Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@H:12]2[OH:13])=[C:4]([S:20][NH2:21])[N:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:27]>C(O)C.O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@H:12]2[OH:13])=[C:4]([S:20]([NH2:21])=[O:27])[N:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: NSc1nc(N)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Solvent: CCO
Solvent: O
Product: Nc1nc(S(N)=O)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@@H]3O)c2n1
Reaction time: 1.5 h
Yield: 64.6 %

Procedure:
A solution of 49 (1.5 g, 4.7 mmol) in ethanol (350 mL) and water (50 mL) was cooled to 0° C. To this cold solution was added m-chloroperoxybenzoic acid (80%, 0.90 g, 4.45 mmol) in ethanol (50 mL) during 1.5 h. After the addition, the reaction mixture was stirred at ice-bath temperature for 1.5 h. The solvent was evaporated under reduced pressure and the residue was dissolved in methanol (50 mL). Silica gel (≈5 g) was added and evaporated to dryness. The dried silica gel was placed on top of a flash silica gel column and the column was eluted with ethyl acetate→methanol gradient. The pure compound crystallized out after concentration of the homogeneous fractions. The product was collected by filtration and dried to give 0.95 g (60%) of the title compound, mp >200° C. (dec.): IR (KBr): 1120 (S=O), 3100-3600 (NH2, OH)cm-1 : UV: λmax (pH 1) 220 nm (ε17,900), 249 (7,600), 330 (5,100): λmax (pH 7) 225 nm (ε24,100), 248 (sh) (6,100), 323 (8,000): λmax (pH 11) 224 nm (ε 21,000), 244 (sh) (6,600), 322 (6,600): 1H NMR (DMSO-d6): δ 6.17 (d, J 4.08 Hz, C1'H), 6.50 (s, 2, SONH2, exchanged with D2O), 6.97 (s, 2, NH2, exchanged with D2O), 8.25 (s, 1, C8H), and other sugar protons. Anal. Calcd. for C10H14N6O5S (330.32): C, 36.36; H, 4.27; N, 25.44; S, 9.71. Found: C, 36.65; H, 4.09; N, 25.19; S, 9.56.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][SiH2]C(C)(C)CCC)[CH:5]=[CH:4][C:3]=1[C:16]#[C:17]I.[Cu](C#N)[C:20]#[N:21].[Br-].[Li+].Cl>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:16]#[C:17][C:20]#[N:21]
Reactant: CCCC(C)(C)[SiH2]Oc1ccc(C#CI)c(F)c1
Reactant: N#C[Cu]C#N
Agent: Cl
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CC#Cc1ccc(O)cc1F

Procedure:
To a solution of 25 mmol of 1-(2-fluoro-4-dimethylbutylsilyloxyphenyl)-2-iodoethyne in 50 ml of tetrahydrofuran were added copper cyanide and lithium bromide and the solution was reacted under reflux heating for 3 hours. After completion of the reaction, the solution was poured into a hydrochloric acid solution of ferric chloride and extracted with toluene. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford 20 mmol of 2-fluoro-4-hydroxyphenylpropiolonitrile as a colourless solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][O:6][C:7](=[O:22])[C:8]1[C:13]([C:14]2([Cl:21])[CH2:18][C:17]([F:19])=[C:16]([NH2:20])[S:15]2)=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].C(=O)([O-])[O-].[Ca+2].[C:28](Cl)(Cl)=[S:29].C(=O)=O>ClCCl.O>[CH3:1][O:2][C:3]([CH2:5][O:6][C:7](=[O:22])[C:8]1[C:13]([C:14]2([Cl:21])[CH2:18][C:17]([F:19])=[C:16]([N:20]=[C:28]=[S:29])[S:15]2)=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: COC(=O)COC(=O)c1ccccc1C1(Cl)CC(F)=C(N)S1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [Ca+2]
Solvent: O
Solvent: ClCCl
Product: COC(=O)COC(=O)c1ccccc1C1(Cl)CC(F)=C(N=C=S)S1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 3.8 g of the 5-amino-2-chloro-4-fluoro-thiolbenzoic acid (methoxycarbonylmethyl) ester obtained in accordance with Example P2 in 100 ml of dichloromethane is added dropwise at 25°-30° C. to a suspension of 6 g of calcium carbonate, 4 ml of thiophosgene, 20 ml of dichloromethane and 20 ml of water. After the evolution of carbon dioxide has ceased, the mixture is stirred for 18 hours at room temperature. After filtration and washing with water, the organic phase is separated off, dried over sodium sulfate and then concentrated by evaporation, yielding 4.8 g of 2-chloro-4-fluoro-5-isothiocyanato-thiolbenzoic acid (methoxycarbonylmethyl) ester in the form of an oil which is used in the next reaction step without further purification.
Reaction SMILES: [CH3:1][C:2]1[S:13][C:5]2[CH2:6][N:7]([CH3:12])[CH2:8][CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=1.[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1F>>[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:11][CH:10]1[CH2:9][CH2:8][N:7]([CH3:12])[CH2:6][C:5]2[S:13][C:2]([CH3:1])=[CH:3][C:4]1=2
Reactant: Cc1cc2c(s1)CN(C)CCC2O
Reactant: Fc1ccccc1Br
Product: Cc1cc2c(s1)CN(C)CCC2Oc1ccccc1Br

