Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:24]=[CH:23][N:22]=[C:21]([C:25]([OH:27])=O)[CH:20]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1.[OH:35][C@H:36]1[CH2:40][CH2:39][NH:38][CH2:37]1>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:24]=[CH:23][N:22]=[C:21]([C:25]([N:38]5[CH2:39][CH2:40][C@H:36]([OH:35])[CH2:37]5)=[O:27])[CH:20]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1
Reactant: CC1Cc2ccc(-c3ccnc(C(=O)O)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: O[C@H]1CCNC1
Product: CC1Cc2ccc(-c3ccnc(C(=O)N4CC[C@H](O)C4)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 61A starting from 4-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}pyridine-2-carboxylic acid (Example 61A, Step 2) and (S)-(−)-3-Hydroxypyrrolidine (Fluka, Cat. No. 56437). LCMS (M+H)+: m/z=529.3.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1([CH2:10][CH2:11][N:12]2[C:16](=[O:17])[CH2:15][S:14][CH:13]2[CH2:18][CH2:19][CH2:20][C:21]2[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.CO.Cl>O>[OH:3][C:4]1([CH2:10][CH2:11][N:12]2[C:16](=[O:17])[CH2:15][S:14][CH:13]2[CH2:18][CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=2)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: CCOC(=O)c1ccc(CCCC2SCC(=O)N2CCC2(O)CCCCC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(CCCC2SCC(=O)N2CCC2(O)CCCCC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium hydroxide solution (5 N, 2.5 ml., 12.5 mmol.) is added to a stirred mixture of ethyl 4-{3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}-benzoate (2.48 g., 5.91 mmol.), methanol (25 ml.) and water (5 ml.). The resulting mixture is stirred at ambient temperature for 16 hours. Then, it is diluted with water, acidified with diluted hydrochloric acid, and extracted with ether. The ethereal extract is washed with water, dried over anhydrous magnesium sulfate, and filtered. Upon cooling the filtrate, the title compound precipitates out as a white solid, which is collected by filtration (7.06 g., 2.57 mmol., 42%). The product is recrystallized from chloroform-ether, m.p. 147°-148° C., ir (KBr) 3320, 1700, 1650 cm-1, pmr (CDCl3) δ 3.54 (2H, s), 4.70 (1H, m), 7.22 (2H, d), 8.00 (2H, d).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:21]=[C:20]([CH3:22])[N:19]=[CH:18][C:7]=3[CH2:8][NH:9][CH:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.[CH2:25]=O>C(O)=O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:21]=[C:20]([CH3:22])[N:19]=[CH:18][C:7]=3[CH2:8][N:9]([CH3:25])[CH:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: C=O
Reactant: Cc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1Cl)NC2
Solvent: O=CO
Product: Cc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1Cl)N(C)C2

Procedure:
A mixture of 4 g (11 mmole) of 9-chloro-7-(2-chlorophenyl)-6,7-dihydro-2-methyl-5H-pyrimido[5,4-d][2]benzazepine 2 ml of 88% formic acid and 2 ml of 37.5% formaldehyde solution was heated on the steambath for 3 hours. The reaction mixture was poured into an excess of dilute ice cold sodium hydroxide and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. The residue was crystallized from ether to give the crude product, m.p. 155°-156° C. Recrystallization from ether gave the pure product as colorless prisms, m.p. 156°-157° C.
Reaction SMILES: [O:1]=[C:2]1[O:7][CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:12](=[O:15])[CH2:13][CH2:14][N:3]1[C:4]=23.[CH2:16](O)[CH2:17][OH:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:1]=[C:2]1[O:7][CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:12]4([O:18][CH2:17][CH2:16][O:15]4)[CH2:13][CH2:14][N:3]1[C:4]=23
Reactant: O=C1CCN2C(=O)OCc3cccc1c32
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C1OCc2cccc3c2N1CCC31OCCO1

