Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:8][N:9]1[CH2:22][CH2:21][CH2:20][N:19]2[CH2:23][CH2:24][CH2:25][N:12]([CH2:13][CH2:14][CH2:15][N:16]([CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])[CH2:17][CH2:18]2)[CH2:11][CH2:10]1)([O:3]C(C)(C)C)=[O:2]>C(C(O)=O)(F)(F)F.C(Cl)Cl>[C:27]([CH2:26][N:16]1[CH2:15][CH2:14][CH2:13][N:12]2[CH2:25][CH2:24][CH2:23][N:19]([CH2:20][CH2:21][CH2:22][N:9]([CH2:8][C:1]([OH:3])=[O:2])[CH2:10][CH2:11]2)[CH2:18][CH2:17]1)([OH:29])=[O:28]
Reactant: CC(C)(C)OC(=O)CN1CCCN2CCCN(CCCN(CC(=O)OC(C)(C)C)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CN1CCCN2CCCN(CCCN(CC(=O)O)CC2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 3373.4 %

Procedure:
Compound 15 (1.23 g, 2.62 mmol) was dissolved in a 1:1 (vol:vol) mixture of CF3CO2H (TFA) and CH2Cl2 (45 mL). The mixture was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure to give an oily residue which was triturated with Et2O to provide white solid 16 (31.505 g, 98% yield) (2 equiv TFA calculated on the basis of mass).
Reaction SMILES: CO[C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[C:10]([C:21]3[C:22]4[S:35][CH:34]=[CH:33][C:23]=4[N:24](C(OC(C)(C)C)=O)[N:25]=3)[N:11]2C(OC(C)(C)C)=O)=[CH:7][CH:6]=1)=[O:4].[CH2:36]([Mg]Br)[CH3:37].O1CC[CH2:42][CH2:41]1>>[NH:24]1[C:23]2[CH:33]=[CH:34][S:35][C:22]=2[C:21]([C:10]2[NH:11][C:12]3[C:8]([CH:9]=2)=[CH:7][CH:6]=[C:5]([C:3]([OH:4])([CH2:36][CH3:37])[CH2:41][CH3:42])[CH:13]=3)=[N:25]1
Reactant: C1CCOC1
Reactant: COC(=O)c1ccc2cc(-c3nn(C(=O)OC(C)(C)C)c4ccsc34)n(C(=O)OC(C)(C)C)c2c1
Reactant: CC[Mg]Br
Product: CCC(O)(CC)c1ccc2cc(-c3n[nH]c4ccsc34)[nH]c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
To 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-indole-1,6-dicarboxylic acid 1-tert-butyl ester 6-methyl ester [250 mg, 0.5 mmol, Intermediate (36)] in tetrahydrofuran (5 mL) was added a 1.0M solution of ethyl magnesium bromide in tetrahydrofuran (2.5 mL, 2.5 mmol) at −45° C. under nitrogen. The mixture was allowed to warm up and stirred at room temperature for 3 hours. An additional 2 mL of 1.0M ethyl magnesium bromide solution was added. The resulting solution was stirred at room temperature overnight. It was then quenched with a mixture of brine and saturated ammonium chloride and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residue was chromatographed through silica gel (n-heptane/ethyl acetate, 50/50 as eluant) to produce 3-[2-(1H-thieno[3,2-c]pyrazol-3-yl)-1H-indol-6-yl]-pentan-3-ol [137 mg, 92%, Example 70] as a white powder. LC/MS: 326.2 (M+H), RT=3.07 minutes; 1H NMR [300 Mhz, (CD3)2SO]: δ 13.18 (s, 1H), 11.43 (s, 1H), 7.73 (d, J=5.2 Hz, 1H), 7.50 (s, 1H), 7.44 (d, J=8.2 Hz, 1H), 7.18 (d, J=5.2 Hz, 1H), 6.94 (dd, J1=1.1 Hz, J2=8.4 Hz, 1H), 6.56 (d, J=1.5 Hz, 1H), 4.41 (s, 1H), 1.76 (m, 4H), 0.66 (t, j=6.2 Hz, 6H).
Reaction SMILES: [NH3:1].C(Cl)Cl.[CH2:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[CH3:11][OH:12]>>[NH2:1][CH2:7][CH2:6][CH2:5][CH2:10][CH2:9][C:5]1[CH:10]=[CH:9][C:8]([O:12][CH3:11])=[CH:7][CH:6]=1
Reactant: N
Reactant: C1CCCCC1
Reactant: CO
Solvent: ClCCl
Product: COc1ccc(CCCCCN)cc1

