CH2:21][O:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[CH:26][NH:27]2>CO.CS(C)=O>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([C:6]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:20][C@H:19]([OH:18])[CH2:21][O:22][C:23]4[CH:31]=[CH:30][CH:29]=[C:28]5[C:24]=4[CH:25]=[CH:26][NH:27]5)[CH2:14][CH2:13]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(C3CCNCC3)c[nH]c2c1Cl
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Solvent: CO
Solvent: CS(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(c2c[nH]c3c(Cl)c(Cl)ccc23)CC1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 193 from 6,7-dichloro-3-(piperidin-4-yl)-1H-indole (0.80 g, 3.0 mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.58 g, 3.1 mmol). The product was isolated as a white solid. Yield 0.64 g (47%). mp 192°-197° C. FDMS m/e=457 (M+ of free base). α[D]589 =+6.46 (c=0.99, methanol/dimethylsulfoxide).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([CH:23]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([N:14]=[C:15]([NH:17][C:18]([CH:20]3[CH2:22][CH2:21]3)=[O:19])[N:16]=2)[CH:13]=1.[CH3:25][N:26]1[C:30]([C:31](Cl)=[O:32])=[CH:29][C:28]([CH3:34])=[N:27]1>CN(C)C(=O)C>[CH:20]1([C:18]([NH:17][C:15]2[N:16]=[C:11]3[CH:10]=[CH:9][C:8]([O:7][C:6]4[CH:23]=[C:2]([NH:1][C:31]([C:30]5[N:26]([CH3:25])[N:27]=[C:28]([CH3:34])[CH:29]=5)=[O:32])[CH:3]=[CH:4][C:5]=4[CH3:24])=[CH:13][N:12]3[N:14]=2)=[O:19])[CH2:22][CH2:21]1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Reactant: Cc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)nn2c1
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(=O)Nc2ccc(C)c(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)c2)n(C)n1
Yield: 91.2 %

Procedure:
In the same manner as in Example 24 and using N-[6-(5-amino-2-methylphenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (265 mg, 0.820 mmol), 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (260 mg, 1.64 mmol) and N,N-dimethylacetamide (5 mL) as starting materials, the title compound (333 mg, 91%) was obtained as a white solid.
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:40])/[C:17](/[CH3:39])=[CH:18]/[CH:19]=[C:20](\[CH3:38])/[C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@@H:24]1[C:28]([O:30]CC1C=CC=CC=1)=[O:29])=[O:22])=[O:10])C1C=CC=CC=1.[H][H]>O1CCOCC1.[Pt](=O)=O>[C:28]([C@H:24]1[CH2:25][CH2:26][CH2:27][N:23]1[C:21](=[O:22])[CH:20]([CH3:38])[CH2:19][CH2:18][CH:17]([CH3:39])[C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@@H:11]1[C:9]([OH:10])=[O:8])=[O:40])([OH:30])=[O:29]
Reactant: C/C(=C\C=C(/C)C(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1)C(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: C1COCCO1
Product: CC(CCC(C)C(=O)N1CCC[C@@H]1C(=O)O)C(=O)N1CCC[C@@H]1C(=O)O
Yield: 99.6 %

Procedure:
A solution of 593 mg (1.09 mmol) (2E,4E)-(R)-1-[6-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-2,5-dimethyl-6-oxo-hexa-2,4-dienoyl]-pyrrolidine-2-carboxylic acid benzyl ester in 15 ml dioxane was stirred with 25 mg (0.11 mmol) platinum (IV) oxide under 1 atm of hydrogen for 72 h at room temperature. After filtration to remove the catalyst, the reaction mixture was concentrated in vacuo and azeotroped three times with chloroform on a rotary evaporator to remove last traces of dioxane, then triturated in ether to afford 400 mg (100%) of the title compound as a white foam. MS m/e (%): 369 (M+H+, 100).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[C:4]([SH:9])[N:3]=1.C(O)(=O)C.[OH:14][C:15]1[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:16]=1[CH:17]=O.O>CN(C=O)C>[OH:14][C:15]1[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:16]=1[CH:17]=[C:7]1[C:6](=[O:8])[NH:5][C:4](=[S:9])[NH:3][C:2]1=[O:1]
Reactant: O=Cc1ccc(O)cc1O
Reactant: Oc1cc(O)nc(S)n1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: O=C1NC(=S)NC(=O)C1=Cc1ccc(O)cc1O
Temperature: 80 °C
Reaction time: 0.02 h