Procedure:
The same method as in Example 1 was conducted using 2,7-dimethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepin-4-ol (Reference Example 23) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2-bromo-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[O:4][CH2:3]1.Br[CH:23]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][N:36]1[C:40](=[O:41])[C:39]2=[CH:42][CH:43]=[CH:44][CH:45]=[C:38]2[C:37]1=[O:46])[C:24]([O:26][CH2:27][CH3:28])=[O:25].C(#N)C>C(N(CC)CC)C>[CH2:27]([O:26][C:24]([C@H:23]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[O:4][CH2:3]1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][N:36]1[C:37](=[O:46])[C:38]2=[CH:45][CH:44]=[CH:43][CH:42]=[C:39]2[C:40]1=[O:41])=[O:25])[CH3:28]
Reactant: CCOC(=O)C(Br)CCCCCCCN1C(=O)c2ccccc2C1=O
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)COc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)[C@@H](CCCCCCCN1C(=O)c2ccccc2C1=O)N[C@H]1COc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Temperature: 80 °C
Yield: 13.4 %

Procedure:
A mixture of tert-butyl 3(S)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (2.1 g), ethyl 2-bromo-9-phthalimidononanoate (3 g), acetonitrile (100 ml) and triethylamine (0.96 g) is heated at 80° C. for 3 days. After evaporation of the solvent, ethyl acetate (200 ml) and water (150 ml) are added to the residue. The ethyl acetate layer is separated, dried over anhydrous magnesium sulfate and evaporated in vacuo. The oily residue is chromatographed on silica gel using hexane-ethyl acetate (2:1-1:1) as an eluent. Evaporation of the first eluate gives tert-butyl 3(S)-[1(R)-ethoxycarbonyl-8-phthalimidooctyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.6 g) as a colorless oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[N:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[CH:24]=[N:25][N:26]([C:29]4[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][N:30]=4)[C:27]=3[CH3:28])=[O:22])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[CH3:28][C:27]1[N:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:37])([F:36])[F:38])=[CH:31][N:30]=2)[N:25]=[CH:24][C:23]=1[C:21]([NH:20][C:17]1[CH:18]=[N:19][C:14]([C:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=2)=[CH:15][CH:16]=1)=[O:22]
Reactant: Cc1c(C(=O)Nc2ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)nc2)cnn1-c1ccc(C(F)(F)F)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C(=O)Nc2ccc(C3=CCNCC3)nc2)cnn1-c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 62.9 %