Procedure:
Rf value: 0.59 (silica gel; methylene chloride/cyclohexane/methanol/conc. aqueous ammonia=68:15:15:2)
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:11][S:12][CH:13]1[N:16]([CH2:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[O:19])[C:15](=[O:31])[CH:14]1[CH:32]([O:34][C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=1)=[O:36])[CH3:33].[C:48](Cl)(=[O:53])[C:49]([CH3:52])([CH3:51])[CH3:50]>O1CCCC1.C1(C)C=CC=CC=1.C(Cl)Cl>[CH3:50][C:49]([CH3:52])([CH3:51])[C:48](=[O:53])[CH:17]([N:16]1[CH:13]([S:12][CH3:11])[CH:14]([CH:32]([O:34][C:35]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=2)=[O:36])[CH3:33])[C:15]1=[O:31])[C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=1)=[O:19]
Reactant: CSC1C(C(C)OC(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)N1CC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)C(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CSC1C(C(C)OC(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)C(C)(C)C
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
1.1 ml of 1M lithium bis(trimethylsilyl)amide are added over the course of 5 minutes to a stirred mixture of 275 mg (0.515 mmol) of p-nitrobenzyl 2-[4-methylthio-3-(1-(p-nitrobenzyloxycarbonyloxy)-ethyl)-2-oxoazetidinyl]-acetate and 67 μl (0.55 mmol) of pivaloyl chloride in 6.7 ml of dry tetrahydrofuran at -70° C., and the reaction mixture is stirred at -70° C. for a further 30 minutes and then diluted with 40 ml of toluene and washed with 30 ml of 2N HCl, then twice with 40 ml of NaCl solution in each case. The organic phase is dried over MgSO4 and filtered, and the solvent is removed in vacuo. The residue is chromatographed over 10 g of silica gel using toluene:ethyl acetate (9:1), to give 268 g of a white, non-crystalline solid. IR spectrum in CH2Cl2 : 2930, 2850, 1775, 1760, 1720, 1610, 1535, 1350 cm-1 .
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH2:8]([OH:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[CH2:8]([O:26][C:4](=[O:5])/[CH:3]=[CH:2]\[C:1]([OH:6])=[O:7])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: O=C1C=CC(=O)O1
Product: CCCCCCCCCCCCCCCCCCOC(=O)/C=C\C(=O)O

Procedure:
Into an autoclave, were charged 295 parts of maleic anhydride and 825 parts of stearyl alcohol. A mixture was reacted at 60° C. for 5 hours under sealed condition, to obtain maleic acid monostearyl ester, containing 1.5% unreacted maleic anhydride. After adding to the mixture, 11.2 parts of toluene, 275 parts of allyl chloride and 530 parts of tri-n-propyl amine, an atmosphere was substituted with nitrogen. The mixture was reacted at 80° C. for 8 hours, and cooled to a room temperature. The mixture was rinsed by 90 parts of 10% hydrochloric acid aqueous solution, followed by distillation of toluene, to obtain 1,200 parts of stearyl allyl maleate of 94.5% purity and of Gardner Color 9. A molar ratio of maleic anhydride:stearyl alcohol was 1:1.02, and maleic acid monostearyl ester:allyl chloride:tri-n-propyl amine was 1:1.19:1.23.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:5][N:6]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[C:25]([C:27]1[CH:28]=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=1)=[O:26]>>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][S:13]([C:10]2[CH:11]=[CH:12][C:7]([C:4]3[O:3][C:2]([CH3:1])=[N:6][CH:5]=3)=[CH:8][CH:9]=2)(=[O:15])=[O:14])=[C:19]([C:25]([C:27]2[CH:28]=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=2)=[O:26])[CH:20]=1
Reactant: Cc1ncc(-c2ccc(S(=O)(=O)Cl)cc2)o1
Reactant: Cc1ccc(C(=O)c2cc(Cl)ccc2N)cn1
Product: Cc1ccc(C(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(-c3cnc(C)o3)cc2)cn1