Procedure:
To a solution of 0.144 9 (1 mmol) of 4,6-dihydroxy-2-mercaptopyrimidine and 2 ml of acetic acid in 2 ml of DMF was added a solution of 2,4-dihydroxybenzaldehyde (1 mmol) in 2 ml of DMF. The suspension was heated to 80° C. under nitrogen for 16 hours. Upon cooling to room temperature, the reaction was poured into water and the precipitate collected by filtration. The crude product was washed with water, and the solid boiled in methanol for 1 minute. Filtration provided 2.6 mg of product.
Reaction SMILES: [CH3:1][C:2]1(O)[CH2:7][CH2:6][C@H:5]([CH:8]=[CH:9][C:10](=[CH2:12])[CH3:11])[CH:4]=[CH:3]1.[CH3:14][C:15]1[CH:16]=[C:17]([OH:22])[CH:18]=[C:19]([CH:21]=1)[OH:20].O.O.C(O)(=O)C(O)=O>C1(C)C=CC=CC=1.C(OCC)C>[CH3:14][C:15]1[C:16]([CH:4]2[CH:5]([CH:8]=[CH:9][C:10](=[CH2:11])[CH3:12])[CH2:6][CH2:7][C:2]([CH3:1])=[CH:3]2)=[C:17]([OH:22])[CH:18]=[C:19]([OH:20])[CH:21]=1
Reactant: Cc1cc(O)cc(O)c1
Reactant: C=C(C)C=C[C@@H]1C=CC(C)(O)CC1
Agent: O=C(O)C(=O)O
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOCC
Product: C=C(C)C=CC1CCC(C)=CC1c1c(C)cc(O)cc1O
Reaction time: 5 h
Yield: 140.7 %

Procedure:
(4R)-1-Methyl-4-isoprenylcyclohex-2-ene-1-ol (300 mg, 2 mmoles) was dissolved in toluene (20 ml) and 5-methylresorcinol (248 mg, 2 mmoles) was added in diethyl ether (5 ml). Oxalic acid dihydrate (252 mg, 2 mmoles) was added and the reaction mixture heated with stirring at 80° for 5 hours. The reaction mixture was allowed to cool and diluted with diethyl ether (30 ml). The ether solution was washed twice with aqueous sodium bicarbonate and dried over anhydrous magnesium sulphate. The solvents were evaporated under reduced pressure to give the crude product as a brown oil (800 mg). The product was purified using a silica column eluted with ethyl acetate:isohexane 1:9 going to ethyl acetate:isohexane 2:8.
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21]([N:23]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][C:35]([O:38]C)=[C:34]([Br:40])[CH:33]=3)=[CH:28][CH:27]=2)[CH3:24])=[O:22])=[CH:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)=O.CC(C)=O.O>C(Cl)Cl>[CH2:5]([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21]([N:23]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([Br:40])[CH:33]=3)=[CH:28][CH:27]=2)[CH3:24])=[O:22])=[CH:13]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COc1ccc(-c2ccc(CN(C)C(=O)c3cn(Cc4ccccc4)c4ccccc34)cc2)cc1Br
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: O
Product: CN(Cc1ccc(-c2ccc(O)c(Br)c2)cc1)C(=O)c1cn(Cc2ccccc2)c2ccccc12
Reaction time: 3.5 h
Yield: 98.3 %

