Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:3].C(N(CC)CC)C.FC(F)(F)C(O[C:29]1[C:34]([F:35])=[C:33]([F:36])[CH:32]=[C:31]([F:37])[C:30]=1[F:38])=O>CN(C=O)C>[F:35][C:34]1[C:33]([F:36])=[CH:32][C:31]([F:37])=[C:30]([F:38])[C:29]=1[O:3][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:1]
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reactant: O=C(Oc1c(F)c(F)cc(F)c1F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1N[C@H]2[C@H](CS[C@H]2CCCCC(=O)Oc2c(F)c(F)cc(F)c2F)N1
Yield: 65 %

Procedure:
A 2.5 g (10.3 mmol) quantity of d-biotin in 20 mL anhydrous DMF under argon atmosphere was warmed to 60° C. with stirring to effect dissolution. 1.7 mL (12.5 mmol) triethylamine was added, followed by 3.4 g (12.5 mmol) 1. The mixture was stirred for 2 hours, after which the solvent was removed by rotary evaporation. The resultant semi-solid was triturated with 15 mL ether twice to produce a white solid (2.6 g, 65%). 1H-NMR. (Ref. Wilbur, D. S., Bioconj. Chem., v8 pp572-584)
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[O:15])=[C:12]([F:19])[CH:11]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.[Li]CCCC.[B:25]([O-])([O-:27])[O-:26]>C1COCC1>[C:14]([C:13]1[CH:17]=[CH:18][C:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][C:2]([B:25]([OH:27])[OH:26])=[CH:3][C:4]=3[CH:9]=2)=[CH:11][C:12]=1[F:19])(=[O:15])[NH2:16]
Reactant: NC(=O)c1ccc(-c2ccc3occc3c2)cc1F
Reactant: [O-]B([O-])[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: NC(=O)c1ccc(-c2ccc3oc(B(O)O)cc3c2)cc1F
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 92 %

Procedure:
Intermediate 20 (100 mg 0.4 mmol) was dissolved in THF (10 ml) and this mixture was cooled to −78° C. under N2 atmosphere. n-BuLi (0.5 ml, 1.3 mmol) was added to the above mixture and stirred at same temperature for 20 mins Reaction mixture warmed to 0° C. and stirred for 2 hrs. After that trisopropyl borate (88 mg, 0.47 mmol) was added and stirred the reaction for 16 h at rt. Reaction mass quenched with 2N HCl worked it up (EtOAC/H2O) to afford the titled compound (110 mg) as a crude. It was used in the next step without further purification.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:9]=[CH:10][C:11]3[CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][CH2:15][O:16][C:17]=3[N:18]=2)[CH2:3]1.Cl.C(OCC)(=O)C>>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:9]=[CH:10][C:11]3[CH2:12][NH:13][CH2:14][CH2:15][O:16][C:17]=3[N:18]=2)[CH2:3]1
Reactant: CC1CCCN(c2ccc3c(n2)OCCN(C(=O)OC(C)(C)C)C3)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC1CCCN(c2ccc3c(n2)OCCNC3)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.6 %

Procedure:
A mixture of the compound (0.15 g) obtained in step 1 and 4N hydrogen chloride/ethyl acetate (2 mL) was stirred at room temperature for 3 hr. The precipitate was collected by filtration, and the aqueous layer was made basic with ethyl acetate and aqueous sodium hydroxide solution. The organic layer was washed with brine and dried, and the solvent was evaporated under reduced pressure. The residue was recrystallized from pentane to give the title compound (0.07 g, 67%) as a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: C1CCNC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCCC1