Procedure:
A solution of 6,7-dihydro-3,7-dioxo-1H,3H,5H-pyrido [3,2,1-ij][3,1]benzoxazine (2 g), ethylene glycol (2.2 ml) and p-toluenesulfonic acid (catalytic amount) in toluene (60 ml) was refluxed by use of Dean-Stark apparatus for 3 hours. After washing the reaction mixture with a saturated aqueous solution of sodium hydrocarbonate, the mixture was dried over anhydrous magnesium sulfate. The solvent was distilled off to give 6,7-dihydro-3-oxo-7,7-ethylenedioxy-1H,3H,5H-pyrido[3,2,1-ij][3,1]benzoxazine (2.1 g).
Reaction SMILES: [OH-:1].[K+].C1(C)C=CC=CC=1.[CH3:10][C:11]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:12]=1[O:13][CH2:14][C:15]1[CH:26]=[CH:25][CH:24]=[CH:23][C:16]=1[C:17]([C:21]#[N:22])=[N:18][O:19][CH3:20].Cl>O>[CH3:10][C:11]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:12]=1[O:13][CH2:14][C:15]1[CH:26]=[CH:25][CH:24]=[CH:23][C:16]=1[C:17](=[N:18][O:19][CH3:20])[C:21]([NH2:22])=[O:1]
Reactant: CON=C(C#N)c1ccccc1COc1cc(C)ccc1C
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CON=C(C(N)=O)c1ccccc1COc1cc(C)ccc1C
Temperature: 95 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
85% Potassium hydroxide (0.40 g, 6.0 mmol) and toluene (5 ml) were added to 2-(2,5-dimethylphenoxymethyl)-α-methoxyiminobenzyl cyanide (E/Z=15/85)(1.47 g, 5.0 mmol). The mixture was stirred at 95° C. for 2 hours. After completion of the reaction, water was added. The mixture was neutralized with conc. hydrochloric acid, extracted with toluene (100 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxyiminoacetamide (1.30 g, Yield: 83.2%, E/Z=15/85).
Reaction SMILES: [CH2:1]([N:4]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:5]1)[CH2:2][CH3:3].[F:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>C(Cl)Cl.N1C=CC=CC=1>[F:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:14][C:11]2[CH:10]=[CH:9][C:8]([CH:6]3[CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[CH2:7]3)=[CH:13][CH:12]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: CCCN1CC(c2ccc(N)cc2)C1
Reactant: O=S(=O)(Cl)c1ccc(CCCF)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCN1CC(c2ccc(NS(=O)(=O)c3ccc(CCCF)cc3)cc2)C1
Yield: 19.7 %

Procedure:
Following the same procedure as described in example 55, 4-(1-propyl-azetidin-3-yl)phenylamine (100 mg, 0.52 mmol) in CH2Cl2/pyridine 1:1 (12 ml) was treated with 4-(3-fluoro-propyl)-benzenesulfonyl chloride (161 mg, 0.68 mmol). Purification of the crude product by chromatography on reversed phase silica gel (H2O+0.1% acetic acid:CH3CN+0.1% acetic acid, 75:25) provided the title compound (40 mg, 20%) as a colourless gum.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]([S:10]([C:13]1[S:14][CH:15]=[CH:16][C:17]=1[CH:18]1OCCO1)(=[O:12])=[O:11])[CH:7]([CH3:9])[CH3:8])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+].C1CCN2C(=NCCC2)CC1>CC(C)=O.C(OCC)(=O)C>[CH3:8][CH:7]([N:6]1[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:23])=[CH:18][C:17]2[CH:16]=[CH:15][S:14][C:13]=2[S:10]1(=[O:12])=[O:11])[CH3:9]
Reactant: CCOC(=O)CN(C(C)C)S(=O)(=O)c1sccc1C1OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=Cc2ccsc2S(=O)(=O)N1C(C)C
Yield: 33.1 %

Procedure:
A solution of the product from Step B (36.25 g) and p-toluenesulfonic acid hydrate (2.0 g) in acetone (300 mL) was heated at reflux temperature for 6 h, cooled and a saturated aqueous solution of sodium bicarbonate (100 mL) was added. Acetone was evaporated and the aqueous mixture was extracted with ether (2×100 mL). The combined extracts were dried (MgSO4) and evaporated to give a dark brown oil which was dissolved in ethyl acetate (200 mL). DBU (2 mL) was added to this solution and after 1 h the reaction mixture was washed with 2N HCl and brine, dried (MgSO4), and evaporated to give a solid which was recrystallized from 25% ethyl acetate/hexane to give 9.95 g of product. The mother liquor was chromatographed (silica, 25% ethyl acetate/hexane) to give an additional 3.57 g of product (total 13.52 g, 50%): mp 97°-99° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C@:8]23[CH2:16][N:15]([C:17]4[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=4)[CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:24][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:9]3)[CH:5]=[CH:6][CH:7]=1.[F:33][C:34]1[C:35]([C:41](O)=[O:42])=[N:36][CH:37]=[C:38]([F:40])[CH:39]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>ClCCl>[C:25]([NH:24][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:14][N:15]([C:17]3[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=3)[CH2:16][C@:8]2([C:4]2[CH:3]=[C:2]([NH:1][C:41]([C:35]3[C:34]([F:33])=[CH:39][C:38]([F:40])=[CH:37][N:36]=3)=[O:42])[CH:7]=[CH:6][CH:5]=2)[N:9]=1)(=[O:32])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(O)c1ncc(F)cc1F
Reactant: Nc1cccc([C@]23CN(c4ncc(F)cn4)C[C@H]2CSC(NC(=O)c2ccccc2)=N3)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1=N[C@@]2(c3cccc(NC(=O)c4ncc(F)cc4F)c3)CN(c3ncc(F)cn3)C[C@H]2CS1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.5 %

