Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[C:40]1[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][N:41]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:40]5[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][N:41]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)CC3)n2CCS1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5ccc(C(F)(F)F)cn5)cc4)CC3)n2CCS1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
A solution of the compound (555 mg, 1.0 mmol) obtained in Example 16-5), 2-chloro-5-trifluoromethyl pyridine (272 mg, 1.5 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 130° C. for 1.5 h under microwave irradiation. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 20:80, gradient) to obtain the title compound (574 mg, quant.) as a light yellow oily substance.
Reaction SMILES: [CH3:1][Si:2]([CH3:22])([CH3:21])[O:3][C:4]#[C:5][C:6]1([Si:12]([CH3:20])([CH3:19])[NH:13][Si:14]([CH3:18])([CH3:17])[CH:15]=[CH2:16])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C=C[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1(C)C=CC=CC=1>[CH3:22][Si:2]([CH3:21])([CH3:1])[O:3][C:4]#[C:5][C:6]1([Si:12]([CH3:20])([CH3:19])[NH:13][Si:14]([CH3:18])([CH3:17])/[CH:15]=[CH:16]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: C=Cc1ccccc1
Reactant: C=C[Si](C)(C)N[Si](C)(C)C1(C#CO[Si](C)(C)C)CCCCC1
Solvent: Cc1ccccc1
Product: C[Si](C)(/C=C/c1ccccc1)N[Si](C)(C)C1(C#CO[Si](C)(C)C)CCCCC1

Procedure:
As in reaction conditions of Example XIX Step 2, to 2.87 mL of toluene, the 0.016 g carbonylchlorohydridebis(tricyclohexylphosphine)ruthenium(H) was added, and the reaction was carried out between the 1-[(1-trimethylsiloxy-1-ethynyl)cyclohexyl]-1,1,3,3-tetramethyl-3-vinyldisilazane obtained in Step 1 and 0.69 g styrene. Product was separated under the purification conditions of Example XII. The product, 1-[(1-trimethylsiloxy-1-ethynyl)cyclohexyl]-1,1,3,3-tetramethyl-3-[(E)-styryl]disilazane, was obtained with a total yield of 85% pure product in the form of an oily liquid, light yellow in color.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:13](=[O:14])[O:12][C:11]([C:19]3[NH:23][C:22]4[CH:24]=[CH:25][C:26]([C:28]#[N:29])=[CH:27][C:21]=4[N:20]=3)([C:15]([F:18])([F:17])[F:16])[C:5]2=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[Li+].[BH4-].O.[NH4+].[Cl-]>C1COCC1>[F:17][C:15]([F:16])([F:18])[C:11]([C:19]1[NH:23][C:22]2[CH:24]=[CH:25][C:26]([C:28]#[N:29])=[CH:27][C:21]=2[N:20]=1)([OH:12])[C:5]1[C:4]([CH2:13][OH:14])=[CH:3][C:2]([CH3:1])=[C:10]2[C:6]=1[CH:7]=[CH:8][NH:9]2
Reactant: Cc1cc2c(c3cc[nH]c13)C(c1nc3cc(C#N)ccc3[nH]1)(C(F)(F)F)OC2=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(CO)c(C(O)(c2nc3cc(C#N)ccc3[nH]2)C(F)(F)F)c2cc[nH]c12
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a solution of (±)-2-(5-methyl-3-oxo-1-(trifluoromethyl)-3,6-dihydro-1H-furo[3,4-e]indol-1-yl)-1H-benzo[d]imidazole-5-carbonitrile (47 mg, 0.119 mmol) in THF (0.5 mL) at 0° C., LiBH4 (2N in THF, 1.19 mL, 2.38 mmol) was added, followed by H2O (43 μL, 2.38 mmol). The reaction was stirred at 50° C. for 16 hours and then cooled to 0° C. A NH4Cl aqueous solution was added and the layers were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over Na2SO4. After concentration under reduced pressure, the residue was separated via silica gel flash column chromatography (CH2Cl2/EtOAc=0 to 100%) to give the title compound. 1H NMR (400 MHz, ACETONITRILE-d3 with about 3% METHANOL-d4) δ ppm 8.05 (s, 1H), 7.54-7.70 (m, 2H), 7.13 (s, 1H), 6.97 (d, J=3.2 Hz, 1H), 5.54 (br. s., 1H), 5.20 (d, J=12.8 Hz, 1H), 4.68 (d, J=12.0 Hz, 1H), 2.48 (s, 3H). HRMS calcd. for C20H16F3N4O2 (M+H)+ 401.122. found 401.1214.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([O:8][CH:9]([CH3:11])[CH3:10])=[N:6][CH:7]=1.B1(C=C)OB([CH:19]=[CH2:20])OB(C=C)O1.C1C=CN=CC=1>COCCOC.C([O-])([O-])=O.[K+].[K+].CCOCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:9]([O:8][C:5]1[C:4]([CH3:12])=[CH:3][C:2]([CH:19]=[CH2:20])=[CH:7][N:6]=1)([CH3:11])[CH3:10]
Reactant: Cc1cc(Br)cnc1OC(C)C
Reactant: C=CB1OB(C=C)OB(C=C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: COCCOC
Solvent: CCOCC
Product: C=Cc1cnc(OC(C)C)c(C)c1
Temperature: 80 °C
Reaction time: 15 h
Yield: 75.4 %

