Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].ClCCl.C(Cl)(C(Cl)=O)=O.C[N:24](C)C=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH2:24])=[O:8]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: NC(=O)c1cc(F)ccc1[N+](=O)[O-]
Temperature: 5 °C

Procedure:
Into a 1-L 3-necked round-bottom flask, was placed 5-fluoro-2-nitrobenzoic acid (25 g, 135.06 mmol, 1.00 equiv), dichloromethane (400 mL) and N,N-dimethylformamide (0.1 g). This was followed by the addition of (COCl)2 (30 g) dropwise with stirring at 0-10° C. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was dissolved in 200 mL of dichloromethane. To this was added ammonia (400 mL) dropwise with stirring at 0-10° C. The resulting solution was stirred for 2 h at room temperature. The solids were collected by filtration. This resulted in 20 g (80%) of 5-fluoro-2-nitrobenzamide as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 7.71 (s, 1H), 7.81 (s, 1H), 8.00 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[C:4]([C:21]#[N:22])[N:3]=1.[NH3:23]>C(O)(C)C>[NH2:23][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[C:4]([C:21]#[N:22])[N:3]=1
Reactant: COc1ccc2c(Cl)nc(C#N)c(-c3cccc(F)c3)c2c1
Reactant: N
Solvent: CC(C)O
Product: COc1ccc2c(N)nc(C#N)c(-c3cccc(F)c3)c2c1

Procedure:
A suspension of 1-chloro-4-(3-fluorophenyl)-6-methoxyisoquinoline-3-carbonitrile in 1.5 mL of 2M NH3 in isopropanol was heated in a sealed tube at 90 C overnight, then heated in a microwave reactor at 170 C for 24 h. The reaction was concentrated and purified by reverse-phase HPLC to give a white solid.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:20][C:19](=[O:21])[NH:18][C:4]=2[N:5]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])[N:7]=1.[NH2:22][C@H:23]([CH3:26])[CH2:24][OH:25]>CN1C(=O)CCC1>[F:17][C:11]1[C:12]([F:16])=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][S:8][C:6]1[N:7]=[C:2]([NH:22][C@H:23]([CH3:26])[CH2:24][OH:25])[C:3]2[CH2:20][C:19](=[O:21])[NH:18][C:4]=2[N:5]=1
Reactant: O=C1Cc2c(Cl)nc(SCc3cccc(F)c3F)nc2N1
Reactant: C[C@@H](N)CO
Solvent: CN1CCCC1=O
Product: C[C@H](CO)Nc1nc(SCc2cccc(F)c2F)nc2c1CC(=O)N2
Temperature: 110 °C
Yield: 24.6 %

Procedure:
The product from example 1, step (e) (0.20 g) in NMP (5 ml) was treated with (R)-2-amino-1-propanol (0.56 g) and the reaction mixture was heated at 110° C. for 2 hours. The mixture was evaporated to dryness and the residue purified (HPLC, Symmetry® C18 column, 0.1% aqueous ammonium acetate:acetonitrile isocratic elution 75:25) to afford the title compound (0.055 g).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=CC=C[CH:2]=1.O1CCC[CH2:16]1>>[C:9]1([C:8]#[C:7][C:1]([CH3:2])([CH3:6])[CH3:16])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: C(#Cc1ccccc1)c1ccccc1
Reactant: C1CCOC1
Product: CC(C)(C)C#Cc1ccccc1
Temperature: 60 °C
Yield: 100 %

