Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:9]1[CH2:18][CH2:17][C@H:16]2[C@@H:11]([CH2:12][CH2:13][C:14]([OH:33])([C:19]3[CH:24]=[CH:23][C:22]([O:25][Si](C(C)(C)C)(C)C)=[CH:21][CH:20]=3)[CH2:15]2)[CH2:10]1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>C1COCC1>[CH2:1]([N:9]1[CH2:18][CH2:17][C@H:16]2[C@@H:11]([CH2:12][CH2:13][C:14]([OH:33])([C:19]3[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=3)[CH2:15]2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C2(O)CC[C@H]3CN(C(=O)c4ccccc4)CC[C@@H]3C2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Oc1ccc(C2(O)CC[C@H]3CN(Cc4ccccc4)CC[C@@H]3C2)cc1
Temperature: 25 °C

Procedure:
A mixture of trans-2-benzoyl-6-hydroxy-6-(4'-t-butyldimethylsilyloxyphenyl)decahydroisoquinoline (Example 48, 740 mg, 1.61 mmol) and lithium aluminum hydride (0.31 g, 8 mmol) in anhydrous THF (20 mL) was stirred at reflux temperature under a nitrogen atmosphere for 19.5 h. The reaction mixture was cooled to room temperature and quenched with excess ethyl acetate, followed by water (0.3 mL), a 1N NaOH solution (0.3 mL) and water (1 mL). The precipitate was filtered through celite; the filtrate was dried over magnesium sulfate and filtered. Removal of solvent in vacuo gave an oil. Column chromatography (ethyl acetate) gave the product, a solid (209 mg): mp 108°-109° C., NMR (CDCl3, 200 MHz): 7.4-7.2 (m, 7H), 6.8 (d, 2H, J=7), 3.55 (s, 2H), 2.95 (br d, 1H, J=8), 2.85 (br d, 1H, J=8), 2.2 (s, 2H), 2.1-1.2 (m, 11H); Anal. Calcd for C22H27NO2.O.3H2O: C, 77.06, H, 8.11, N, 4.09; Found C, 76.82, 76.83, H, 7.95, 8.15, N, 3.88, 3.80.
Reaction SMILES: C(OC([O:9][C:10]([NH:12][CH2:13][CH:14]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:15][C:16]([OH:18])=[O:17])=[O:11])C)(=O)C(C)C.C(=O)([O-])OC1C=C[CH:28]=[C:27]([CH:31]([O:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])C)[C:26]=1[N+]([O-])=O>>[C:34]([O:33][CH:31]([O:11][C:10]([NH:12][CH2:13][CH:14]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:15][C:16]([OH:18])=[O:17])=[O:9])[CH:27]([CH3:26])[CH3:28])(=[O:38])[CH:35]([CH3:36])[CH3:37]
Reactant: CC(C)CC(CNC(=O)OC(C)OC(=O)C(C)C)CC(=O)O
Reactant: CC(C)C(=O)OC(C)c1cccc(OC(=O)[O-])c1[N+](=O)[O-]
Product: CC(C)CC(CNC(=O)OC(OC(=O)C(C)C)C(C)C)CC(=O)O
Yield: 51 %

Procedure:
Following the procedure of preparation for (110), and substituting (114) for (111), provided the title compound as a mixture of two diastereomers in 51% yield. 1H-NMR (CDCl3, 400 MHz): δ 0.89 (m, 12H), 1.17 (m, 8H), 1.65 (m, 1H), 2.02 (m, 1H), 2.16 (m, 1H), 2.33 (m, 2H), 2.56 (m, 1H), 3.13 (m, 1H), 3.30 (m, 1H), 5.00 (m, 1H), 6.57-6.56 (m, 1H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][CH3:22])[CH:18]=4)[N:13](CC4C=CC=CC=4OC)[C:12](=[O:32])[C:11]=3[C:33]([O:35]C)=[O:34])=[CH:9][C:4]=2[O:3][CH2:2]1.[OH-].[K+].O1C2C=CC(C3C4C(=CC=C(OCC)C=4)N([CH2:61][C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=4[O:68][CH3:69])C(=O)C=3C(O)=O)=CC=2OC1>CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][CH3:22])[CH:18]=4)[N:13]=[C:12]([O:32][CH2:61][C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=4[O:68][CH3:69])[C:11]=3[C:33]([OH:35])=[O:34])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCOc1ccc2c(c1)c(-c1ccc3c(c1)OCO3)c(C(=O)O)c(=O)n2Cc1ccccc1OC
Reactant: CCOc1ccc2c(c1)c(-c1ccc3c(c1)OCO3)c(C(=O)OC)c(=O)n2Cc1ccccc1OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCOc1ccc2nc(OCc3ccccc3OC)c(C(=O)O)c(-c3ccc4c(c3)OCO4)c2c1