Procedure:
Using analogous procedures to those described in Note [33] immediately above, 1-(tert-butoxycarbonyl)-L-proline was reacted with pyrrolidine to give (2S)-1-(tert-butoxycarbonyl)-2-(pyrrolidin-1-ylcarbonyl)pyrrolidine which was deprotected and reacted with 2-bromoethanol. There was thus obtained the required starting material; NMR Spectrum: (CDCl3) 1.7–2.05 (m, 8H), 2.1–2.3 (m, 1H), 2.4–2.5 (m, 1H), 2.55–2.7 (m, 1H), 2.8–2.9 (m, 1H), 3.2–3.3 (m, 2H), 3.4–3.7 (m, 5H), 4.1 (br s, 1H); Mass Spectrum: M+H+ 213.
Reaction SMILES: COP([CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[O:8]1)(=O)OC.[CH:17]([C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][N:26]=1)[C:22]#[N:23])=O.C(N(CC)CC)C>C1COCC1>[O:16]=[C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7](=[CH:17][C:19]2[CH:20]=[C:21]([CH:24]=[CH:25][N:26]=2)[C:22]#[N:23])[O:8]1
Reactant: N#Cc1ccnc(C=O)c1
Reactant: COP(=O)(OC)C1OC(=O)c2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#Cc1ccnc(C=C2OC(=O)c3ccccc32)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a cooled suspension (ca 0° C.) of [(3-Oxo-1,3-dihydro-isobenzofuran-1-yl)-phosphonic acid dimethyl ester] phosphonate (i) (8.0 g, 33.0 mmol) in THF (400 mL) was added crude 2-formyl-isonicotinonitrile (iid)(30.0 mmol) followed by triethylamine (6.2 mL, 33.0 mmol). The mixture was stirred for 30 minutes at 0° C. and then allowed to warm overnight.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:15]=2)[C:10]([CH:25]=O)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-].C1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:47](#[N:49])[CH3:48]>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:15]=2)[C:10]([CH:25]=[CH:48][C:47]#[N:49])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC#N
Reactant: O=Cc1cn(Cc2ccccc2)c2ccc(OCc3ccccc3)cc12
Agent: [Br-]
Agent: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Product: N#CC=Cc1cn(Cc2ccccc2)c2ccc(OCc3ccccc3)cc12

Procedure:
Following the procedure of Example 55, N-benzyl-5-benzyloxy-3-formylindole is treated with acetonitrile triphenylphosphonium bromide to give N-benzyl-5-benzyloxy-3-(2-cyanovinyl)indole.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:16][O:17][CH2:18][C:19]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)[CH:7]=1.[CH3:38]B1OB(C)OB(C)O1.O1CCOCC1.O.C(=O)([O-])[O-].[K+].[K+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>[C:14]([C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:7]=[C:2]([CH3:38])[CH:3]=[C:4]([CH2:16][O:17][CH2:18][C:19]3([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:23][CH2:24]3)[CH:5]=2)=[CH:9][CH:10]=1)#[N:15]
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(Br)cc(-c3ccc(C#N)cc3)c2)(c2ccccc2)CC1
Reactant: CB1OB(C)OB(C)O1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(COCC2(c3ccccc3)CCN(C(=O)OC(C)(C)C)CC2)cc(-c2ccc(C#N)cc2)c1
Temperature: 120 °C

Procedure:
A microwave tube was charged with tert-butyl 4-(((5-bromo-4′-cyanobiphenyl-3-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (48 mg, 0.09 mmol), trimethyl boroxine (13 μL, 0.09 mmol), and tetrakis(triphenylphosphine) palladium(0) (10 mg, 9 μmol). The tube was flushed with nitrogen, treated with a mixture of 1,4-dioxane/water (9:1, 2 mL) and potassium carbonate (35.1 mg, 0.25 mmol). The tube was sealed and heated at 120° C. for 1 h via microwave. After cooling to room temperature, the reaction was concentrated and purified by preparative HPLC to give 11 mg (27%). LC/MS: tR=3.50 min, 497.33 (MH)+. (Phenomenex C18 4.6×50 mm, 10% MeOH/90% H2O/0.1% TFA→90% MeOH/10% H2O/0.1% TFA, Gradient time=4 min., Flow rate=4 mL/min.).
Reaction SMILES: [CH3:1][CH:2]1[CH:6]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:5][CH2:4][O:3]1.[Cl:13][C:14]1[N:15]=[C:16]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:17]2[S:22][C:21]([CH:23]=O)=[CH:20][C:18]=2[N:19]=1>>[Cl:13][C:14]1[N:15]=[C:16]([N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)[C:17]2[S:22][C:21]([CH2:23][N:10]3[CH2:9][CH2:8][N:7]([CH:6]4[CH2:5][CH2:4][O:3][CH:2]4[CH3:1])[CH2:12][CH2:11]3)=[CH:20][C:18]=2[N:19]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC1OCCC1N1CCNCC1
Product: CC1OCCC1N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
1-(2-methyl-tetrahydro-furan-3-yl)-piperazine was reacted with 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde under reductive amination conditions described in Reference Example 39, to give, after silica chromatography purification the title compound as a white solid (110 mg, 43%).
Reaction SMILES: C(OP([CH:9]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[S:10]1)(=O)OCC)C.[CH2:20]=O.O.C[O-].[Na+]>CO>[CH2:20]=[C:9]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[S:10]1
Reactant: C=O
Reactant: CCOP(=O)(OCC)C1Sc2ccccc2NC1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C=C1Sc2ccccc2NC1=O
Temperature: 0 °C
Yield: 72 %