Procedure:
A solution containing W(CCMe3)(Cl3)(OPEt3) (0.43 g, 0.866 mmol) and diphenylacetylene (0.18 g, 1.0 mmol) in 2 ml of tetrahydrofuran was heated to 60° C. for 2 hours. During this time, the color of the reaction mixture changed from blue to green. Phenyl-t-butylacetylene (100% yield versus tungsten) was observed in the reaction mixture by gas chromatography. The reaction mixture was filtered and PMe3 (0.30 ml, 3.0 mmol) was added by syringe. The color of the solution turned yellow, and after the addition of 2 ml pentane, yellow crystals precipitated from solution. The product was collected by filtration and was recrystallized from a mixture of tetrahydrofuran and pentane at -30° C.; total yield 0.47 g (89%) W(CPh)Cl3 (PMe3)3.
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH3:13][C:14]1([CH3:21])[CH2:17][CH:16]([C:18](Cl)=[O:19])[CH2:15]1>O1CCCC1.Cl>[CH2:9]([O:8][C:6](=[O:7])[C:5]1[CH:11]=[CH:12][C:2]([C:18]([CH:16]2[CH2:17][C:14]([CH3:21])([CH3:13])[CH2:15]2)=[O:19])=[CH:3][CH:4]=1)[CH3:10]
Reactant: CC1(C)CC(C(=O)Cl)C1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C(=O)C2CC(C)(C)C2)cc1
Temperature: -40 °C
Reaction time: 0.67 h
Yield: 104.1 %

Procedure:
Ethyl 4-iodobenzoate (600 mg, 2.17 mmol) was dissolved in tetrahydrofuran (6.0 mL) and brought to −40° C. Isopropylmagnesium chloride lithium chloride complex solution (1.0 M in tetrahydrofuran, 0.365 mL, 2.17 mmol) was added dropwise and the yellow-red solution was stirred at −40° C. for 40 min. Cul (124 mg, 0.65 mmol) was added in one portion and the mixture was then stirred at −15° C. for 20 min to dissolve all the solids. The yellow solution was then brought back to −40° C. and 3,3-dimethylcyclobutanecarbonyl chloride (Intermediate 22) (450 mg, 3.07 mmol) was added dropwise. The color changed from slightly green to yellow, then red, then yellow. The mixture was warmed to 0° C. over 2 h in the same bath. The mixture was diluted with 1 N HCl and extracted with ethyl acetate (3 times). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude material was partially purified by silica gel flash chromatography (ethyl acetate/heptane) to give impure 4-(3,3-dimethyl-cyclobutanecarbonyl)-benzoic acid ethyl ester (588 mg). 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J=8.4 Hz, 2H) 7.94 (d, J=8.4 Hz, 2H) 4.38-4.48 (m, 2H) 3.90 (quin, J=8.8 Hz, 1H) 2.16-2.29 (m, 2H) 2.04-2.13 (m, 2H) 1.42 (t, J=7.2 Hz, 3H) 1.28 (s, 3H) 1.09 (s, 3H); MS (M+1): 261.4.
Reaction SMILES: S(Cl)(Cl)=O.[O:5]1[CH:9]=[CH:8][C:7]([C:10]([OH:12])=O)=[CH:6]1.[NH2:13][NH:14][C:15]([NH2:17])=[S:16].C(=O)(O)[O-].[Na+]>C1COCC1.ClCCl>[O:5]1[CH:9]=[CH:8][C:7]([C:10]([NH:13][NH:14][C:15]([NH2:17])=[S:16])=[O:12])=[CH:6]1
Reactant: O=C(O)c1ccoc1
Reactant: NNC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: NC(=S)NNC(=O)c1ccoc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