Procedure:
N-[(4aR,7aS)-7a-(3-Aminophenyl)-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (0.30 g, 0.67 mmol) is dissolved in dichloromethane (10 mL) and 3,5-difluoropyridine-2-carboxylic acid (138 mg, 0.87 mmol), 1-hydroxybenzotriazole (185 mg, 1.34 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (169 mg, 0.87 mmol) are added. Diisopropylethylamine (0.35 mL, 2 mmol) is added and the reaction is stirred at room temperature overnight. The reaction is purified directly with silica gel chromatography eluting with a 0-100% ethyl acetate/hexanes gradient to give the title compound (330 mg, 84%). ES/MS (m/e): 590 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:14][CH3:15])[C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7].CN(C)C=O.[H-].[Na+].I[CH2:24][CH3:25]>C(OCC)(=O)C.C(OCC)(=O)C.CCCCCC>[CH3:15][O:14][C:11]1[CH:10]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:12]=1[O:13][CH2:24][CH3:25])[C:6]([O:8][CH3:9])=[O:7]
Reactant: CCI
Reactant: COC(=O)c1cc(OC)c(O)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCOc1c(OC)cc(C(=O)OC)cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Combine methyl 3,5-dimethoxy-4-hydroxy-benzoate (2.12 g, 10 mmol) and dimethylformamide (50 mL). Cool in an ice bath. Add portionwise, sodium hydride (0.4 g, 16.7 mmol). after 2 hours, add iodoethane (4 mL, 50 mmol). Warm to ambient temperature. After 18 hours, dilute the reaction mixture with ethyl acetate and extract with water, 1M hydrochloric acid solution, a saturated sodium bicarbonate solution, and then brine. Dry the organic layer over MgSO4, filtered and evaporated in vacuo to give a residue. chromatograph the residue on silica gel eluting with 5% ethyl acetate/hexane to give methyl 3,5-dimethoxy-4-ethoxy-benzoate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=O)[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[N:13]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2].P(Cl)(Cl)([Cl:21])=O>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:21])=[N:13][C:12]([O:17][CH3:18])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c[nH]c2ccc(OC)nc2c1=O
Product: CCOC(=O)c1cnc2ccc(OC)nc2c1Cl
Temperature: 25 °C
Yield: 62 %

Procedure:
A solution of 6-methoxy-4-oxo-1,4-dihydro-[1,5]naphthyridine-3-carboxylic acid ethyl ester (110.0 g, 407.67 mmol, 1.0 eq) in phosphorus oxychloride (650 mL) is refluxed for 4 hours. Then the reaction mixture is cooled to room temperature and the solvent is evaporated. The residue is poured into ice water and the resulting mixture is basified with 25% ammonium hydroxide to pH=8-9 and extracted with ethyl acetate (3×500 mL). The combined organic layers are dried over sodium sulfate, filtered and evaporated to give a brown solid as crude product, which is then purified by column chromatography (silica gel, eluent: ethyl acetate:petroleum ether, 1:4, v/v) to afford 4-chloro-6-methoxy-[1,5]naphthyridine-3-carboxylic acid ethyl ester as a light yellow solid (78 g, 62% yield).
Reaction SMILES: CS(NCCCCCCC(OCC)=O)(=O)=O.C(S(NCCCCCCC(OCC)=O)(=O)=O)C.C([O:37][CH:38]([CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH2:39][CH2:40][CH2:41][N:42]([CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][C:54]([O:56]CC)=[O:55])[S:43]([CH2:46]C)(=[O:45])=[O:44])(=O)C>>[OH:37][C@H:38]([CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[C:39]#[C:40][CH2:41][N:42]([CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][C:54]([OH:56])=[O:55])[S:43]([CH3:46])(=[O:44])=[O:45]
Reactant: CCCCCC(CCCN(CCCCCCC(=O)OCC)S(=O)(=O)CC)OC(C)=O
Agent: CCOC(=O)CCCCCCNS(=O)(=O)CC
Agent: CCOC(=O)CCCCCCNS(C)(=O)=O
Product: CCCCC[C@@H](O)C#CCN(CCCCCCC(=O)O)S(C)(=O)=O