Procedure:
(3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-yl)-phosphonic acid diethyl ester (12.2 mmol) is dissolved in 40 mL of anhydrous MeOH and formaldehyde (37%) in water (12.2 mmol) is added to the orange solution. NaOMe (2N in MeOH) (12.2 mmol) is added and the reaction is cooled down to 0° C. The solid that precipitates is filtered to give 2-methylene-4H-benzo[1,4]thiazin-3-one. Yield: 72%. 1H NMR (400 MHz, CDCl3): δ 9.03 (s, 1H), 7.06 (m, 2H), 6.94 (m, 1H), 6.81 (m, 1H), 6.80 (s, 1H), 5.62 (s, 1H). MS: (ES+): 178.2 [M+1].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15]O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-].[Li+].P(Br)(Br)[Br:20]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][Br:20])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccc(OCc2ccccc2)cc1
Reactant: BrP(Br)Br
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: BrCc1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of (4-(benzyloxy)phenyl)methanol (2.14 g) and lithium bromide (1.0 g) in N,N-dimethylformamide (20 mL) was cooled to 0° C. To this solution was added PBr3 (1.0 mL). The solution was stirred at room temperature for 2 hours. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate, twice. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 5% ethyl acetate in hexanes to provide the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13](C(OCC)=O)[S:12][N:11]=2)=[CH:6][CH:5]=1)([O-])=O.Cl>O>[S:12]1[CH:13]=[N:14][C:10]([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)=[N:11]1
Reactant: CCOC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)ns1
Agent: Cl
Solvent: O
Product: Nc1ccc(-c2ncsn2)cc1
Temperature: 80 °C

Procedure:
Ethyl cianoformate was added to a dodecane suspension of 5-(4-nitrophenyl)-1,3,4-oxathiazol-2-on, and the mixture was refluxed under heating for 3 hours. After cooling the reaction mixture to room temperature, the precipitation was separated by filtration and washed with hexane. The crude product obtained was purified by silica gel column chromatography to obtain ethyl 3-(4-nitrophenyl)-1,2,4-thiadiazole-5-carboxylate (pale yellow solid). The ethanol suspension of this product was added with water and sodium hydroxide and heated at 85° C. for 40 minutes while stirring. After cooling to room temperature, the mixture was added with 1M hydrochloric acid to make it acidic. The resulting mixture was heated for one hour while stirring on an oil bath at 95° C. The mixture was then cooled to room temperature and added with chloroform and an aqueous sodium hydrogencarbonate to separate an organic layer, which was then washed and dried. The solvent was evaporated under reduced pressure to obtain 3-(4-nitrophenyl)-1,2,4-thiadiazol (pale yellow solid). The ethanol suspension of this product was added with water and 1M hydrochloric acid, heated to 80° C. and added with reduced iron. The reaction mixture was further heated at 80° C. for 50 minutes while stirring and then filtered through Celite. After evaporation of the ethanol in the resulting filtrate under reduced pressure, chloroform and an aqueous sodium hydrogencarbonate were added to the residue to separate an organic layer, which was then washed and dried. The solvent was evaporated under reduced pressure to obtain 4-(1,2,4-thiadiazol-3-yl)aniline (pale yellow solid). Electron Impact-MS (M)+: 177.
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][C:5]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH:22]1[CH2:24][CH2:23]1.O>CN(C=O)C>[CH:22]1([CH2:21][O:12][C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][C:4]=2[O:3][CH:2]([F:13])[F:1])[CH:8]=[O:9])[CH2:24][CH2:23]1
Reactant: O=Cc1ccc(OC(F)F)c(O)c1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.9 %