Procedure:
To N-[6-(1-tert-butyloxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)pyridin-3-yl]-5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (3.53 g) were added dichloromethane (70 ml) and trifluoroacetic acid (14 ml), and stirred at room temperature for 4.5 hours. To the reaction solution was added 4 N aqueous solution of sodium hydroxide under ice-cooling, and the precipitated solid was purified with basic silica gel chromatography (chloroform/methanol) to give the titled compound (1.8 g) as a yellow solid. MS (ESI) m/z: 429 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:32]([F:35])([F:34])[F:33])=[C:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[C:20]4[CH2:21][N:22](C(OC(C)(C)C)=O)[CH2:23][CH2:24][C:19]=4[NH:18][N:17]=3)=[O:15])[CH2:10][CH2:9]2)[CH:7]=1.[ClH:36]>C(Cl)Cl.CCOCC>[ClH:36].[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:32]([F:35])([F:33])[F:34])=[C:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[C:20]4[CH2:21][NH:22][CH2:23][CH2:24][C:19]=4[NH:18][N:17]=3)=[O:15])[CH2:10][CH2:9]2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(C(=O)N3CCC(c4cc(F)ccc4C(F)(F)F)CC3)c2C1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(c1n[nH]c2c1CNCC2)N1CCC(c2cc(F)ccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
To a solution of tert-butyl 3-(4-(5-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (45, 120 mg, 0.24 mmol) in CH2Cl2 (2 mL) was added HCl (2N in Et2O, 2 mL). The mixture stirred for 18 h at ambient temperature. Additional HCl (2N in Et2O, 1 mL) was added and the mixture was stirred at ambient temperature for 3 h. The reaction mixture was diluted with Et2O (20 mL) and the resulting solids were collected by filtration to provide (4-(5-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone hydrochloride (46) as a white solid (104 mg, 99%): 1H NMR (300 MHz, DMSO-d6) δ 9.54-9.19 (m, 2H), 7.84 (dd, J=9.0, 5.7 Hz, 1H), 7.60-7.51 (m, 1H), 7.32-7.20 (m, 1H), 5.32-5.12 (m, 1H), 4.78-4.60 (m, 1H), 4.29-4.16 (m, 2H), 3.43-3.30 (m, 2H, overlaps with H2O), 3.26-3.06 (m, 2H), 2.95 (t, J=5.4 Hz, 2H), 2.89-2.72 (m, 1H), 1.84-1.65 (m, 4H) missing N—H pyrazole; ESI MS m/z 397 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([C:9]1[S:13][C:12]([CH2:14]O)=[N:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].C(N(CC)CC)C.CS(Cl)(=O)=O.[CH:30]1([CH2:33][NH:34][C:35]([NH:37][C:38]2[CH:43]=[CH:42][C:41]([C:44]([N:46]3[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]3)=[O:45])=[CH:40][CH:39]=2)=[O:36])[CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH:30]1([CH2:33][NH:34][C:35]([NH:37][C:38]2[CH:39]=[CH:40][C:41]([C:44]([N:46]3[CH2:51][CH2:50][N:49]([CH2:14][C:12]4[S:13][C:9]([C:3]([OH:8])([C:4]([F:7])([F:6])[F:5])[C:2]([F:17])([F:16])[F:1])=[CH:10][N:11]=4)[CH2:48][CH2:47]3)=[O:45])=[CH:42][CH:43]=2)=[O:36])[CH2:31][CH2:32]1
Reactant: O=C(NCC1CC1)Nc1ccc(C(=O)N2CCNCC2)cc1
Reactant: OCc1ncc(C(O)(C(F)(F)F)C(F)(F)F)s1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCC1CC1)Nc1ccc(C(=O)N2CCN(Cc3ncc(C(O)(C(F)(F)F)C(F)(F)F)s3)CC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 0.5 %

Procedure:
To a stirring solution of 1,1,1,3,3,3-hexafluoro-2-(2-(hydroxymethyl)thiazol-5-yl)propan-2-ol (0.533 mmol, 150 mg) and triethylamine (1.600 mmol, 162 mg) in dichloromethane (4 mL) at 0° C. was added methanesulfonyl chloride (0.533 mmol, 61.1 mg). The mixture was stirred at 0° C. for 1 hour before warming to room temperature and stirring for 1 hour. The reaction mixture was diluted with dichloromethane (50 mL) and washed with water (2×20 mL). The organic phase was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in acetonitrile (4 mL) and 1-(cyclopropylmethyl)-3-(4-(piperazine-1-carbonyl)phenyl)urea (0.635 mmol, 192 mg) was added followed by potassium carbonate (1.905 mmol, 263 mg). The mixture was heated to reflux for 6 hours then was cooled, diluted with dichloromethane (75 mL) and washed with water (2×20 mL). The organic phase was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by HPLC, strong cation exchange column chromatography and silica gel column chromatography (10% methanol/90% dichloromethane) to afford the title compound (1.5 mg).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=2)(O)[CH:11]([N:13]2[N:17]=[N:16][CH:15]=[N:14]2)[CH3:12])=[CH:6][CH:5]=1.C(N(S(F)(F)[F:38])CC)C.[OH-].[K+].O>ClCCl>[F:1][C:2]([F:31])([F:30])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=2)([F:38])[CH:11]([N:13]2[N:17]=[N:16][CH:15]=[N:14]2)[CH3:12])=[CH:6][CH:5]=1
Reactant: CC(n1ncnn1)C(O)(c1ccc(OC(F)(F)F)cc1)c1ccc(OC(F)(F)F)cc1
Reactant: CCN(CC)S(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(n1ncnn1)C(F)(c1ccc(OC(F)(F)F)cc1)c1ccc(OC(F)(F)F)cc1
Reaction time: 18 h
Yield: 90.7 %