Procedure:
Boron tribromide (41.4 mL of a 1 M solution in methylene chloride; 41.4 mmol) was added under nitrogen dropwise over 30 minutes to a solution of 1-benzyl-N-[(3′-bromo-4′-methoxy-1,1′-biphenyl-4-yl)methyl]-N-methyl-1H-indole-3-carboxamide (7.46 g, 13.8 mmol), prepared in the previous step, in 200 mL of methylene chloride at dry ice-acetone temperature. After the addition the dry ice-acetone bath was replaced with an ice bath and the stirring was continued for 3.5 h. At ice bath temperature 50 mL of water was added dropwise. The reaction was then partitioned between additional amounts of methylene chloride and water. The aqueous layer was separated and extracted three times with methylene chloride. The combined extracts were dried (MgSO4) and the solvent removed under reduced pressure to give 1-benzyl-N-[(3′-bromo-4′-hydroxy-1,1′-biphenyl-4-yl)methyl]-N-methyl-1H-indole-3-carboxamide (7.13 g, 98%) as a light tan solid, mp 164-170° C. Elemental Analysis for C30H25BrN2O2 Calc'd: C, 68.58; H, 4.80; N, 5.33. Found: C, 67.27; H, 4.78; N, 5.19
Reaction SMILES: [OH:1][C:2]1[C:12]2[NH:11][CH:10](OC)[CH:9]3[CH2:15][CH2:16][CH2:17][N:8]3[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:19]>C(#N)C>[OH:1][C:2]1[C:12]2[N:11]=[CH:10][CH:9]3[CH2:15][CH2:16][CH2:17][N:8]3[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:19]
Reactant: COC1Nc2c(ccc(C)c2O)C(=O)N2CCCC12
Solvent: CC#N
Product: Cc1ccc2c(c1O)N=CC1CCCN1C2=O
Yield: 80 %

Procedure:
90.4 mg of 2,3,5,10,11,11 a-hexahydro-9-hydroxy-11-methoxy-8-methyl-1H-pyrrolo[2,1-C][1,4]benzodiazepin-5-one was dissolved in 15 ml of acetonitrile at an elevated temperature. After dissolution, the solution was concentrated first at ordinary pressure and then under a reduced pressure. The concentrate was dissolved in 1.5 ml of hot benzene, and then 25 ml of n-hexane was added thereto, and the separated precipitate was collected by filtration. This procedure was repeated 2 to 3 times, and there was obtained 63.5 mg of 2,3,5,11 a-tetrahydro-9-hydroxy-8-methyl-1H-pyrrolo[2,1-C][1,4]benzodiazepin-5-one as a light yellow powdery product. It had a melting point of 147.5° to 150° C.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])(=[O:15])=[O:14])=[CH:9][CH:8]=1.[C:25](Cl)(=[O:29])[CH2:26][CH2:27][CH3:28].Cl>O1CCCC1.CCCCCC>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH:16]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[C:25](=[O:29])[CH2:26][CH2:27][CH3:28])(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: CCCC(=O)Cl
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC(=O)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In an argon gas stream and at −78° C., n-butyl lithium (a 1.57M hexane solution, 1.27 ml, 2.00 mmol) was added to a tetrahydrofuran (10 ml) solution of the 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (606 mg, 2.00 mmol) obtained in Example 5. The temperature of the resulting mixture was then raised to room temperature. After cooling to −78° C., butyryl chloride (0.218 ml, 2.10 mmol) was added dropwise to the reaction mixture. The reaction mixture was stirred at −78° C. for 1.5 hours, and added with 1N hydrochloric acid (2.0 ml). The temperature of the mixture was then raised to room temperature. The reaction mixture was extracted with diethyl ether. The extracts were combined, washed successively with water and brine, dried over MgSO4, and concentrated. The residue thus obtained was purified by medium-pressure chromatography on a silica gel column (10% ethyl acetate-hexane). The solid thus obtained was recrystallized from hexane, whereby the title compound (330 mg, 44%) was obtained as colorless needle crystals.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:10][N:9]=[C:8]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([O:20][CH3:21])[CH:14]=2)[CH:7]=1)=[O:5])C.[OH-].[K+].Cl>CCO.O>[CH3:21][O:20][C:15]1[CH:14]=[C:13]([CH:12]=[CH:11][C:8]2[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[NH:10][N:9]=2)[CH:18]=[CH:17][C:16]=1[OH:19]
Reactant: CCOC(=O)c1cc(C=Cc2ccc(O)c(OC)c2)n[nH]1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(C=Cc2cc(C(=O)O)[nH]n2)ccc1O
Temperature: 25 °C
Yield: 67.8 %