Procedure:
To a solution of 4-(difluoromethoxy)-3-hydroxybenzaldehyde (18.4 g, 98 mmol) in DMF (200 ml), potassium carbonate (29.7 g, 215 mmol) and KI (16.3 g, 98 mmol) were added followed by (bromomethyl)cyclopropane (14.28 ml, 148 mmol), and the resulting suspension was stirred at RT for 24 hours. The mixture was poured into water (800 ml) and extracted with diethyl ether (3×300 ml); the combined organic layers were dried over Na2SO4 and the solvent was removed under vacuum affording 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzaldehyde (22.5 g, 93 mmol, 94.8% yield, MS/ESI+ 243.1 [MH]+). This product was used without purification.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:9][C:10]([C:12]2[CH:36]=[CH:35][C:15]3[N:16]([CH3:34])[C:17]([NH:19][C:20]4[S:21][C:22]5[CH:28]=[C:27]([O:29][C:30]([F:33])([F:32])[F:31])[CH:26]=[CH:25][C:23]=5[N:24]=4)=[N:18][C:14]=3[CH:13]=2)=[O:11])[CH2:8][CH2:7]1)=[O:5])C.[Li+].[OH-]>>[CH3:34][N:16]1[C:15]2[CH:35]=[CH:36][C:12]([C:10]([NH:9][C:6]3([C:4]([OH:5])=[O:3])[CH2:8][CH2:7]3)=[O:11])=[CH:13][C:14]=2[N:18]=[C:17]1[NH:19][C:20]1[S:21][C:22]2[CH:28]=[C:27]([O:29][C:30]([F:32])([F:31])[F:33])[CH:26]=[CH:25][C:23]=2[N:24]=1
Reactant: CCOC(=O)C1(NC(=O)c2ccc3c(c2)nc(Nc2nc4ccc(OC(F)(F)F)cc4s2)n3C)CC1
Agent: [Li+]
Agent: [OH-]
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NC3(C(=O)O)CC3)ccc21
Yield: 92.5 %

Procedure:
1-{[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carbonyl]-amino}-cyclopropanecarboxylic acid (91 mg) was prepared by following General Procedure E starting from 1-{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carbonyl]-amino}-cyclopropanecarboxylic acid ethyl ester (104 mg), and LiOH (0.5 ml, 2.0 N solution in water). LC/MS: m/z 493.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1.[NH2:32][C@H:33]1[CH2:37][CH2:36][CH2:35][C@H:34]1[C:38]([OH:40])=[O:39]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][C:27]([CH2:28][NH:32][C@@H:33]4[CH2:37][CH2:36][CH2:35][C@@H:34]4[C:38]([OH:40])=[O:39])=[CH:30][CH:31]=3)[N:20]=2)[N:10]=[N:9]1
Reactant: N[C@H]1CCC[C@H]1C(=O)O
Reactant: O=Cc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1
Product: O=C(O)[C@H]1CCC[C@H]1NCc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1

Procedure:
The title compound was prepared following the procedure described for Example 94, but starting from 4-(5-(1-(2-fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde, obtained as described in Example 113, Step 1, (200 mg; 0.48 mmol) and (1R,2S)-2-aminocyclopentanecarboxylic acid (125 mg; 0.97 mmol), to give Example 177 as a white solid. 1H NMR: (TFA-d, 400 MHz) δ 10.08 (2H, d, J=6.0 Hz), 9.40 (2H, d, J=5.9 Hz), 9.18 (2H, d, J=7.9 Hz), 8.87 (1H, t, J=7.5 Hz), 8.79-8.66 (3H, m), 8.55 (1H, t, J=7.9 Hz), 8.28 (1H, t, J=9.3 Hz), 5.62 (1H, d, J=13.2 Hz), 5.48 (1H, d, J=13.3 Hz), 5.01-4.88 (1H, m), 4.49-4.37 (1H, m), 3.46-3.37 (1H, m), 3.36-3.25 (2H, m), 3.20-3.00 (2H, m), 2.97-2.89 (1H, m). LC/MS (Method C): 524 (M+H)+. HPLC (Method I) Rt 13.12 min (Purity: 96.4%).
Reaction SMILES: [NH3:1].[CH:2]1([C:8](Cl)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1>C(Cl)(Cl)Cl>[CH:2]1([C:8]([NH2:1])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: N
Solvent: ClC(Cl)Cl
Product: NC(=O)C1CCCCC1
Yield: 46.1 %