Procedure:
The title compound was prepared according to the general procedure for the preparation of N-aryl-benzenesulfonamides using 4-(2-methyl-oxazol-5-yl)-benzenesulfonyl chloride and (2-amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone and purified by HPLC. MS: m/z 468.0 (M++1).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([N:9]([CH2:12][C:13](Cl)=[O:14])[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].[Cl:16][C:17]1[CH:31]=[CH:30][C:20]2[O:21][C:22]3[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=3[CH2:24][NH:25][C:19]=2[CH:18]=1.C(N(CC)CC)C.Cl>C1(C)C=CC=CC=1>[Cl:16][C:17]1[CH:31]=[CH:30][C:20]2[O:21][C:22]3[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=3[CH2:24][N:25]([C:13](=[O:14])[CH2:12][N:9]3[C:7](=[O:8])[C:5]4[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=4)[C:10]3=[O:11])[C:19]=2[CH:18]=1
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Reactant: Clc1ccc2c(c1)NCc1ccccc1O2
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
1,3-dihydro-1,3-dioxo-2H-isoindole-2-acetyl chloride (4.00 grams), 8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine (4.16 grams) and triethylamine (2.8 mL) were refluxed in toluene (100 mL) under nitrogen for 3 hours. The resulting mixture was poured into 1N HCl at 0° C., and the biphasic mixture was shaken vigorously. The insoluble product was collected by filtration, washed with toluene and ethyl ether, and dried in vacuo at 56° C. The yield of the title compound was 6.36 grams (85%). Mp: 184°-185° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][S:4]([CH2:7][CH:8]([CH2:12][C:13]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[C:9]([OH:11])=O)(=[O:6])=[O:5].[NH2:22][CH:23]([CH2:37][CH3:38])[C@@H:24]([C:26]1[O:30][N:29]=[C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:27]=1)[OH:25]>>[CH3:21][CH:2]([CH3:1])[CH2:3][S:4]([CH2:7][C@H:8]([CH2:12][C:13]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[C:9]([NH:22][C@H:23]([C:24]([C:26]1[O:30][N:29]=[C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:27]=1)=[O:25])[CH2:37][CH3:38])=[O:11])(=[O:5])=[O:6]
Reactant: CC(C)CS(=O)(=O)CC(CC(=O)N1CCOCC1)C(=O)O
Reactant: CCC(N)[C@H](O)c1nc(-c2ccccc2)no1
Product: CC[C@H](NC(=O)[C@@H](CC(=O)N1CCOCC1)CS(=O)(=O)CC(C)C)C(=O)c1nc(-c2ccccc2)no1

Procedure:
It is similarly prepared according to general procedure given for Example 2 above but using 2-(2-Methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyric acid and (S)-2-Amino-1-(3-phenyl-1,2,4-oxadiazol-5-yl)-butan-1-ol.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:12])=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH2:7])=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[NH2:1][C:2]1[C:3]([F:12])=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[CH2:5][NH2:7]
Reactant: NC(=O)c1ccc(Cl)c(N)c1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: NCc1ccc(Cl)c(N)c1F