Procedure:
A solution of 0.5 g of methyl 4-(1,3-benzodioxol-5-yl)-1,2-dihydro-6-ethoxy-1-(2-methoxybenzyl)-2-oxoquinoline-3-carboxylate and 6 ml of 5N KOH in 10 ml of methanol is boiled under reflux for 2 hours. The usual working up results in 4-(1,3-benzodioxol-5-yl)-1,2-dihydro-6-ethoxy-1-(2-methoxybenzyl)-2-oxoquinoline-3-carboxylic acid, m.p. 225°-226°. Analogously, the O-alkylation product 4-(1, 3-benzodioxol-5-yl)-6-ethoxy-2-(2-methoxybenzyloxy)quinoline-3-carboxylic acid is obtained from methyl 4-(1,3-benzodioxol-5-yl)-6-ethoxy-2-(2-methoxybenzyloxy) quinoline-3-carboxylate.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=3[F:31])=[O:19])=[CH:13][CH:12]=2)=[C:5]([C:8]([NH2:10])=[O:9])[NH:6][CH:7]=1.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(N(CC)CC)C>O1CCCC1.ClCCl>[C:32]([NH:2][C:3]1[C:4]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:24]=[CH:23][C:22]=3[F:31])=[O:19])=[CH:13][CH:12]=2)=[C:5]([C:8]([NH2:10])=[O:9])[NH:6][CH:7]=1)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: NC(=O)c1[nH]cc(N)c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)c1[nH]cc(NC(=O)c2ccccc2)c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
To 0.15 g (0.328 mmol) of 4-amino-3-{4-[3-(2-fluoro-5-trifluoromethyl-phenyl)ureido]phenyl}-1H-pyrrole-2-carboxamide hydrochloride dissolved in 4.5 cm3 of tetrahydrofuran are added, at a temperature in the region of 20° C. under an argon atmosphere, 0.038 cm3 of benzoyl chloride and 0.091 cm3 of triethylamine. After stirring for 4 hours at a temperature in the region of 20° C., the reaction mixture is diluted with 15 cm3 of dichloromethane and then washed with twice 10 cm3 of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure (2.7 kPa) to give a solid, which is recrystallized while hot in 5 cm3 of methanol. The recrystallized solid is filtered through a No 3 sinter funnel, washed with twice 2 cm3 of methanol and then dried under reduced pressure (2.7 kPa) at a temperature in the region of 35° C. for 5 hours to give 0.075 g of 4-benzoylamino-3-{4-[3-(2-fluoro-5-trifluoromethylphenyl)-ureido]phenyl}-1H-pyrrole-2-carboxamide in the form of a white solid melting at 239.7° C.; ES+: m/z=526: [M+H]+.
Reaction SMILES: [C:1]1([C@H:7]2[C@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][C:9](=[S:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH3:21]I>CO.O>[CH3:21][S:18][C:9]1[NH:8][C@@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@H:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1
Reactant: CI
Reactant: S=C1N[C@@H](c2ccccc2)[C@H](c2ccccc2)N1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CSC1=N[C@@H](c2ccccc2)[C@H](c2ccccc2)N1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.8 g of trans-4,5-diphenyl-imidazolidine-2-thione are dissolved in 20 ml of methanol, a solution of 0.3 g of sodium hydroxide in 2 ml of water and also 1.2 g of methyl iodide are added and the mixture is stirred at room temperature for 4 hours and left to stand overnight at 0°. The reaction mixture is evaporated to dryness, the residue is shaken with a mixture of 40 ml of water and 40 ml of ethyl acetate, the organic phase is separated off and the aqueous phase is washed with ethyl acetate. The organic phases are dried over sodium sulfate and evaporated to dryness. The crystalline residue is recrystallised, first from methanol and then from a mixture of diethyl ether and petroleum ether. Trans-2-methylthio-4,5-diphenyl-imidazoline with a melting point of 135°-137° is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([CH3:20])[CH:19]=1)[CH2:15]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(OCC)(=O)C>[CH3:11][C:12]1[CH:19]=[C:18]([CH:17]=[C:14]([CH3:15])[CH:13]=1)[CH2:20][S:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: Cc1cc(C)cc(CO)c1
Reactant: O=[N+]([O-])c1ccc(S)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(CSc2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.8 %