Procedure:
Aqueous Ammonia was Added to solution of cyclohexanecarbonyl chloride (500 mg, 3.41 mmol) in CHCl3 (10 ml). After completion of reaction, the reaction mixture was diluted with CHCl3 (2×30 ml). The organic layer was washed with saturated sodium bicarbonate solution, brine and dried over anhydrous sodium sulfate. The organic layer was concentrated under vacuum, crude compound was washed with hexane (2×8 ml) and dried to afford 200 mg (46.1%) of cyclohexanecarboxamide.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][C:15]([N:17]1[C@H:22]([C:23](=[O:34])[NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=3[F:33])[CH2:21][C@@H:20]3[C@H:18]1[CH2:19]3)=[O:16])[CH:9]=[C:8]2[C:35](=[O:37])[CH3:36])=[O:4].[Li+].[OH-].Cl>C1COCC1.O>[C:35]([C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=2)[N:10]([CH2:14][C:15]([N:17]2[C@H:22]([C:23](=[O:34])[NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=3[F:33])[CH2:21][C@@H:20]3[C@H:18]2[CH2:19]3)=[O:16])[CH:9]=1)(=[O:37])[CH3:36]
Reactant: COC(=O)c1ccc2c(c1)c(C(C)=O)cn2CC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)NCc1cccc(Cl)c1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1cn(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2ccc(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a solution of 3-acetyl-1-{2-[(1R,3S,5R)-3-(3-chloro-2-fluoro-benzylcarbamoyl)-2-aza-bicyclo[3.1.0]hex-2-yl]-2-oxo-ethyl}-1H-indole-5-carboxylic acid methyl ester (141 mg, 0.268 mmol) in THF (3 mL) and water (0.3 mL) was added 2N LiOH (1.07 mL, 2.14 mmol). Stirring of the reaction mixture was continued at 50° C. for 60 h. After cooling to RT, a 1N HCl solution was added to adjust to pH=2-3, and the resulting aqueous suspension was extracted with CH2Cl2 (3×). The combined organics were dried (phase separator) and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30×100 mm, flow: 40 mL/min, eluent: 20-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA) to afford after lyophilization of the purified fractions the title compound as a white solid. MS (LC/MS): 512 [M+H]+; tR (HPLC conditions c): 4.33 min.
Reaction SMILES: [Cl:1][C:2]1[C:9]([NH:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[C:18]([N:22]4[CH2:27][CH2:26][CH:25]([C:28]([F:31])([F:30])[F:29])[CH2:24][CH2:23]4)[C:19]([Cl:21])=[CH:20][C:13]=3[N:12]=2)=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([F:32])[CH:3]=1.[F:33][C:34]([F:42])([F:41])[C:35]1([C:38](O)=[O:39])[CH2:37][CH2:36]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[C:9]([NH:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[C:18]([N:22]4[CH2:27][CH2:26][CH:25]([C:28]([F:30])([F:29])[F:31])[CH2:24][CH2:23]4)[C:19]([Cl:21])=[CH:20][C:13]=3[N:12]=2)=[CH:8][C:5]([CH2:6][NH:7][C:38]([C:35]2([C:34]([F:42])([F:41])[F:33])[CH2:37][CH2:36]2)=[O:39])=[C:4]([F:32])[CH:3]=1
Reactant: Cn1c(Nc2cc(CN)c(F)cc2Cl)nc2cc(Cl)c(N3CCC(C(F)(F)F)CC3)cc21
Reactant: O=C(O)C1(C(F)(F)F)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cn1c(Nc2cc(CNC(=O)C3(C(F)(F)F)CC3)c(F)cc2Cl)nc2cc(Cl)c(N3CCC(C(F)(F)F)CC3)cc21