Procedure:
The crude sub-title compound is prepared from 3-amino-4-chloro-2-fluoro-benzamide and LiAlH4 in analogy to step Ad. HPLC-method B: Rt=0.37 min. MS m/z: 175 [M+H]+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:11]#[N:12])=[CH:6][CH:5]=1.Cl[CH2:22][N:23]1[CH:27]=[N:26][CH:25]=[N:24]1>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([C:11]#[N:12])([CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[CH2:22][N:23]2[CH:27]=[N:26][CH:25]=[N:24]2)=[CH:8][CH:9]=1
Reactant: N#CC(CCN1CCOCC1)c1ccc(Cl)cc1
Reactant: ClCn1cncn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(CCN1CCOCC1)(Cn1cncn1)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a flask was added 0.24 g. (5.5 mmoles) of a 55% oil dispersion of sodium hydride. After washing the sodium hydride with hexane to remove the mineral oil, 25 ml. of DMF was added, the solution cooled to 0° C., and then 1.3 g. (5.0 mmoles) of 2-(4-chlorophenyl)-4-(4-morpholinyl)butyronitrile in 15 ml. of DMF was slowly added. The solution was stirred for 30 minutes and then 0.59 g. (5.0 mmoles) of 1-(chloromethyl)-1,2,4-triazole in 10 ml. of DMF was added slowly. The reaction was stirred overnight at room temperature and then was poured into ice water. The organics were extracted into ethyl acetate, washed with water, dried over magnesium sulfate, filtered, and concentrated. The product was purified using chromatography by eluting the impurities with ethyl acetate and the desired 1-[2-(4-chlorophenyl)-2-cyano-4-(4-morpholinyl)butyl]-1,2,4-triazole product with acetone to give 1.0 g. (58% yield) of an orange oil.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:8][O:9][C:10]1[C:15]([CH2:16][N:17]2[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]2)=[CH:14][CH:13]=[CH:12][N:11]=1.[OH2:24]>>[CH3:8][O:9][C:10]1[C:15]([CH2:16][N:17]2[CH2:22][CH2:21][C:20](=[CH:3][C:2]([O:1][CH2:5][CH3:4])=[O:24])[CH2:19][CH2:18]2)=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: C1CCOC1
Reactant: COc1ncccc1CN1CCC(=O)CC1
Reactant: O
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C=C1CCN(Cc2cccnc2OC)CC1
Reaction time: 0.08 h

Procedure:
Under ice-cooling, a mixed solution of 2.2 ml of triethyl phosphonoacetate and 18 ml of tetrahydrofuran was added dropwise into a suspension of 0.40 g of 60% sodium hydride (oil suspension) and 18 ml of tetrahydrofuran. After stirring for 5 minutes, a mixed solution of 2.0 g of 1-[(2-methoxy-3-pyridyl)methyl]-4-piperidone and 9 ml of tetrahydrofuran was added dropwise thereinto. After completing the dropwise addition, the mixture was further stirred under ice-cooling for 30 minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified by silica gel column chromatography (ethyl acetate:hexane=1:1), to give 2.6 g of the title compound as a pale yellow oil.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=O)=[C:9]3[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=3)[CH:6]=2)[CH2:3][CH2:2]1.N1CCCCC1.[NH:29]1[CH2:35][C:33](=[O:34])[NH:32][C:30]1=[O:31]>CCO>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=[C:35]4[NH:29][C:30](=[O:31])[NH:32][C:33]4=[O:34])=[C:9]3[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=3)[CH:6]=2)[CH2:3][CH2:2]1
Reactant: O=Cc1cnn2c(NC3CC3)cc(-c3cccc(O)c3)nc12
Reactant: O=C1CNC(=O)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1NC(=O)C(=Cc2cnn3c(NC4CC4)cc(-c4cccc(O)c4)nc23)N1
Temperature: 50 °C
Reaction time: 8 h
Yield: 54.7 %

Procedure:
To 7-(cyclopropylamino)-5-(3hydroxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (100 mg, 0.340 mmol) in EtOH (2 mL) was added piperidine (67 μL, 0.680 mmol), and hydantoin (34 mg, 0.34 mmol). The reaction was stirred at 50° C. overnight. The solid formed was isolated by filtration to provide 70 mg of 5-((7-(cyclopropylamino)-5-(3-hydroxyphenyl)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. (55%). LCMS (M+1=377)
Reaction SMILES: [Cl:1]C1C2C(=O)N[C@H]3CN(C(OC(C)(C)C)=O)C[C@@H]3C=2C(CC)=CC=1.[Cl:25][C:26]1[C:35]2[C:34](=[O:36])[NH:33][C@@H:32]3[CH2:37][N:38](C(OC(C)(C)C)=O)[CH2:39][C@H:31]3[C:30]=2[C:29]([CH2:47][CH3:48])=[CH:28][CH:27]=1>>[ClH:1].[Cl:25][C:26]1[C:35]2[C:34](=[O:36])[NH:33][C@H:32]3[CH2:37][NH:38][CH2:39][C@@H:31]3[C:30]=2[C:29]([CH2:47][CH3:48])=[CH:28][CH:27]=1
Reactant: CCc1ccc(Cl)c2c1[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1NC2=O
Reactant: CCc1ccc(Cl)c2c1[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1NC2=O
Product: CCc1ccc(Cl)c2c1[C@H]1CNC[C@@H]1NC2=O
Product: Cl