Thionyl chloride (3 mL) was added to a dichloromethane (10 mL) solution of 3-furancarboxylic acid (2.50 g, 22.3 mmol) under ice cooling, and the mixture was heated to reflux for 2 hours. The solvent was distilled off. After that, the residue was concentrated by the addition of toluene and added to a THF (50 mL) solution of thiosemicarbazide (4.47 g, 49.1 mmol) under ice cooling, and the mixture was stirred overnight at room temperature. To the reaction solution, a saturated aqueous solution of sodium bicarbonate was added. The mixture was subjected to extraction with ethyl acetate and dried over anhydrous sodium sulfate, and then, the solvent was distilled off to obtain 1-(3-furoyl)thiosemicarbazide (3.03 g, 16.4 mmol) (yield: 74%).
Reaction SMILES: Cl.[C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12]([C@@H:14]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][NH:15]2)=[O:13])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.[O:30]=[S:31]1(=[O:40])[CH2:36][CH2:35][N:34]([C:37](Cl)=[O:38])[CH2:33][CH2:32]1>CN(C1C=CN=CC=1)C.CCOC(C)=O>[C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12]([C@@H:14]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]2[C:37]([N:34]2[CH2:35][CH2:36][S:31](=[O:40])(=[O:30])[CH2:32][CH2:33]2)=[O:38])=[O:13])[CH:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCCN2)no1
Reactant: O=C(Cl)N1CCS(=O)(=O)CC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCCN2C(=O)N2CCS(=O)(=O)CC2)no1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of (S)-perhydro-azepine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide hydrochloride (0.30 g, 1.13 mmol), DIPEA (0.32 g, 2.48 mmol) and DMAP (16.0 mg, 0.13 mmol) is stirred at room temperature for 15 minutes. 1,1-Dioxo-1λ6-thiomorpholine-4-carbonyl chloride (0.27 g, 1.35 mmol) (prepared according to method M step 1) is added drop wise at 0° C. to the reaction mixture that is slowly warmed up to room temperature and stirred for 14 hours. The reaction mixture is diluted with EtOAc, washed with water and brine. After drying the organic phase over anhydrous Na2SO4, removal of the solvent under reduced pressured affords the crude product that is purified by prep TLC to afford the title product; m/z 427 [M+H+].
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1)[N:9]=[CH:8]2)#[C:2][CH2:3][CH3:4].I[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[C:27](/[CH:29]=[CH:30]/[C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)#[N:28]>>[C:21]1(/[C:2](/[CH2:3][CH3:4])=[C:1](\[C:34]2[CH:35]=[CH:36][C:31](/[CH:30]=[CH:29]/[C:27]#[N:28])=[CH:32][CH:33]=2)/[C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[N:10]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[N:9]=[CH:8]3)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Ic1ccccc1
Reactant: CCC#Cc1ccc2c(cnn2C2CCCCO2)c1
Reactant: N#C/C=C/c1ccc(B(O)O)cc1
Product: CC/C(=C(/c1ccc(/C=C/C#N)cc1)c1ccc2c(cnn2C2CCCCO2)c1)c1ccccc1