Procedure:
The synthesis of this compound is carried out as described in Example 1 except that, in Step A, the ethyl 7-(methanesulfonamido)heptanoate is replaced by an equimolar amount of ethyl 7-ethanesulfonamidoheptanoate (Example P). The product of Step A is thus ethyl 7-[N-(4-acetoxynonyl)ethanesulfonamido]heptanoate. The subsequent step yields 7-[N-(4-hydroxynonyl)ethanesulfonamido]heptanoic acid (B).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:4][CH:3]=1.[C:18]1([CH3:27])[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O>>[CH2:12]([NH:11][C:9](=[O:10])[C:8]([CH3:17])([C:5]1[CH:6]=[CH:7][C:2]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH3:27])=[CH:3][CH:4]=1)[CH3:16])[CH:13]([CH3:15])[CH3:14]
Reactant: Cc1ccccc1B(O)O
Reactant: CC(C)CNC(=O)C(C)(C)c1ccc(Br)cc1
Product: Cc1ccccc1-c1ccc(C(C)(C)C(=O)NCC(C)C)cc1
Yield: 80 %

Procedure:
Prepared in a similar manner to Example 8 from 2-(4-Bromophenyl)-N-isobutyl-2-methylpropanamide (Example 1a) and o-tolylboronic acid. Yield: 80%. 1H NMR (400 MHz, CDCl3): δ 0.8 (d, 6H), 1.65 (s, 6H), 1.67-1.70 (m,1H), 2.3 (s, 3H), 3 (t, 2H), 5.2 (broad, 1H), 7.2-7.25 (m, 4H), 7.3 (d, 2H), 7.4 (d, 2H). MS (M+H, 310).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[N:17]([CH3:27])[S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)(=[O:20])=[O:19])=[N:5][CH2:4]1.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37].O>O1CCCC1>[CH3:35][S:36]([O:1][CH2:2][CH:3]1[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[N:17]([CH3:27])[S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)(=[O:19])=[O:20])=[N:5][CH2:4]1)(=[O:38])=[O:37]
Reactant: CN(c1cccc2cc(C3=NCC(CO)S3)[nH]c12)S(=O)(=O)c1ccccn1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(c1cccc2cc(C3=NCC(COS(C)(=O)=O)S3)[nH]c12)S(=O)(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
To a solution of N-{2-[5-(hydroxymethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylpyridine-2-sulfonamide (2.0 g) and triethylamine (1.4 mL) in tetrahydrofuran (50 mL) was added methanesulfonyl chloride (860 mg), and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (1.85 g, yield 77%) as a white amorphous solid from a fraction eluted with ethyl acetate. MS: 481 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:20]=[CH:19][C:11]3[NH:12][C:13](=O)[O:14][C:15]([CH3:17])([CH3:16])[C:10]=3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>CC1C=CC=CC=1C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:20]=[CH:19][C:11]3[NH:12][C:13](=[S:30])[O:14][C:15]([CH3:17])([CH3:16])[C:10]=3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cccc(Cl)c3)cc21
Solvent: Cc1ccccc1C
Product: CC1(C)OC(=S)Nc2ccc(-c3cccc(Cl)c3)cc21
Yield: 52.7 %