Procedure:
Ethyl-3-[β-(3-methoxy-4-hydroxyphenyl)ethenyl]-1H-pyrazole-5-carboxylate 0.49 g, 1.7 mmoles) is added to a solution of KOH (0.38 g, 6.8 mmoles) in 50 ml EtOH. The reaction is warmed to reflux overnight. After cooling to room temperature, the reaction is diluted to 200 ml with H2O, and acidified to pH=4 with HCl. A white precipitate forms, and it is collected by filtration. Drying in vacuum in the presence of P2O5 gives 0.3 g (68%) of the desired product, mp=270°-271° C. (dec).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].[F:20][CH:21]([F:30])[C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[F:29])[NH2:25].Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[F:30][CH:21]([F:20])[C:22]1[CH:23]=[C:24]([NH:25][C:16](=[O:18])[CH2:15][C:3]2[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([N:9]3[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)[N:4]=2)[CH:26]=[CH:27][C:28]=1[F:29]
Reactant: Nc1ccc(F)c(C(F)F)c1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cn1c(CC(=O)Nc2ccc(F)c(C(F)F)c2)nc(N2CCOCC2)cc1=O
Yield: 24.7 %

Procedure:
The product is prepared according to the procedure described in example 5, but using 275 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 1 of example 68, 322 mg of 3-(difluoromethyl)-4-fluoroaniline (example 76, stage 2), and 250 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.16 ml of pyridine and 4 ml of N,N-dimethylformamide. 98 mg of N-[3-(difluoromethyl)-4-fluorophenyl]-2-[1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:13]([C:14](O)=[O:15])=[CH:12][N:11]=[C:10]3[NH:17][CH:18]=[CH:19][C:9]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O[N:21]1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[Cl-].[NH4+]>CN(C)C=O.C(Cl)(Cl)Cl.O>[CH:1]1([NH:7][C:8]2[C:13]([C:14]([NH2:21])=[O:15])=[CH:12][N:11]=[C:10]3[NH:17][CH:18]=[CH:19][C:9]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cnc2[nH]ccc2c1NC1CCCCC1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: NC(=O)c1cnc2[nH]ccc2c1NC1CCCCC1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 60.2 %

Procedure:
To a solution of 4-(cyclohexylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (5.0 mg) in N,N-dimethylformamide (0.1 mL) were added 1-hydroxybenzotriazole (3.9 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (4.5 mg). The mixture was stirred at 60° C. for 30 minutes. To the solution was added ammonium chloride and the mixture was stirred at ambient temperature for 18 hours. To the solution were added water and chloroform and the mixture was extracted with chloroform. The extract was dried over MgSO4, filtrated and evaporated in vacuo. The residue was purified by column chromatography on silica gel with chloroform and methanol (100:0 to 90:10) to give 4-(cyclohexylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (3 mg) as a white powder.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[CH:10]=[C:11]1[CH2:14][CH:13]([C:15]([OH:17])=O)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[CH3:35][O:36][NH:37][CH3:38]>C(Cl)Cl>[CH3:35][O:36][N:37]([CH3:38])[C:15]([CH:13]1[CH2:12][C:11](=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:18])[CH2:14]1)=[O:17]
Reactant: CNOC
Reactant: O=C(C=C1CC(C(=O)O)C1)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)C1CC(=CC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 65.6 %

Procedure:
To an ice cold solution of 3-[2-(benzyloxy)-2-oxoethylidene]cyclobutane-1-carboxylic acid (2.0 g, 8.12 mmol), N-Methyl-morpholine (2.70 ml, 24.36 mmol) in DCM (50 ml) was added isobutyl chloroformate (1.70 ml, 12.99 mmol) drop-wise over 5 min. After an additional 5 min, methoxy(methyl)amine hydrochloride (1.58 g, 16.24 mmol) was added and the mixture was stirred overnight whilst allowing to warm to RT. The reaction mixture was then diluted with DCM (30 ml), washed with 0.1N HCl (50 ml) then sat. NaHCO3 (50 ml), dried over Na2SO4, filtered and evaporated. Purification by silica gel column chromatography, eluting with EtOAc:heptanes from 1:9 to 3:7 gave the desired product (1.54 g, 65%); MS (ESI+) for C16H19NO4 m/z 290.10 [M+H]+; HPLC purity 100% (ret. time, 1.86 min); 1H NMR (500 MHz, CHLOROFORM-d) δH ppm 2.96 (1 H, ddd, J=16.98, 8.79, 1.81 Hz), 3.17-3.30 (4 H, m), 3.30-3.48 (2 H, m), 3.51-3.63 (1 H, m), 3.64-3.75 (3 H, m), 5.15 (2 H, s), 5.73 (1 H, quirt, J=2.25 Hz), 7.29-7.42 (5 H, m).