Procedure:
A solution of 1,1-bis(4-trifluoromethoxyphenyl)-2-(1,2,3,4-2H-tetrazol-2-yl)propan-1-ol (3.5 g) prepared as described in Example 3 in dichloromethane (50 cm3) was added dropwise to a stirred solution of diethylaminosulphurtrifluoride (1.51 g) kept at a temperature of -70° C. under a nitrogen atmosphere. After 1 hour a further quantity of diethylaminosulphurtrifluoride (1.5 g) was added and the mixture stirred for 18 hours at the ambient temperture, during which time any vapours emitted were vented through a column of potassium hydroxide pellets. Water (30 cm3) was added carefully to the mixture, the organic layer separated and washed with more water (3×30 cm3), dried over anhydrous magnesium sulphate and concentrated by evaporation of the solvent under reduced pressure. The residual oil (4.5 g) was purified by hplc using a silica gel column eluted with a mixture of hexane (5 parts by volume and ethylacetate (1 part by volume) to yield 1,1-bis(4-trifluoromethoxyphenyl)-1-fluoro- 2-(1,2,3,4-2H-tetrazol-2-yl)propane as an oil (3.19 g) which crystallised on standing (mp. 68°-70° C.).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:22])[NH:5][C:6]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]([C:10]([OH:12])=O)=[CH:8][N:7]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl:56][C:57]1[CH:63]=[CH:62][CH:61]=[CH:60][C:58]=1[NH2:59]>CN(C=O)C>[Cl:56][C:57]1[CH:63]=[CH:62][CH:61]=[CH:60][C:58]=1[NH:59][C:10](=[O:12])[C:9]1[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][C:6]([NH:5][C:4]([NH:3][CH2:1][CH3:2])=[O:22])=[N:7][CH:8]=1
Reactant: CCNC(=O)Nc1cc(Nc2ccccc2)c(C(=O)O)cn1
Reactant: Nc1ccccc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1cc(Nc2ccccc2)c(C(=O)Nc2ccccc2Cl)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.2 %

Procedure:
To an ice-cold solution of 6-(3-ethylureido)-4-(phenylamino)nicotinic acid (50 mg, 0.16 mmol, 1.0 eq) in DMF (2.0 mL) was added HBTU (91 mg, 0.24 mmol, 1.50 eq) followed by DIPEA (62 mg, 0.48 mmol, 3.0 eq) and finally 2-chloroaniline (24 mg, 0.19 mmol, 1.20 eq). The resulting reaction mixture was stirred overnight at room temperature. The reaction mass was then poured onto ice-cold water followed by extraction with EtOAc (3×20 mL). The organics were combined, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified over silica gel (60-120 M, 1-2.5% MeOH-DCM) to obtain Compound 9 (10 mg, 15%). NMR (300 MHz, DMSO-d6): δ 10.17 (br s, 1H), 10.08 (br s, 1H), 9.12 (s, 1H), 8.67 (s, 1H), 7.87 (m, 1H), 7.56 (m, 1H), 7.24-7.40 (m, 8H), 7.15 (m, 1H), 3.14 (m, 2H), 1.06 (t, J=7.20 Hz, 3H). [M+H]+ m/z=410.15.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[S:15](=[O:24])(=[O:23])[CH2:14][CH2:13]1)[CH:6]=[C:5]2[NH:25][CH:26]1[CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]1.Cl>O1CCOCC1>[NH:28]1[CH2:29][CH:26]([NH:25][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=3)[N:8]=[C:7]([N:12]3[CH2:18][C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[S:15](=[O:23])(=[O:24])[CH2:14][CH2:13]3)[CH:6]=2)[CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CC(Nc2cc(N3CCS(=O)(=O)c4ccccc4C3)nc3ccc(Cl)cc23)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=S1(=O)CCN(c2cc(NC3CNC3)c3cc(Cl)ccc3n2)Cc2ccccc21
Yield: 58.3 %