Procedure:
Following the procedure described in Example 45, Part I, (3aR,9bS)-tert-butyl 6-chloro-9-ethyl-5-oxo-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate, the first eluting compound from Part B above, was converted into the title compound of Example 56 as a white solid. 1H NMR (DMSO-D6): δ 9.77 (broad s, 1H), 9.61 (broad s, 1H), 8.84 (s, 1H), 7.32 (d, 1H, J=8.2 Hz), 7.27 (d, 1H, J=8.2 Hz), 3.93-3.86 (m, 1H), 3.60-3.53 (m, 1H), 3.33-3.20 (m, 3H), 3.04-2.96 (m, 1H), 2.47 (q, 2H, J=7.5 Hz), 1.05 (t, 3H, J=7.5 Hz). LRMS (ESI): 251.1/253.1 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:16]=1[C:24]#[N:25])=O)(C)(C)C.[ClH:26]>>[Cl-:26].[C:24]([C:16]1[C:17]([N+:21]([O-:23])=[O:22])=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][CH2:13][C@@H:9]1[CH2:10][CH2:11][CH2:12][NH2+:8]1)#[N:25]
Reactant: Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cccc([N+](=O)[O-])c1C#N
Product: N#Cc1c(OC[C@@H]2CCC[NH2+]2)cccc1[N+](=O)[O-]
Product: [Cl-]
Yield: 81 %

Procedure:
Prepared as in Example 166 from (S)-tert-butyl-2-((2-cyano-3-nitrophenoxy)methyl)pyrrolidine-1-carboxylate (Example 209c) in 81% yield as an off-white solid. MS 248 (MH+—HCl).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1)=[O:4].C(Cl)Cl.[I:20]Cl.S(=O)(O)[O-].[Na+]>C(O)(=O)C.O>[F:16][C:2]([F:1])([F:15])[C:3]([N:5]1[C:10]2[CH:11]=[C:12]([I:20])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1)=[O:4]
Reactant: ClI
Reactant: O=C(N1CCOc2ccccc21)C(F)(F)F
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: O=C(N1CCOc2ccc(I)cc21)C(F)(F)F
Reaction time: 0.75 h

Procedure:
A mixture of 0.5 g (2.16 mmol) of this 4-(trifluoroacetyl)-3,4-dihydro-2H-1,4-benzoxazine, 20 ml of glacial acetic acid and 5 ml of methylene chloride was cooled to 10° in an ice bath. A solution of 1 ml of iodine monochloride in 1 ml of acetic acid was added slowly over a period of 5 minutes. Following the addition, the mixture was stirred for 45 minutes and was then diluted with water and a aqueous solution of sodium bisulfite. The product was extracted with ether. The extracts were washed with water, dried and evaporated. Crystallization of the residue from hexane yielded colorless crystals with m.p. 78°-80°.
Reaction SMILES: [CH:1]([C:3]1(O)[CH2:7][CH2:6][CH2:5][CH2:4]1)=[CH2:2].C[O:10][C:11]([CH3:13])=[CH2:12].P(=O)(O)(O)O.C(N(CC)CC)C>CC(OC)(C)C>[C:3]1(=[CH:1][CH2:2][CH2:12][C:11](=[O:10])[CH3:13])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: C=C(C)OC
Reactant: C=CC1(O)CCCC1
Agent: O=P(O)(O)O
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: CC(=O)CCC=C1CCCC1
Temperature: 130 °C
Yield: 72.1 %