Procedure:
The title compound was prepared from Intermediate 3, iodobenzene, and (E)-(4-(2-cyanovinyl)phenyl)boronic acid following General Procedure C. 1H NMR (DMSO-d6, 300 MHz): δ 8.11 (s, 1H), 7.81 (d, 1H), 7.64 (m, 1H), 7.47 (d, 1H), 7.32 (d, 2H), 7.27-7.12 (m, 6H), 6.90 (d, 2H), 6.29 (d, 1H), 5.86 (dd, 1H), 3.97-3.85 (m, 1H), 3.78-3.70 (m, 1H), 2.47-2.36 (m, 3H), 2.06-1.96 (m, 2H), 1.78-1.67 (m, 1H), 1.63-1.51 (m, 2H), 0.89 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][OH:18])=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:22]([O:26][C:27]1(OCCCC)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[CH2:23][CH2:24][CH3:25]>>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][O:18][C:27]3([O:26][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CCCCOC1(OCCCC)CCCCC1
Reactant: CC(C)c1nc(CCO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Product: CCCCOC1(OCCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)n2C)CCCCC1
Yield: 29 %

Procedure:
The compound 22 (345 mg, 1 mmol) was converted to the acetal with 1,1-di-n-butoxycyclohexane (2.28 g, 00 mmol) in the same manner as the example 20 to give the compound 34 (145 mg, 29%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]([C:28]2[CH:29]=[CH:30][C:25]([C:24]([F:35])([F:34])[F:23])=[CH:26][CH:27]=2)=[CH:17][CH:16]=1)=[O:22]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Yield: 48.8 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-(trifluoromethyl)biphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), 4-(trifluoromethyl)phenylboronic acid (0.035 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.038 g (49%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-(trifluoromethyl)biphenyl-4-carboxamide as a white solid.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]([NH:5][CH2:6][CH:7]=[CH:8][C:9]1[C:10]([NH2:24])=[N:11][C:12](=[O:23])[N:13]([CH:22]=1)[C@@H:14]1[O:21][C@H:18]([CH2:19][OH:20])[C@@H:16]([OH:17])[CH2:15]1)=[O:4].FC(F)(F)[C:29]([CH:31](N)[CH:32]=[CH:33][C:34]1[C:35](N)=NC(=O)N([CH:47]=1)[C@@H]1O[C@H](CO)[C@@H](O)C1)=O.C([OH:55])C>>[C:35]([NH:24][C:10]1[C:9]([CH:8]=[CH:7][CH2:6][NH:5][C:3](=[O:4])[C:2]([F:25])([F:1])[F:26])=[CH:22][N:13]([C@@H:14]2[O:21][C@H:18]([CH2:19][OH:20])[C@@H:16]([OH:17])[CH2:15]2)[C:12](=[O:23])[N:11]=1)(=[O:55])[C:34]1[CH:47]=[CH:29][CH:31]=[CH:32][CH:33]=1
Reactant: Nc1nc(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1C=CCNC(=O)C(F)(F)F
Reactant: Nc1nc(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1C=CC(N)C(=O)C(F)(F)F
Reactant: CCO
Product: O=C(Nc1nc(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1C=CCNC(=O)C(F)(F)F)c1ccccc1

Procedure:
Repeating the nucleoside precursor synthesis procedure of Example I, but replacing 5-chloromercuri-2'-deoxyuridine with 5-chloromercuri-2'-deoxycytidine is productive of 5-(3-trifluoroacetylaminopropenyl)-2'-deoxycytidine (UV max 287 mn). Purified 5-(3-trifluoroacetyl-aminopropenyl)-2'-deoxycytidine (1.3 g, 4.6 mmol) is stirred in 80 ml anhydrous ethanol, benzoyl anhydride (1.5 g, 7 mmol) is added, and the reaction refluxed. Five additional 1.5 g portions of benzoyl anhydride are added hourly. After the reaction is judged complete by thin layer chromatography [silica plates eluting n-butanol/methanol/conc NH4OH/H2O (60:20:1:20)in 6-10 hours, the reaction is cooled and concentrated under reduced pressure to a semisolid. The solid is triturated with ether three times, decanted and dried. The crude product is crystallized from water to give chromatographically pure N4 -benzoyl-5- (3-trifluoroacetylaminopropenyl)-2'-deoxycytidine as a white solid. The product decomposes above 120° C.; UV λmax 311 nm.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([N:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[C:17]([O:19][CH2:20][CH3:21])=N)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N1C=CC=CC=1.[SH2:28]>C1COCC1>[CH2:2]([O:9][C:10]([N:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[C:17]([O:19][CH2:20][CH3:21])=[S:28])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=N)C1CCCN1C(=O)OCc1ccccc1
Reactant: S
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=S)C1CCCN1C(=O)OCc1ccccc1
Temperature: -20 °C
Yield: 47 %