Procedure:
A solution of 5-bromo-2-isopropoxy-3-methyl-pyridine (1.24 g, 5.39 mmol) and 2,4,6-trivinylcyclotriboroxane pyridine complex (1.27 g, 5.26 mmol) in DME (12 mL) and 2 M aq. K2CO3 (5 mL) is degassed and put under argon before Pd(PPh3)4 (112 mg, 0.097 mmol) is added. The mixture is stirred at 80° C. for 15 h before it is cooled to rt, diluted with ether (50 mL), washed with sat. aq. NaHCO3 solution (2×30 mL), dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 9:1 to give 2-isopropoxy-3-methyl-5-vinyl-pyridine (703 mg) as pale yellow oil; LC-MS: tR=1.01 min; [M+1]+=178.11.
Reaction SMILES: [CH:1]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:3]([N:4]([CH2:12][CH2:13][C:14]([C:27]4[NH:31][N:30]=NN=4)([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:5]3)[CH2:2]1)[CH2:9]2.[C:32](OC(=O)C)(=[O:34])[CH3:33].N1C=CC=CC=1>O>[CH:8]12[CH2:7][CH:6]3[CH2:11][CH:1]([CH2:2][CH:3]([N:4]([CH2:12][CH2:13][C:14]([C:27]4[O:34][C:32]([CH3:33])=[N:30][N:31]=4)([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:5]3)[CH2:10]1)[CH2:9]2
Reactant: c1ccc(C(CCN2CC3CC4CC(C3)CC2C4)(c2ccccc2)c2nnn[nH]2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: Cc1nnc(C(CCN2CC3CC4CC(C3)CC2C4)(c2ccccc2)c2ccccc2)o1

Procedure:
A solution of 48 parts of 5-{3-[4-azatricyclo(4.3.1.13,8)undecan-4-yl]-1,1-diphenylpropyl}-1H-tetrazole and 140 parts of acetic anhydride in 400 parts of pyridine is heated at the boiling point under reflux for 3 hours, then cooled and thereupon diluted with 100 parts of water. The resultant mixture is stirred for 10 minutes, whereupon solvent is removed by vacuum distillation and the residue partitioned between a saturated aqueous solution of sodium bicarbonate and diethyl ether. The ethereal phase is separated and consecutively washed with a saturated aqueous solution of sodium bicarbonate and water, then extracted with 2% hydrochloric acid. The acid extract is made alkaline, and the resultant mixture is extracted with ether. The ether extract is washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate, stripped of solvent by vacuum distillation, affords 2-{3-[4-azatricyclo(4.3.1.13,8)undecan-4-yl]-1,1-diphenylpropyl}-5-methyl-1,3,4-oxadiazole melting at approximately 120°-121° as the residue. It has the formula ##STR11##
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([C:7](=[O:17])[CH2:8][N:9]2[CH2:16][CH2:15][CH2:14][C@H:10]2[C:11](O)=[O:12])=[CH:3][CH:2]=1.C(N1CCOCC1)C.ClCCl.[CH2:35]([NH:42][C:43](=[O:50])[C@H:44]([CH2:46][CH2:47][S:48][CH3:49])[NH2:45])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(#N)C>[C:1]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:2]=[CH:3][C:4]([C:7](=[O:17])[CH2:8][N:9]2[CH2:16][CH2:15][CH2:14][C@H:10]2[C:11]([N:42]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:43](=[O:50])[C@H:44]([CH2:46][CH2:47][S:48][CH3:49])[NH2:45])=[O:12])=[CH:5][CH:6]=1
Reactant: CSCC[C@H](N)C(=O)NCc1ccccc1
Reactant: O=C(CN1CCC[C@H]1C(=O)O)c1ccc(-c2ccccc2)cc1
Agent: CCN1CCOCC1
Solvent: ClCCl
Solvent: CC#N
Product: CSCC[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)c1ccc(-c2ccccc2)cc1
Yield: 38.9 %