Procedure:
In an autoclave under N2, a mixture of 1-vinylcyclopentanol (65 g, 0.58 mol), 2-methoxypropene (108 ml, 1.15 mol), 85% phosphoric acid (0.29 ml), triethylamine (0.63 ml) was heated at 130° C. for 15 h. The reaction mixture was cooled to 20° C., diluted with MTBE (500 ml), washed three times with water (25 ml), once with a saturated aqueous solution of NaCl (25 ml), dried (MgSO4) and concentrated. Widmer-Distillation (0.13 mbar, head temp. 58° C.) of the crude product gave 5-cyclopentylidenepentan-2-one (63.67 g, 72%).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[NH2:11][C:12]1[C:17]([CH2:18][O:19][CH3:20])=[C:16]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:15]([C:28](OC)=[O:29])=[C:14]([CH:32]([CH3:34])[CH3:33])[N:13]=1.C1(C)C=CC=CC=1.O>C(OCC)(=O)C>[NH2:11][C:12]1[C:17]([CH2:18][O:19][CH3:20])=[C:16]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:15]([CH2:28][OH:29])=[C:14]([CH:32]([CH3:34])[CH3:33])[N:13]=1
Reactant: COCc1c(N)nc(C(C)C)c(C(=O)OC)c1-c1ccc(F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: COCc1c(N)nc(C(C)C)c(CO)c1-c1ccc(F)cc1
Reaction time: 1 h

Procedure:
140 ml (210 mmol) of a 1.5 M solution of diisobutylaluminum hydride are added dropwise at 78° C. to -75° C. under argon to a solution of 23.1 g (70 mmol) of the compound of Example 30 in 1 1 of toluene and the mixture is stirred at this temperature for 1 h. While it is allowed to warm, 40 ml of water and 50 ml of ethyl acetate are added dropwise, kieselguhr is added, filtered off with suction and washed with ethyl acetate. The aqueous phase is extracted with ethyl acetate, and the combined organic phases are washed with saturated NaCl solution and dried over sodium sulphate. The solution is concentrated to dryness and the residue is thoroughly stirred in ether.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][C:9]2[NH:10][CH:11]=[N:12][C:8]=2[CH:7]=1)=[O:4].[CH2:15]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(OCC)C>[CH2:15]([CH:22]1[CH2:27][CH2:26][N:25]([CH2:2][C:3]([NH:5][C:6]2[CH:14]=[CH:13][C:9]3[NH:10][CH:11]=[N:12][C:8]=3[CH:7]=2)=[O:4])[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(CCl)Nc1ccc2[nH]cnc2c1
Reactant: c1ccc(CC2CCNCC2)cc1
Solvent: CCOCC
Product: O=C(CN1CCC(Cc2ccccc2)CC1)Nc1ccc2[nH]cnc2c1

Procedure:
The title compound is prepared from 2-chloro-N-(1H-benzimidazol-5-yl)-acetamide and 4-benzyl-piperidine according to the method described in Example 142b. Melting Point: 185-189° C. (diethylether)
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([NH:31][C@@H:32]2[C@@H:37]3[CH2:38][C@@H:34]([CH:35]=[CH:36]3)[C@@H:33]2[C:39]([NH2:41])=[O:40])=[C:11]2[N:17]=[C:16]([C:18]3[CH:23]=CC(CN4CCOCC4)=C[CH:19]=3)[NH:15][C:12]2=[N:13][CH:14]=1.NC1C(N)=C(N[C@@H]2[C@@H]3C[C@@H](C=C3)[C@@H]2C(N)=O)C(Cl)=CN=1.[C:62]([O:66][C:67]([N:69]1CCC[CH:71](C=O)[CH2:70]1)=[O:68])([CH3:65])([CH3:64])[CH3:63]>>[C:62]([O:66][C:67]([N:69]1[CH2:70][CH2:71][CH2:19][CH:18]([C:16]2[NH:15][C:12]3=[N:13][CH:14]=[C:9]([Cl:8])[C:10]([NH:31][C@H:32]4[C@@H:33]([C:39](=[O:40])[NH2:41])[C@H:34]5[CH2:38][C@@H:37]4[CH:36]=[CH:35]5)=[C:11]3[N:17]=2)[CH2:23]1)=[O:68])([CH3:65])([CH3:64])[CH3:63]
Reactant: CC(C)(C)OC(=O)N1CCCC(C=O)C1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)nc23)[C@H]2C=C[C@@H]1C2
Agent: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCCC(c2nc3c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)c(Cl)cnc3[nH]2)C1
Yield: 65 %