Procedure:
2-Ethoxycarbonimidoyl-pyrrolidine-1-carboxylic acid benzyl ester hydrochloride (42.8 g, 146.0 mmol) was dissolved in THF (150 mL) and cooled to −20° C. Pyridine (80 ml) was added to the reaction and H2S was bubbled through the reaction for 60 min. The reaction's temperature was maintained at −20° C. for 2 hours while stirring. The pH was adjust to pH=4 by addition of 5M HCl. The resulting solution was transferred to a separatory funnel and extracted with diethyl ether (3×100 mL). The organic layers were combined and washed with brine (100 ml). The organic layer was dried over MgSO4 and concentrated under vacuo to afford 20.0 g (47%) of 2-ethoxythiocarbonyl-pyrrolidine-1-carboxylic acid benzyl ester as a yellow oil.
Reaction SMILES: [F:1][C:2]1[C:11]([CH:12]([C:14]2[N:18]3[N:19]=[C:20](/[C:23](=[N:25]/[OH:26])/[CH3:24])[CH:21]=[CH:22][C:17]3=[N:16][N:15]=2)[CH3:13])=[C:10]([F:27])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.O=C(Cl)[O:30][C:31](Cl)(Cl)Cl.[NH3:36]>C1COCC1>[C:31]([O:26]/[N:25]=[C:23](/[C:20]1[CH:21]=[CH:22][C:17]2[N:18]([C:14]([C@@H:12]([C:11]3[C:2]([F:1])=[C:3]4[C:8](=[CH:9][C:10]=3[F:27])[N:7]=[CH:6][CH:5]=[CH:4]4)[CH3:13])=[N:15][N:16]=2)[N:19]=1)\[CH3:24])(=[O:30])[NH2:36]
Reactant: N
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: C/C(=N\O)c1ccc2nnc(C(C)c3c(F)cc4ncccc4c3F)n2n1
Solvent: C1CCOC1
Product: C/C(=N\OC(N)=O)c1ccc2nnc([C@H](C)c3c(F)cc4ncccc4c3F)n2n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 57.4 %

Procedure:
Previously prepared (E)-1-(3-(1-(5,7-difluoroquinolin-6-yl)ethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone oxime (75-R, 100 mg, 0.271 mmol) in anhydrous THF (8 mL) was added diphosgene (0.1 mL, 0.829 mmol) dropwise at 0° C., and the reaction mixture was heated at 50° C. for 4 hr. Oil bath was removed, and the reaction mixture was cooled in an ice-water bath. An ammonia solution (0.5 N in dioxane, 8.0 mL, 4.0 mmol) was added dropwise. The temperature was allowed to rise to rt naturally, and the reaction mixture was stirred at rt overnight. Solvent was evaporated, and the residue was purified by column chromatography (8% methanol in ethyl acetate as eluent) to afford 64 mg (45.8% yield) of title compound as white solid, which was unstable at nucleophiles such as methanol, and was pro to degrade into starting material 75-R. 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.96 (d, 1H), 8.44 (d, 1H), 8.34 (d, 1H), 8.10 (d, 1H), 7.56-7.74 (m, 2H), 7.34 (s br, 2H), 5.27 (q, 1H), 2.02 (d, 3H), 2.03 (s, 3H). LCMS (method B): [MH]+=412, tR=2.25 min.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=O.[NH2:11][C:12]1[CH:13]=[C:14]2[C:18]3=[C:19]([CH2:21][S:22][CH2:23][CH2:24][N:17]3[C@H:16]3[CH2:25][CH2:26][N:27](C(OC(C)(C)C)=O)[CH2:28][C@@H:15]23)[CH:20]=1>>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4][NH:11][C:12]1[CH:13]=[C:14]2[C:18]3=[C:19]([CH2:21][S:22][CH2:23][CH2:24][N:17]3[C@H:16]3[CH2:25][CH2:26][NH:27][CH2:28][C@@H:15]23)[CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCSC3
Reactant: O=Cc1c(F)cccc1F
Product: Fc1cccc(F)c1CNc1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCSC2