Procedure:
A solution of N-[2-(biphenyl-4-yl)-2-oxoethyl] L-proline (54 mg, 0.17 mmol, 1.0 eq), N-ethylmorpholine (133 uL, 1.04 mmol, 6 eq) in acetonitrile (0.5 mL) was cooled to 0° C. and treated with a 50% solution of 1-n-propylphosphonic acid cyclic anhydride in dichloromethane (180 uL, 0.27 mmol, 1.6 eq) followed by the L-methionine benzylamide (71.36 mg, 0.30 mmol, 1.7 eq). Purification by HPLC provided 35 mg (38%) of L-methionine, N-[1-(2-(biphenyl-4-yl)-2-oxoethyl)-L-prolyl] benzylamide.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].Br[C:9]1[CH:10]=[N:11][N:12](C(OC(C)(C)C)=O)[CH:13]=1.[C:21]([CH2:23][C:24]1([N:40]2[CH:44]=[C:43](B3OC(C)(C)C(C)(C)O3)[C:42]([CH3:54])=[N:41]2)[CH2:27][N:26]([C:28]2[N:29]=[CH:30][C:31]([C:34]([NH:36][CH:37]([CH3:39])[CH3:38])=[O:35])=[N:32][CH:33]=2)[CH2:25]1)#[N:22]>>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[C:21]([CH2:23][C:24]1([N:40]2[CH:44]=[C:43]([C:9]3[CH:10]=[N:11][NH:12][CH:13]=3)[C:42]([CH3:54])=[N:41]2)[CH2:25][N:26]([C:28]2[N:29]=[CH:30][C:31]([C:34]([NH:36][CH:37]([CH3:38])[CH3:39])=[O:35])=[N:32][CH:33]=2)[CH2:27]1)#[N:22]
Reactant: Cc1nn(C2(CC#N)CN(c3cnc(C(=O)NC(C)C)cn3)C2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)n1cc(Br)cn1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nn(C2(CC#N)CN(c3cnc(C(=O)NC(C)C)cn3)C2)cc1-c1cn[nH]c1

Procedure:
This compound was prepared as TFA salt by using procedures analogous to those described for the synthesis of Example 4, Step 6 starting from tert-butyl 4-bromo-1H-pyrazole-1-carboxylate and 5-{3-(cyanomethyl)-3-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-isopropylpyrazine-2-carboxamide. LCMS calculated for C20H24N9O (M+1)+: m/z=406.2. Found: 406.1.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:8][CH:9]=[C:10]([C:12](=O)[CH3:13])[CH:11]=1)(=O)C.[CH3:21][C:22]([S@:25]([NH2:27])=[O:26])([CH3:24])[CH3:23]>>[OH:4][CH2:5][C:6]1[CH:11]=[C:10]([CH:12]([NH:27][S@@:25]([C:22]([CH3:24])([CH3:23])[CH3:21])=[O:26])[CH3:13])[CH:9]=[N:8][C:7]=1[O:15][CH2:16][C:17]([F:18])([F:19])[F:20]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)OCc1cc(C(C)=O)cnc1OCC(F)(F)F
Product: CC(N[S@](=O)C(C)(C)C)c1cnc(OCC(F)(F)F)c(CO)c1
Yield: 57 %