Procedure:
In the same fashion as for Compound III, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 3-formyl-piperidine-1-carboxylic acid tert-butyl ester were reacted to produce the title compound (65%). 1H NMR (d-chloroform): 15.20 (br s, 1H), 8.42 (m, 1H), 7.83 (s, 1H), 6.45 (m, 1H), 6.38 (m, 1H), 5.90 (m, 1H), 5.64 (s, 1H), 5.25 (m, 1H), 4.03 (m, 1H), 2.80-3.25 (m, 5H), 2.62 (t, J=8 Hz, 1H), 2.39 (d, J=10 Hz, 2H), 1.32-2.00 (m, 14H). MS: 488.07 (M+H). HPLC retention time: 2.67 minutes (G Method).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[Cl:7][C:8]1[N:9]=[CH:10][N:11]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]3[N:37]=[C:23]4[C@@H:24]([C:30]5[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=5)[CH2:25][C:26](=C)[CH2:27][CH2:28][N:22]4[N:21]=3)=[CH:15][C:14]=2[O:38][CH3:39])[CH:12]=1>O.C1COCC1.[Cl-].[Na+].O.[Os](=O)(=O)(=O)=O>[Cl:7][C:8]1[N:9]=[CH:10][N:11]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]3[N:37]=[C:23]4[C@@H:24]([C:30]5[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=5)[CH2:25][C:26](=[O:2])[CH2:27][CH2:28][N:22]4[N:21]=3)=[CH:15][C:14]=2[O:38][CH3:39])[CH:12]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=C1CCn2nc(Nc3ccc(-n4cnc(Cl)c4)c(OC)c3)nc2[C@@H](c2ccc(F)cc2)C1
Agent: O=[Os](=O)(=O)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Nc2nc3n(n2)CCC(=O)C[C@@H]3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Reaction time: 1 h
Yield: 95.6 %

Procedure:
A solution of sodium periodate (276 mg, 1.29 mmol) in water (5.0 mL) was added over a 10 min period to a vigorously stirred solution of the (R)—N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-9-(4-fluorophenyl)-7-methylene-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine (200 mg, 0.430 mmol, from example 134) and osmium tetroxide (10.9 mg, 0.043 mmol) in THF (5.0 mL). The reaction was stirred for 1 h and then diluted with water (150 mL)/brine (100 mL) and extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford (R)-2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-9-(4-fluorophenyl)-8,9-dihydro-5H-[1,2,4]triazolo[1,5-a]azepin-7(6H)-one (192 mg, 77% yield). LC-MS (M+H)+ 467.1.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=O.[CH3:15][N:16]([CH3:20])[C:17]([NH2:19])=[O:18].C(OCC)(=O)C>CN(C)C=O>[CH3:15][N:16]([CH3:20])[C:17]1[O:18][CH:2]=[C:3]([C:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7][CH:6]=2)[N:19]=1
Reactant: CN(C)C(N)=O
Reactant: O=C(CBr)c1cccc2ccccc12
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)c1nc(-c2cccc3ccccc23)co1

Procedure:
1-(α-Bromoacetyl)naphthalene (5 g) and 1,1-dimethylurea (6 g) were stirred in anhydrous dimethylformamide (20 ml) at 105° C. overnight. The mixture was cooled, added to ethyl acetate, washed with sodium bicarbonate solution, water, brine, dried with sodium sulphate, filtered and evaporated in vacuo. The title compound was obtained (0.60 g; m.p. 30-32° C.) following silica gel column chromatography of the residue in dichloromethane.