Procedure:
Using 2,6-difluorobenzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate from EXAMPLE 33, Part B was converted into the title compound of EXAMPLE 161. 1H NMR(CDCl3) δ 7.23-7.15 (m, 1H), 6.88-6.80 (m, 2H), 6.42 (s, 1H), 6.28 (s, 1H), 4.31 (broad s, 2H), 3.64 (s, 2H), 3.55-3.45 (m, 1H), 3.37-3.23 (m, 2H), 3.15-2.80 (m, 6H), 2.60-2.50 (m, 1H), 2.05-1.82 (m, 2H). LRMS (ES)+: 388.4 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[N:15][N:14]=[N:13]2)=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].O.[OH-].[Li+]>O1CCCC1.O.C(OCC)C>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[N:15][N:14]=[N:13]2)=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(-n2cnnn2)ccc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: Cc1ccc(-n2cnnn2)cc1C(=O)O
Reaction time: 2 h

Procedure:
Combine methyl 2-methyl-5-(1H-tetrazol-1-yl)benzoate (5.2 g, 23.9 mmol) and lithium hydroxide hydrate (2.0 g, 47.7 mmol) in tetrahydrofuran/water (50 mL/50 mL). Heat to reflux. After 2 hours, dilute with diethyl ether and separate the layers. Extract the aqueous layer three times with diethyl ether. Extract the combined diethyl ether layers three times with a 1 M sodium hydroxide solution (20 mL). Combine the aqueous layers, acidify with a 1 M aqueous hydrochloric acid solution (pH about 1) to give a solid. Collect the solid by filtration and recrystallize form water to give the title compound.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5]O.[Cl:7][C:8]1[CH:16]=[C:12]([C:13]([OH:15])=[O:14])[C:11]([OH:17])=[C:10]([I:18])[CH:9]=1>CCOC(C)=O>[Cl:7][C:8]1[CH:16]=[C:12]([C:13]([O:15][CH3:5])=[O:14])[C:11]([OH:17])=[C:10]([I:18])[CH:9]=1
Reactant: CO
Reactant: O=C(O)c1cc(Cl)cc(I)c1O
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Cl)cc(I)c1O

Procedure:
Thionyl chloride (30 mL, 411 mmol) is added dropwise to methanol (100 mL) in an ice bath. The addition is controlled to hold the temperature at 25° C. Upon completion of the addition 6 (25 g, 84 mmol) is added and the reaction heated to reflux for 4 hours. The solids dissolve at first then after 2 hours solids start to come out of solution. After 4 hours TLC (hex:EtOAc; 9:1) shows no starting material. The reaction is cooled in the refrigerator for 12h. The solids formed are filtered washed with water (30 mL), and dried under vacuum at 27° C. to yield methyl 5-chloro-3-iodosalicylate as an off white solid. (mp 143°-145° C.)
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=[O:7])=[C:4]([Cl:12])[CH:3]=1.[N+](=[CH2:15])=[N-]>C(OCC)(=O)C.C(OCC)C>[CH3:15][O:7][C:6](=[O:8])[C:5]1[C:9]([CH3:11])=[CH:10][C:2]([Br:1])=[CH:3][C:4]=1[Cl:12]
Reactant: Cc1cc(Br)cc(Cl)c1C(=O)O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COC(=O)c1c(C)cc(Br)cc1Cl
Reaction time: 1 h
Yield: 113 %

Procedure:
4-Bromo-2-chloro-6-methylbenzoic acid (1.10 g, 4.41 mmol) was dissolved in ethyl acetate (15 mL). A solution of diazomethane in diethyl ether was added until the yellow colour persisted. After fifteen minutes the reaction was quenched with acetic acid. After one hour, the mixture was washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, filtered and concentrated to provide the title compound as a yellow oil (1.31 g, 113%). 1H NMR CDCl3: 7.43 (s, 1H), 7.31 (s, 1H), 3.94 (s, 3H), 2.33 (s, 3H).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:24]2[C:23]([CH3:25])=[C:22]([CH3:26])[N:21]=[C:20]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:19]=2[N:18]=[C:17]1[CH3:34]>CN(C)C=O>[CH3:34][C:17]1[N:16]([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:24]2[C:23]([CH3:25])=[C:22]([CH3:26])[N:21]=[C:20]([O:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:19]=2[N:18]=1
Reactant: Sc1ccccc1
Reactant: Cc1nc(Oc2ccccc2)c2nc(C)n(CCCCCCl)c2c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(Oc2ccccc2)c2nc(C)n(CCCCCSc3ccccc3)c2c1C
Yield: 91.7 %