Procedure:
To a solution of 4-nitrothiophenol (0.400 g, 2.57 mmol), 3,5-dimethylbenzyl alcohol (0.38 ml, 2.57 mmol) and triphenylphosphine (0.743 g, 2.84 mmol) in 10 ml anhydrous tetrahydrofuran was added diethyl azodicarboxylate (0.446 ml, 2.84 mmol). The reaction mixture was stirred overnight at room temperature under nitrogen. It was then diluted with 90 ml ethyl acetate and the resulting solution was washed sequentially with 70 ml saturated aqueous sodium bicarbonate solution, 70 ml water and 70 ml brine, dried (anhydrous sodium sulfate) and concentrated under reduced pressure. The solid residue was triturated with 95:5 hexane/ethyl acetate (20 ml) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 15 g), eluting with 95:5 hexane/ethyl acetate to yield title compound as a yellow solid (0.35 g, 50% yield). 1H NMR (400 MHz, CD3Cl): δ2.30 (s, 6H), 4.18 (s, 2H), 6.92 (s, 1H), 7.0 (s, 2H), 7.33 (d, 2H), 8.10 (d, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[C:3]=1[CH3:9].C(=O)([O-])[O-].[Na+].[Na+].[I:16]I.S([O-])([O-])=O.[Na+].[Na+].S([O-])([O-])=O>C1COCC1.CO>[NH2:1][C:2]1[CH2:7][CH2:6][CH:5]([I:16])[C:4](=[O:8])[C:3]=1[CH3:9]
Reactant: II
Reactant: CC1=C(N)CCCC1=O
Agent: O=C([O-])[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC1=C(N)CCC(I)C1=O
Temperature: 10 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
50 g (0.4 mol, 1 eq) of 3-amino-2-methyl-2-cyclohexen-1-one and 106 g (1 ml, 2.5 eq) of sodium carbonate are dispensed into the reactor. 480 mL of MeOH is added. The mixture is cooled in an ice bath to 10° C. A solution of iodine in THF, made by dissolving 253 g (1 mol, 2.5 eq) of iodine in 300 ml of THF, is added to above suspension slowly so that the temperature does not exceed 25° C. The resulting dark suspension is stirred for ˜1 h at room temperature and HPLC shows the ending point of reaction (product area percentage at 265 nm was larger than 70%). To the reaction mixture in the ice bath, is added an aqueous saturated solution of sodium sulfite slowly, until the peroxide level is below 3 ppm (by peroxide test strips), and at same time, the sulfite level is below 50 ppm (by sulfite test strips). Approximately 1.5 q of sodium sulfite is used. The suspension is filtered through a celite pad and the pad is washed with 150 mL×3 of THF (washings not optimized). The combined filtrate and washes are concentrated under vacuum until solid crashes out. 250 mL of MTBE is added and the two layer mixture is concentrated again under vacuum until all upper layer evaporates. 250 mL of MTBE and 100 mL of H2O are added and the mixture is stirred at room temperature for 30 minutes. A dark yellow solid crashes out upon stirring and is filtered and washed with water to give 3-amino-6-iodo-2-methyl-2-cyclohexen-1-one 65 g (65% yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[NH2:26][C:27]1[CH:32]=[N:31][C:30](Br)=[CH:29][N:28]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:30]3[N:31]=[CH:32][C:27]([NH2:26])=[N:28][CH:29]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Nc1cnc(Br)cn1
Product: Nc1cnc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cn1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (178 mg, 0.5 mmol) and commercially available 2-amino-5-bromo-pyrazine (87 mg, 0.5 mmol) according to general procedure II. Obtained as an orange solid (63 mg, 28%). MS (EI) 448.0 [(M)+]; mp 200° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=3[F:17])[C:6]=2[CH:18]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:30](B(O)O)=[CH:29][CH:28]=[N:27]2)=[CH:22][CH:21]=1>>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([N:7]2[C:6]3[CH:18]=[C:2]([C:30]4[N:26]([C:23]5[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=5)[N:27]=[CH:28][CH:29]=4)[CH:3]=[CH:4][C:5]=3[N:9]=[CH:8]2)=[C:11]([F:17])[CH:12]=1
Reactant: Fc1cc(Cl)ccc1-n1cnc2ccc(Br)cc21
Reactant: OB(O)c1ccnn1-c1ccc(Cl)cc1
Product: Fc1cc(Cl)ccc1-n1cnc2ccc(-c3ccnn3-c3ccc(Cl)cc3)cc21