Procedure:
The title compound is prepared in 57% yield (0.11 g, colorless oil) from (5-acetyl-2-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl acetate (0.16 g, 0.55 mmol, Step-7) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: [NH2:1][C:2](=O)[CH2:3][C@@:4]1([CH3:35])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:32][CH3:33])[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:5]1=[O:34].C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C1COCC1>[Cl:16][C:12]1[CH:11]=[C:10]([C@@H:8]2[C@@H:7]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[N:6]([C@@H:24]([CH2:32][CH3:33])[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:5](=[O:34])[C@:4]([CH2:3][C:2]#[N:1])([CH3:35])[CH2:9]2)[CH:15]=[CH:14][CH:13]=1
Reactant: CC[C@@H](C(=O)OC(C)(C)C)N1C(=O)[C@@](C)(CC(N)=O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC[C@@H](C(=O)OC(C)(C)C)N1C(=O)[C@@](C)(CC#N)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of (S)-tert-butyl 2-((3R,5R,6S)-3-(2-amino-2-oxoethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanoate (105 mg, 0.197 mmol; Example 128, Step A) and triethylamine (137 μL, 0.984 mmol) in THF (3.3 mL) was treated with 2,2,2-trifluoroacetic anhydride (69.8 μL, 0.492 mmol) at 0° C. After being stirred at 0° C. for 3 h, the reaction was quenched (10% citric acid), extracted (2×EtOAc) and washed (sat. aq. NaCl solution). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Purification of the residue by chromatography on silica gel (12 g SiO2, 20 to 50% EtOAc/Hex, a gradient elution) provided the title compound as a colorless foam.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:5])[CH3:4].[H-].[Na+].[C:8]([O:12][C:13]([NH:15][CH:16]([C:18]1[C:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[C:26]([C:34](OC)=O)[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([F:38])[CH:24]=2)[N:19]=1)[CH3:17])=[O:14])([CH3:11])([CH3:10])[CH3:9]>C1COCC1>[F:38][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([CH:16]([NH:15][C:13](=[O:14])[O:12][C:8]([CH3:10])([CH3:11])[CH3:9])[CH3:17])[C:27]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)=[C:26]2[C:34]1[O:1][N:2]=[C:3]([CH3:4])[N:5]=1
Reactant: COC(=O)c1c(-c2ccccn2)c(C(C)NC(=O)OC(C)(C)C)nc2ccc(F)cc12
Reactant: CC(N)=NO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(-c2c(-c3ccccn3)c(C(C)NC(=O)OC(C)(C)C)nc3ccc(F)cc23)n1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of N′-hydroxyacetimidamide (0.081 g, 1.093 mmol) and molecular sieves 4 Å (powder, 0.3 g) in THF (3.64 mL) was added 60% sodium hydride in mineral oil (0.109 g, 2.73 mmol) at rt and the mixture was stirred at 50° C. After being stirred at 50° C. for 30 min, a solution of methyl 2-(1-(tert-butoxycarbonylamino)ethyl)-6-fluoro-3-(pyridin-2-yl)quinoline-4-carboxylate (0.233 g, 0.547 mmol) in THF (1.822 mL) was added. The mixture was heated under reflux. After 3 h, the mixture was removed by filtration though a Celite™ pad and the pad was washed with DCM (2×100 mL). The organic filtrate was washed with water (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give tert-butyl 1-(6-fluoro-4-(3-methyl-1,2,4-oxadiazol-5-yl)-3-(pyridin-2-yl)quinolin-2-yl)ethylcarbamate as a light yellow syrup: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.60 (1H, d, J=4.5 Hz), 8.28 (1H, dd, J=9.3, 5.6 Hz), 7.83-7.94 (2H, m), 7.76 (1H, dd, J=10.0, 2.7 Hz), 7.38-7.51 (2H, m), 7.18 (1H, d, J=7.2 Hz), 4.89 (1H, quin, J=6.7 Hz), 2.38 (3H, s), 1.21-1.35 (12H, m); LC-MS (ESI) m/z 450.1 [M+H]+. The light yellow syrup was carried on crude without purification for the next step.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([C:33]3[CH:38]=[CH:37][C:36]([CH2:39][OH:40])=[CH:35][CH:34]=3)=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[NH2:68][C:69]1[N:73]([C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])[N:72]=[C:71]([C:81]2[CH:86]=[CH:85][C:84](O)=[CH:83][CH:82]=2)[C:70]=1[C:88]#[N:89].C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1>C1COCC1>[NH2:68][C:69]1[N:73]([C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])[N:72]=[C:71]([C:81]2[CH:86]=[CH:85][C:84]([O:40][CH2:39][C:36]3[CH:35]=[CH:34][C:33]([C:25]4[S:24][C:23]([N:20]5[CH2:19][CH2:18][C:17]6[C:22](=[C:13]([C:11](=[O:12])[N:10]([C:2]7[S:1][C:5]8[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=8[N:3]=7)[CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:47])([CH3:46])[CH3:48])[CH:14]=[CH:15][CH:16]=6)[CH2:21]5)=[N:27][C:26]=4[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:38][CH:37]=3)=[CH:83][CH:82]=2)[C:70]=1[C:88]#[N:89]
Reactant: CC(C)(C)OC(=O)n1nc(-c2ccc(O)cc2)c(C#N)c1N
Reactant: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1-c1ccc(CO)cc1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1-c1ccc(COc2ccc(-c3nn(C(=O)OC(C)(C)C)c(N)c3C#N)cc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 601 %