Procedure:
Benzenethiol (2.42 mL, 23.6 mmol) was added dropwise to a suspension of sodium hydride (0.944 g of 60%, 23.6 mmol) in anhydrous N,N-dimethylformamide (50 mL) and stirred until a clear solution was obtained. A solution of 1-(5-chloropentyl)-2,6,7-trimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridine (6.5 g, 18.2 mmol) in anhydrous N,N-dimethylformamide (50 mL) was added dropwise. The reaction mixture was stirred at ambient temperature for 2 hours, then it was quenched with water and extracted with ethyl acetate (300 mL). The extract was washed with water (5×75 mL), dried over magnesium sulfate and then concentrated under reduced pressure to provide 7.20 g of 2,6,7-trimethyl-4-phenoxy-1-[5-(phenylthio)pentyl]-1H-imidazo[4,5-c]pyridine.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:19]=[C:13]3[CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][N:12]3[N:11]=2)=[CH:5][C:4]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([N:26]3[C:38](=[O:39])[C:37]4[N:29]([C:30]5[C@@H:31]6[CH2:40][C@H:34]([C:35]=5[CH:36]=4)[CH2:33][CH2:32]6)[CH2:28][CH2:27]3)[C:21]=2[CH:41]=[O:42])=[CH:3]1.[BH4-].[Na+]>CO>[OH:42][CH2:41][C:21]1[C:22]([N:26]2[CH2:27][CH2:28][N:29]3[C:30]4[CH:31]5[CH2:40][CH:34]([C:35]=4[CH:36]=[C:37]3[C:38]2=[O:39])[CH2:33][CH2:32]5)=[N:23][CH:24]=[CH:25][C:20]=1[C:4]1[CH:5]=[C:6]([NH:9][C:10]2[CH:19]=[C:13]3[CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][N:12]3[N:11]=2)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1
Reactant: CN1CCn2nc(Nc3cc(-c4ccnc(N5CCn6c(cc7c6[C@H]6CC[C@@H]7C6)C5=O)c4C=O)cn(C)c3=O)cc2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1CCn2nc(Nc3cc(-c4ccnc(N5CCn6c(cc7c6C6CCC7C6)C5=O)c4CO)cn(C)c3=O)cc2C1
Temperature: 20 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
A solution of 167h (120 mg, 0.21 mmol) in methanol (20 mL) was added NaBH4 (24 mg, 0.63 mmol). The mixture was stirred at 20° C. for 2 h. The reaction was quenched with water and concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 167 (98 mg, 83%) as a yellow solid. MS-ESI: [M+H]+ 567.3. 1H NMR (500 MHz, DMSO-d6) δ 8.48 (d, J=5.0 Hz, 1H), 8.19 (s, 1H), 8.05 (d, J=2.5 Hz, 1H), 7.40 (s, 1H), 7.32 (d, J=5.0 Hz, 1H), 6.53 (d, J=5.5 Hz, 1H), 5.89 (s, 1H), 4.98 (t, J=5.0 Hz, 1H), 4.48-4.30 (m, 3H), 4.27-4.22 (m, 2H), 3.92-3.91 (m, 2H), 3.86-3.84 (m, 1H), 3.60 (s, 3H), 3.52-3.33 (m, 3H), 3.29 (ps, 1H), 2.79-2.77 (m, 2H), 2.35 (s, 3H), 1.87-1.76 (m, 3H), 1.60-1.59 (m, 1H), 1.09-0.91 (m, 2H).