Procedure:
A mixture of tert-butyl 3-[6-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-quinolin-4-ylamino]-azetidine-1-carboxylate (120 mg, 0.2 mmol) and a solution of hydrochloride in 1,4-dioxane (4 N, 20 mL) was stirred at room temperature for 16 hours. The resulting mixture was concentrated in vacuo. The residue was purified by preparative HPLC to afford 50 mg of the desired product (yield was 51%). MS obsd. (ESI+) [(M+H)+] 429, 1H NMR (400 MHz, CD3OD) δ ppm 8.31 (s, 1 H), 8.08-8.06 (d, J=8 Hz, 1 H), 7.87-7.80 (m, 2 H), 7.73-7.68 (m, 2 H), 7.55-7.53 (m, 1 H), 5.84 (s, 1 H), 5.30 (s, 2 H), 4.99-4.96 (m, 1 H), 4.59-4.52 (m, 4 H), 4.32-4.27 (m, 2 H), 3.72 (s, 2 H).
Reaction SMILES: [NH:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:6]=[C:5]([C:21]([F:24])([F:23])[F:22])[N:4]=1)[NH2:2].[C:25]([C:27](=[C:37](SC)[S:38][CH3:39])[C:28]([NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:29])#[N:26]>CO>[NH2:26][C:25]1[N:1]([C:3]2[C:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)=[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:6]=[C:5]([C:21]([F:24])([F:23])[F:22])[N:4]=2)[N:2]=[C:37]([S:38][CH3:39])[C:27]=1[C:28]([NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:29]
Reactant: NNc1nc(C(F)(F)F)nc(-c2ccccc2)c1-c1ccccc1
Reactant: CSC(SC)=C(C#N)C(=O)Nc1ccccc1
Solvent: CO
Product: CSc1nn(-c2nc(C(F)(F)F)nc(-c3ccccc3)c2-c2ccccc2)c(N)c1C(=O)Nc1ccccc1

Procedure:
A solution of 4-hydrazino-5,6-diphenyl-2-(trifluoromethyl)pyrimidine (0.2 g, 0.63 mmol) in methanol (6 ml) was heated with 2-cyano-3,3-bis(methylthio)-N-phenylacrylamide (0.5 g, 1.89 mmol), overnight, at 60-65° C. The solid that separated out was filtered and washed with isopropyl alcohol (3 ml) to yield the required product. 1H-NMR (CDCl3) δ: 1.98 (s, 3H), 6.96-7.57 (m, 15H), 7.25-7.30 (2H, D2O exchangeable), 8.86 (br, 1H, D2O exchangeable); MS m/z: 547.1 (M++1).
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][C:5](=O)[CH2:4][C:3]1([CH3:12])[CH3:11].[NH3:13]>>[NH2:13][CH:5]1[CH2:6][C:7]([CH3:9])([CH3:8])[N:2]([CH3:1])[C:3]([CH3:12])([CH3:11])[CH2:4]1
Reactant: CN1C(C)(C)CC(=O)CC1(C)C
Reactant: N
Product: CN1C(C)(C)CC(N)CC1(C)C

Procedure:
The procedure described in Preparation 1(a) was repeated, but using as starting materials 1,2,2,6,6-pentamethyl-4-piperidone and ammonia, to give the title compound, boiling at 76°-79.5° C./5 mmHg (667 Pascals).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1.[CH2:10]([Sn](CCCC)(CCCC)CCCC)[CH:11]=[CH2:12]>CN(C=O)C.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:12]([C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1)[CH:11]=[CH2:10]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCc1ccc(C#N)cn1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A mixture of 6-chloropyridine-3-carbonitrile (7.0 g, 50 mmol), allyl tri-n-butyltin (18.2 g, 55.0 mmol) and Pd(PPh3)2Cl2 (1 g) in 80 mL DMF was stirred at 90° C. for 3 hours. The mixture was cooled down and diluted with 1 L of EtOAc, washed with water (100 mL×2) and brine (100 mL), then concentrated. The residue was purified by column chromatography (PE:EtOAc=10:1) to afford the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1)#[CH:2].[Br:11][C:12]1[CH:17]=[C:16](I)[CH:15]=[CH:14][C:13]=1[F:19].C(N(CC)CC)C>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Br:11][C:12]1[CH:17]=[C:16]([C:2]#[C:1][C:3]2[CH:4]=[N:5][CH:6]=[C:7]([O:9][CH3:10])[CH:8]=2)[CH:15]=[CH:14][C:13]=1[F:19]
Reactant: Fc1ccc(I)cc1Br
Reactant: C#Cc1cncc(OC)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1cncc(C#Cc2ccc(F)c(Br)c2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 94.2 %