Procedure:
The title compound, white solid (23 mg, 18%), MS (ISP) m/z=423.4 [(M+H)+], mp 158° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-(4-chloro-2-fluoro-phenyl)-1H-benzo[d]imidazole (intermediate M) (100 mg, 307 μmol) and 1-(4-chloro-phenyl)-1H-pyrazol-5-ylboronic acid (intermediate D) (82.1 mg, 369 μmol).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:12][CH3:13])[CH:8]=[C:9](I)[CH:10]=1)=[O:5])[CH3:2].CCN(CC)CC.[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1)#[CH:22]>C(#N)C.[Cu]I>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:12][CH3:13])[CH:8]=[C:9]([C:22]#[C:21][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(I)cn1CC
Reactant: C#Cc1cccc(OC)c1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1cc(C#Cc2cccc(OC)c2)cn1CC
Temperature: 25 °C
Yield: 86.5 %

Procedure:
Argon was gently bubbled to a mixture of ethyl-4-iodo-1H-pyrrole-2-carboxylic acid ethyl ester (4.1 g, 14 mmol), CuI (0.14 g, 0.76 mmol), Et3N (40 ml, 287 mmol) and tetrakis(triphenylphosphosphine)palladium (0) (0.64 g, 0.554 mmol) in ACN (20 mL) over 5 minutes. A prepared solution of 1-ethynyl-3-methoxy-benzene (2.03 g, 15.4 mmol) in ACN (5 mL) was added into it and the new mixture was reflux under Nitrogen for 3 hours. The resulting brown colored reaction mixture was cooled to room temperature and concentrated in vacuo. The concentrate was diluted with water and extracted with ether. The combined ether extracts were washed with saturated aqueous solution of NH4Cl, brine, dried (MgSO4) and filtered. Evaporation and purification by flash chromatography on silica gel (Hexane/EtOAc 9.7/0.3) gave the title compound as a yellow brownish oil (3.6 g, 84% yield), 1H NMR (400 MHZ, CDCl3) δ 1.31-1.34 (t, 3H), 1.38-1.40 (t, 3H), 3.78 (s, 3H), 4.25-4.27 (q, 2H), 4.30-4.33 (q, 2H), 6.83 (m, 1H), 6.89 (m, 1H), 7.06 (m, 3H), 7.19 (m, 1H), MS m/e (M+H)+ 298.1.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH2:29]([O:31][CH2:32][CH2:33][CH2:34][NH2:35])[CH3:30].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:29]([O:31][CH2:32][CH2:33][CH2:34][NH:35][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:26])([F:27])[F:28])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:13])[CH3:30]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CCOCCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOCCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 80.3 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (3-ethoxy-propyl)-amide (97 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100 mg), 3-ethoxy-propylamine (28 mg), HBTU (111 mg), and DIEA (64 uL). LC/MS: m/z 494.9. 1H NMR (DMSO-d6, 400 MHz): δ 12.36 (bs, 1H), 8.41 (s, 1H), 8.06 (s, 1H), 7.89 (s, 1H), 7.78-7.64 (m, 2H), 7.46 (d, 1H), 7.34 (d, 1H), 3.62 (bs, 3H), 3.45-3.37 (m, 4H), 3.36-3.31 (m, 2H), 1.83-1.70 (m, 2H), 1.10 (t, 3H).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[C:12](=[O:13])[CH:11]([CH3:14])[C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[C:8]2[C:19]([NH2:23])=[CH:20][CH:21]=[CH:22][C:7]1=2)=[O:5])[CH3:3].N1C=CC=CC=1.[CH2:30]([S:34](Cl)(=[O:36])=[O:35])[CH2:31][CH2:32][CH3:33]>CN(C=O)C>[CH2:30]([S:34]([NH:1][C@H:2]([C:4]([N:6]1[C:12](=[O:13])[CH:11]([CH3:14])[C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[C:8]2[C:19]([NH2:23])=[CH:20][CH:21]=[CH:22][C:7]1=2)=[O:5])[CH3:3])(=[O:36])=[O:35])[CH2:31][CH2:32][CH3:33]
Reactant: CCCCS(=O)(=O)Cl
Reactant: CC1C(=O)N(C(=O)[C@H](C)N)c2cccc(N)c2-c2ccccc21
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCCCS(=O)(=O)N[C@@H](C)C(=O)N1C(=O)C(C)c2ccccc2-c2c(N)cccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 342.7 %