Procedure:
A mixture of compound 34D (0.14 g, 0.2 mmol), PPh3 (0.079 g, 0.3 mmol), and compound 31F (0.066 g, 0.022 mmol) was dissolved in THF (3 mL). The solution was cooled to 0° C. To this solution was added DBAD. The reaction mixture was stirred at rt for 2 hours. The solvent was removed, and the residue was purified by flash column chromatography on silica gel eluting with 2:1/hexanes:EtOAc to afford 0.13 g of the title compound as a mixture of two inseparable isomers. MS (ESI(+)): m/z 982 (M+NH4—H2O).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[H-].[Na+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[C:14]1([S:20]([N:8]2[C:6]3[N:7]=[C:2]([Cl:1])[N:3]=[C:4]([Cl:11])[C:5]=3[CH:10]=[CH:9]2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ccc2c(Cl)nc(Cl)nc21
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 87.4 %

Procedure:
A solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (1 g, 5.3 mmol) in anhydrous THF (5 mL) was added to a suspension of sodium hydride (234 mg, 5.83 mmol, 60% dispersion in mineral oil) in anhydrous THF (15 mL) at 0° C. The resulting mixture was stirred at 0° C. for 45 min, and benzenesulfonyl chloride (1.12 g, 6.36 mmol) was added dropwise. The reaction mixture was allowed to warm to ambient temperature and stirred at RT for 1 h. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The resulting residue was triturated with cyclohexane affording 7-Benzenesulfonyl-2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine as a yellow solid (1.52 g, 87%). 1H NMR (400 MHz, CDCl3): δ 8.24 (2H, m), 7.76 (1H, d, J=4.0 Hz), 7.69 (1H, m), 7.58 (2H, m), 6.69 (1H, d, J=4.0 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N:13]1[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][CH:14]=1.[OH-].[Na+]>O.O.C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10](=[O:12])/[CH:11]=[CH:19]/[C:16]2[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: O=Cc1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(/C=C/c1ccncc1)c1ccc([N+](=O)[O-])cc1
Reaction time: 8 h
Yield: 25.3 %

Procedure:
A suspension of 4′-nitroacetophenone (5 g, 30.3 mmol) and 4-pyridinecarboxaldehyde (2.89 mL, 30.3 mmol) in water (45 mL) at room temperature was treated with 6% NaOH in H2O/ethanol (2:1)(0.606 mL), stirred overnight, and filtered. The filter cake was washed with water and small amount of ethanol then triturated with dichloromethane to provide 1.95 g (25%) of the desired product. MS(ESI(+)) m/e 255 (M+H)+.
Reaction SMILES: CS[C:3]1[N:4]=[C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=[C:6]2[N:7]=1.Cl.C([OH:16])C.C(=O)([O-])O.[Na+]>O>[OH:16][C:3]1[N:4]=[C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=[C:6]2[N:7]=1
Reactant: CSc1nc2cccccc-2n1
Reactant: CCO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Oc1nc2cccccc-2n1
Temperature: 25 °C
Yield: 80.3 %