Procedure:
The title compound was prepared in analogy to the procedure in Example 94, step (c) using 4-chloro-2-fluoro-5-[5-chloro-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzimidazol-2-ylamino]-benzylamine (270 mg; 0.55 mmol), 1-trifluoromethyl-cyclopropanecarboxylic acid (85 mg; 0.55 mmol), HBTU (209 mg; 0.55 mmol), TEA (111 mg; 1.10 mmol) and DMF (5 mL)
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[S:15]([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16].[NH2:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[NH2:35])[C:30]#[N:31].C1N2CCN(CC2)C1>CN1C(=O)CCC1>[CH3:13][C:12]1[C:4]([CH2:3][C:2]2[NH:35][C:34]3[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][C:27]=3[N:26]=2)=[C:5]2[C:9](=[C:10]([CH3:14])[CH:11]=1)[N:8]([S:15]([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:16])=[O:17])[CH:7]=[CH:6]2
Reactant: N#Cc1ccc(N)c(N)c1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C=C(Br)Br)c(C)cc(C)c32)cc1
Agent: C1CN2CCN1CC2
Solvent: CN1CCCC1=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Cc4nc5cc(C#N)ccc5[nH]4)c(C)cc(C)c32)cc1
Temperature: 25 °C

Procedure:
A solution of 4-(2,2-dibromovinyl)-5,7-dimethyl-1-tosyl-1H-indole (130 mg, 0.269 mmol), 3,4-diaminobenzonitrile (46.6 mg, 0.350 mmol), and DABCO (75 mg, 0.673 mmol) in NMP (0.5 mL) was stirred at 100° C. for 19 h. The reaction mixture was cooled to room temperature. The reaction mixture was concentrated and purified by silica gel flash column chromatography (heptanes/EtOAc=1/3 to 0/1) to give the title compound. MS (ESI+) m/z 455.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:18][CH3:19].Cl.[OH-].[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:11](=[O:12])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:18][CH3:19]
Reactant: COc1cc(N2CCC3(CC2)OCCO3)ccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(N2CCC(=O)CC2)ccc1Cl
Temperature: 25 °C
Yield: 99.7 %

Procedure:
A sample of 8-(4-chloro-3-methoxyphenyl)-1,4-dioxa-8-azaspiro[4.5]decane (1.1 g, 2.89 mmol) was treated with 6 M HCl (15 mL) and heated at reflux for 3 h. The mixture was cooled to RT and made basic with 2 M NaOH. The basic mixture was extracted with EtOAc. The extract was dried (Na2SO4) and concentrated on a rotary evaporator to give the crude product. The crude product was purified by flash chromatography (40 g silica gel cartridge and gradient elution from 10 to 40% EtOAc/hexanes) to give 1-(4-chloro-3-methoxyphenyl)piperidin-4-one (690 mg, 2.88 mmol, 51.5% yield) as a yellow oil. 1H-NMR (400 MHz, CDCl3) δ ppm 7.21 (1 H, d, J=8.57 Hz), 6.52 (1 H, d, J=2.64 Hz), 6.47 (1 H, dd, J=8.68, 2.75 Hz), 3.88 (3 H, s), 3.57 (4 H, t, J=6.04 Hz), 2.55 (4 H, t, J=6.04 Hz).
Reaction SMILES: C(OC([N:6]1[CH2:11][CH:10]([O:12][CH2:13][CH3:14])[O:9][C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[N:7]1)=O)C.[OH-].[K+].C(O)C>O>[CH2:13]([O:12][CH:10]1[O:9][C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=2)=[N:7][NH:6][CH2:11]1)[CH3:14]
Reactant: CCOC(=O)N1CC(OCC)OC(c2cccc(C(F)(F)F)c2)=N1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC1CNN=C(c2cccc(C(F)(F)F)c2)O1
Yield: 52 %

Procedure:
The crude 6-ethoxy-5,6-dihydro-2-[3-(trifluoromethyl)phenyl]-4H-1,3,4-oxadiazine-4-carboxylic acid ethyl ester (17 g) from Step C above, was mixed with 12 g of KOH, 20 g of ethanol, and 40 g of water to create a reaction mixture. The reaction mixture was refluxed for 6 hours and then cooled. 50 ml of water was then added to the reaction mixture, followed by extraction with ethyl acetate (4×100 ml). The ethyl acetate extracts were conbined, dried (MgSO4) and the solvent removed, to give 7 g of crude 6-ethoxy-5,6-dihydro-2-[3-(trifluoromethyl)phenyl]-4H-1,3,4-oxadiazine, which was not purified and was used in Step E below.