Procedure:
To 5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 7B) (0.1500 g, 0.0485 mmol) in DMF (4 ml) were added pyridine (0.059 ml, 0.728 mmol) and 1-butanesulfonyl chloride (Aldrich) (0.063 ml, 0.485 mmol), stirred at RT overnight. The reaction mixture was evaporated to dryness. Water was added, extracted with EtOAc, washed with brine, dried over MgSO4. Evaporation and flash chromatography (silica, 5% MeOH/CH2Cl2), gave the title compound (0.0714 g, 34%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-])=O)=[C:9]([CH:13]=1)[C:10]([NH2:12])=[O:11])=[O:4]>CO.[Pd]>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:9]([C:10]([NH2:12])=[O:11])[C:8]([NH2:14])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(C(N)=O)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(N)c(C(N)=O)c1
Reaction time: 6 h

Procedure:
5-Methoxycarbonyl-2-nitrobenzamide (28 g.) was dissolved in methanol (600 ml.), 10% palladium-on-charcoal catalyst (3 g.) was added, and the mixture was hydrogenated for 6 hours at about 35° C. The catalyst was filtered off, extracted with methanol (350 ml.) at reflux temperature under an atmosphere of nitrogen for 20 minutes, and filtered again. Both filtrates were evaporated to dryness, and the combined residues were crystallised from water (3 l.) to give 5-methoxycarbonylanthranilamide, m.p. 188°-193° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][O:5][C:6]1[C:7]2[C:18]([C:19](=[O:23])[C:20]([NH2:22])=[O:21])=[C:17]([CH2:24][CH3:25])[N:16]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:8]=2[N:9]=[C:10](S(C)(=O)=O)[N:11]=1.[O:34]1CCC[CH2:35]1>CO.C[O-].[Na+]>[CH3:1][O:2][C:3](=[O:33])[CH2:4][O:5][C:6]1[C:7]2[C:18]([C:19](=[O:23])[C:20]([NH2:22])=[O:21])=[C:17]([CH2:24][CH3:25])[N:16]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:8]=2[N:9]=[C:10]([O:34][CH3:35])[N:11]=1
Reactant: C1CCOC1
Reactant: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)OC)nc(S(C)(=O)=O)nc2n1Cc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)OC)nc(OC)nc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 150 mg (0.316 mmol) of [[2-(methylsulfonyl)-5-(aminooxoacetyl)-6-ethyl-7-(phenylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy] acetic acid methyl ester in 3 mL of tetrahydrofuran and 0.5 mL of methanol was added 4 drops of 28% sodium methoxide in methanol solution. The reaction was stirred at ambient temperature for 3 hours. The reaction was quenched by the addition of 3 mL of saturated sodium bicarbonate solution and the phases separated. The organic phase was dried with sodium sulfate and concentrated to a yellow solid. The solid was purified by flash chromatography (5.0 g silica, ethyl acetate) to provide 41 mg of [[2-methoxy-5-(aminooxoacetyl)-6-ethyl-7-(phenylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester as an off white solid. nmr (500 MHz, CDCl3) δ1.11 (t, J=7.5 Hz, 3H), 2.90 (q, J=7.5 Hz, 2H), 3.77 (s, 3H), 3.96 (s, 3H), 5.04 (s, 2H), 5.43 (s, 2H), 5.74 (s, 1H), 6.58 (s, 1H), 7.16 (d, J=7.0 Hz, 2H), 7.29 (m, 3H)
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[CH:16][NH:17]2)=[CH:13][CH:12]=1)=O.O.Cl>[Na].O1CCCC1>[OH:8][CH2:9][C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[CH:16][NH:17]2)=[CH:13][CH:12]=1
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc2cc[nH]c2c1