Procedure:
In accordance with the method described in Journal of the Americal Chemical Society, Vol. 76, pages 3352 to 3353 (1954), 60 g of 2-methylthiocycloheptimidazole, as obtained in Example 1-(c), was added to 300 ml of concentrated hydrochloric acid (hydrogen chloride content: 35%) and heated under reflux for 2 hours and 30 minutes. Next, 500 ml of ethanol was added and everything was stirred at room temperature, and then the crystals precipitated were separated by filtration. The crystals thus obtained were dissolved in 0.5 liter of water, and sodium hydrogencarbonate was added to adjust the pH thereof to about pH 7 or so. The crystals precipitated were separated by filtration, washed with water and then dried. 40 g of pale yellow crystals were obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]2[C:12]3([CH2:22][O:23][C:8]=2[CH:7]=1)[C:20]1[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH:14][C:13]3=[O:21].CC1C=CC(S(O[CH2:36][C@H:37]2[CH2:41][CH2:40][CH2:39][O:38]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(=O)CC>[CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]2[C:12]3([CH2:22][O:23][C:8]=2[CH:7]=1)[C:20]1[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=1)[N:14]([CH2:36][C@H:37]1[CH2:41][CH2:40][CH2:39][O:38]1)[C:13]3=[O:21]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Reactant: CN(C)CCOc1ccc2c(c1)OCC21C(=O)Nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Product: CN(C)CCOc1ccc2c(c1)OCC21C(=O)N(C[C@H]2CCCO2)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.5 %

Procedure:
To a stirred solution of 6-[2-(dimethylamino)ethoxy]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (0.21 g, 0.64 mmol) in 2-butanone (10 mL) was added (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate (0.20 g, 0.76 mmol) followed by cesium carbonate (0.63 g, 1.90 mmol) at 0° C. The mixture was stirred at ambient temperature for 16 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was subjected to column chromatography (ethyl acetate/methanol/ammonium hydroxide, 10/1/0.2) to give 6-[2-(dimethylamino)ethoxy]-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (0.20 g, 76%): 1H NMR (300 MHz, CDCl3) δ 7.31-7.24 (m, 1H), 7.14-6.96 (m, 3H), 6.57 (d, J=8.3 Hz, 1H), 6.52 (d, J=2.2 Hz, 1H), 6.36 (dd, J=8.3, 2.2 Hz, 1H), 4.91 (d, J=9.0 Hz, 1H), 4.66 (d, J=9.0 Hz, 1H), 4.31-4.19 (m, 1H), 4.00 (t, J=5.8 Hz, 2H), 3.94-3.63 (m, 4H), 2.68 (t, J=5.8 Hz, 2H), 2.97 (s, 6H), 2.09-1.63 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 178.1, 177.9, 162.0, 160.7, 142.9, 142.8, 132.5, 132.4, 128.7, 128.6, 123.7, 123.6, 123.5, 123.4, 123.2, 121.1, 121.0, 109.6, 109.4, 108.1, 97.2, 80.6, 80.5, 68.24, 68.2, 66.3, 58.2, 57.5, 45.9, 44.6, 44.5, 29.2, 28.9, 25.7, 25.5; MS (ES+) m/z 409.3 (M+1).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([CH:22]([CH3:27])[C:23]([O:25]C)=[O:24])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:28]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[OH-].[Li+]>>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([CH:22]([CH3:27])[C:23]([OH:25])=[O:24])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:28]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)C(C)c1ccc2c(c1)OCCn1cc(-c3ncnn3C(C)C)nc1-2
Agent: [Li+]
Agent: [OH-]
Product: CC(C(=O)O)c1ccc2c(c1)OCCn1cc(-c3ncnn3C(C)C)nc1-2

Procedure:
Methyl 2-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)propanoate and lithium hydroxide were reacted to give 2-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)propanoic acid. M/z 368.2, calc. 367.16, which was reacted with ammonium chloride and HATU following the procedure of Example 215 to give a racemic mixture of enantiomers 344 and 345. M/z 367.1, calc. 366.18. 1H NMR (400 MHz, DMSO) δ 8.32 (d, J=8.3, 1H), 7.90 (s, 2H), 7.41 (s, 1H), 7.10 (d, J=8.5, 1H), 7.00 (s, 1H), 6.87 (s, 1H), 5.88 (dt, J=12.5, 6.2, 1H), 4.50 (d, J=4.7, 4H), 3.57 (q, J=6.9, 1H), 1.48 (d, J=6.5, 6H), 1.31 (d, J=6.9, 3H)