Procedure:
Add bis(triphenylphosphine)palladium (II) dichloride (93 mg, 0.13 mmol), copper (I) iodide (50 mg, 0.26 mmol), and 3-ethynyl-5-methoxypyridine, (prepared as described in PREPARATION 10), (350 mg, 2.6 mmol) to a solution of 2-bromo-1-fluoro-4-iodobenzene, (prepared as described in PREPARATION 43), (1.03 g, 3.4 mmol) in triethylamine (4.0 mL, 39.5 mmol). Stir at room temperature for 20 h then concentrate. Purify by silica gel chromatography, eluting with 100:0 to 80:20 dichloromethane:ethyl acetate, followed by a second silica gel chromatography, eluting with 75:25 to 60:40 hexanes:ethyl acetate, to give the title compound as a white solid (750 mg, 93%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](O)=[O:9])[C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([O:19][CH3:20])[CH:3]=1.C(Cl)(=O)C([Cl:24])=O>C1C=CC=CC=1.CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]([C:8]([Cl:24])=[O:9])[C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([O:19][CH3:20])[CH:3]=1
Reactant: COc1cc(Br)nc(C(=O)O)c1OCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: COc1cc(Br)nc(C(=O)Cl)c1OCc1ccccc1
Reaction time: 0.25 h

Procedure:
To a stirred mixture of 16 (2.54 g., 7.5 mmol) in benzene (30 mL) containing DMF (3 drops) was added oxalyl chloride (1.90 g, 15 mmol) in one portion. After gas evolution had ceased (about 45 min.), the now homogeneous solution was stirred an additional 15 min., then the solvent was evaporated. 1,2-dichloroethane (30 mL) was added and again the solvent was evaporated to give a quantitative yield of 3 as a nearly colorless oil. This material was dissolved in CH2Cl2 (10 mL) or THF (10 mL) and used directly in subsequent coupling reactions. 6-Bromo-3-Hydroxypicolinic Acid (17).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:23])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[CH:18])[CH:15]=2)[N:10]([C:19](=[O:21])[CH3:20])[C@@H:9]([CH3:22])[CH2:8]1)[CH3:3].CO.[N:26]([CH2:29][C:30]([O:32][CH3:33])=[O:31])=[N+:27]=[N-:28]>CN(C)C=O.[Cu]I>[C:19]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:17]3[N:28]=[N:27][N:26]([CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:18]=3)=[CH:13][CH:12]=2)[C@H:7]([NH:6][C:5]([O:4][CH:2]([CH3:1])[CH3:3])=[O:23])[CH2:8][C@@H:9]1[CH3:22])(=[O:21])[CH3:20]
Reactant: C#Cc1ccc2c(c1)[C@H](NC(=O)OC(C)C)C[C@H](C)N2C(C)=O
Reactant: COC(=O)CN=[N+]=[N-]
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)Cn1cc(-c2ccc3c(c2)[C@H](NC(=O)OC(C)C)C[C@H](C)N3C(C)=O)nn1
Temperature: 100 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of 1-methylethyl[(2S,4R)-1-acetyl-6-ethynyl-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation, see Intermediate 58) (408 mg, 1.298 mmol) in N,N-dimethylformamide (DMF) (8 mL) and methanol (0.9 mL) were successively added methyl azidoacetate (299 mg, 2.60 mmol) and copper(I) iodide (12.36 mg, 0.065 mmol). The resulting mixture was stirred at 100° C. under microwave irradiation for 2 h then cooled to room temperature and partitioned between brine and AcOEt. The layers were separated. The aqueous phase was extracted with EtOAc (3×) and the combined organic layers were washed with brine, dried over a Na2SO4 cartridge and concentrated in vacuo. Purification of the residue on SP4 using a 25 G silica cartridge (gradient: 2 to 10% MeOH in DCM) gave methyl {4-[(2S,4R)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]-1H-1,2,3-triazol-1-yl}acetate (468 mg, 1.046 mmol, 96%) as a viscous yellow oil.