Procedure:
Lithium aluminium hydride (3.48 g, 91.70 mmol) was suspended in sodium-dried tetrahydrofuran (150 ml). The suspension was stirred under a nitrogen atmosphere. Methyl-(indol-6-yl)methanoate (8.0 g, 45.7 mmol) was dissolved in dry tetrahydrofuran (50 ml) and added dropwise to the lithium aluminium hydride suspension. The mixture was stirred at ambient temperature for three hours. Water (10 ml) was added dropwise, followed by 2N hydrogen chloride (30 ml). The mixture was extracted with diethyl ether (3×150 ml) to yield a light purple oil.
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH3:14])[C:10]([O:12]C)=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li+].[OH-]>C1COCC1>[Si:1]([O:8][C@H:9]([CH3:14])[C:10]([OH:12])=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H](C)O[Si](C)(C)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 110.7 %

Procedure:
To a solution of (R)-(+)-Methyl 2-(tert-butyldimethylsilyloxy)propanoate (5.26 g, 24.09 mmol) in THF (283 mL) at 0° C. was added an aqueous LiOH solution (0.2 M, 283 mL). After stirring at room temperature for 4 hr, the reaction mixture was concentrated to 50% of the original volume and extracted with petroleum ether (2×50 mL). The ether extracts were combined and extracted with a saturated aqueous NaHCO3 solution (50 mL). The aqueous layers were combined and acidified to pH 3 to 4 with an aqueous KHSO4 solution (1M, 100 mL). The aqueous solution was extracted with petroleum ether (3×250 mL) and the combined organic layers were dried over Na2SO4 and concentrated to afford 5.45 g of (R)-(+)-2-(tert-butyldimethylsilyloxy)propanoic acid as colorless oil (100%, product contains ˜10% water). 1H NMR (CDCl3): δ 4.29 (q, 1H, J=6.8 Hz, —CH), 1.38 (d, 3H, J=6.8 Hz, —CH3), 0.86 (s, 9H, Si—(CH3)3), 0.07 (s, 3H, Si—CH3), 0.06 (s, 3H, Si—CH3).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:16])=[C:4]([CH:7]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:9]=1)[C:5]#[N:6].B.C1COCC1>C1COCC1>[Cl:1][C:2]1[C:3]([F:16])=[C:4]([CH:7]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:9]=1)[CH2:5][NH2:6]
Reactant: N#Cc1cc(N2CCOCC2)cc(Cl)c1F
Agent: B
Solvent: C1CCOC1
Product: NCc1cc(N2CCOCC2)cc(Cl)c1F
Temperature: 25 °C

Procedure:
To a solution of 3-Chloro-2-fluoro-5-morpholin-4-yl-benzonitrile (215 mg, 0.85 mmol) in THF (2 mL) was added dropwise a solution of BH3-THF. The reaction mixture was heated under reflux for several hours, cooled to ambient temperature and quenched carefully by addition of methanol. The solvent was removed in vacuo and the crude product was purified by RP-preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30×100 mm, 5-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 40 mL/min) to give the title compound. MS (LC/MS): 244.9 [M]+; tR (HPLC conditions c): 3.02 min.