Procedure:
A mixture of 6-(3-chlorophenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one (0.15 g, 0.5 mmol) and Lawesson's reagent (0.24 g, 0.6 mmol) in anhydrous o-xylene was heated at reflux under nitrogen for 3 hours. The solvent was removed and the residue was purified by a flash chromatography (silica gel, hexane:ethyl acetate/6:1) to afford the title compound as a white solid (80 mg, 52%): mp 183-184° C.; 1H-NMR (DMSO-d6) δ12.25 (s, 1H, D2O exchangeable), 7.78 (t, 1H, J=1.7 Hz), 7.63-7.70 (m, 3H), 7.49 (t, 1H, J=7.8 Hz), 7.42 (d, 1H, J=8.1 Hz), 7.12 (d, 8.8 Hz), 1.72 (s, 6H); MS (EI) m/z 303 (M+, 100%), 305 (M+, 32%); Anal. Calc. For C16H14ClNOS: C, 63.26; H, 4.64; N, 4.61. Found: C, 63.37; H, 4.62; N, 4.54.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:7]=[CH:6][N:5]([CH2:8][C:9]([OH:11])=O)[N:4]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:29]3[CH2:28][CH2:27][CH2:26][NH:25][C:24]=3[CH:23]=[N:22]2)=[CH:17][CH:16]=1>>[F:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[C:29]3[CH2:28][CH2:27][CH2:26][N:25]([C:9](=[O:11])[CH2:8][N:5]4[CH:6]=[N:7][C:3]([C:2]([F:1])([F:13])[F:12])=[N:4]4)[C:24]=3[CH:23]=[N:22]2)=[CH:19][CH:20]=1
Reactant: O=C(O)Cn1cnc(C(F)(F)F)n1
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Product: O=C(Cn1cnc(C(F)(F)F)n1)N1CCCc2c1cnn2-c1ccc(F)cc1

Procedure:
The title compound was prepared from 2-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)acetic acid and 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine using General Method B. The product mixture was washed with 2× brine. The reaction slurry was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to provide 33 mg of the title compound as a white solid. 1H NMR (400 MHz, CD3OD, mixture of rotamers) δ 8.41 (s, 1H), 8.35 (s, 0.75H), 7.60 (s, 0.25H), 7.43-7.50 (m, 2H), 7.15-7.23 (m, 2H), 5.41 (s, 0.5H), 5.30 (s, 1.5H), 3.94 (m, 0.5H), 3.84 (m, 1.5H), 2.89 (m, 2H), 2.15 (m, 1.5H), 2.07 (m, 0.5H); MS: (ES) m/z calculated for C17H15F4N6O [M+H]+ 395.1, found 395.1.
Reaction SMILES: I[C:2]1[C:3](=[O:28])[NH:4][C:5](=[O:27])[N:6]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][C@H:15]3[C@:13]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=4)([CH2:14]3)[CH2:12]2)[CH:7]=1.[NH:29]1[CH:33]=[CH:32][CH:31]=[N:30]1.CN(C)CC(O)=O.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.CCOC(C)=O.[Cu](I)I>[N:29]1([C:2]2[C:3](=[O:28])[NH:4][C:5](=[O:27])[N:6]([CH2:8][CH2:9][CH2:10][N:11]3[CH2:16][C@H:15]4[C@:13]([C:17]5[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=5)([CH2:14]4)[CH2:12]3)[CH:7]=2)[CH:33]=[CH:32][CH:31]=[N:30]1
Reactant: c1cn[nH]c1
Reactant: O=c1[nH]c(=O)n(CCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)cc1I
Agent: I[Cu]I
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=c1[nH]c(=O)n(CCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)cc1-n1cccn1
Temperature: 150 °C
Reaction time: 18 h
Yield: 18.5 %

Procedure:
5-iodo-1-(3-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)-2,4(1H,3H)-pyrimidinedione (Prep10, 60 mg, 0.119 mmol), 1H-pyrazole (26.7 mg, 0.392 mmol), copper iodide (24.88 mg, 0.131 mmol), N,N-dimethylglycine (13.47 mg, 0.131 mmol) and K2CO3 (36.1 mg, 0.261 mmol) were dissolved in Dimethyl Sulfoxide (DMSO) (1 ml) to give a colorless suspension with a white solid. After shaking at 150° C. for 18 h, the reaction mixture was diluted with EtOAc (5 ml) and the organic phase was washed with water (4×10 ml), then brine (5 ml), dried over Na2SO4, filtered ant the solvent evaporated. The obtained residue was purified by preparative LC-MS to give 9.8 mg (18.48% yield) of the title compound as a yellow oil.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([OH:9])[CH2:5][C:6]([CH3:8])=[CH2:7].[Br:16][C:17]1[CH:22]=[CH:21][C:20]([C@@H:23]([N:25]=[C:26]=[O:27])[CH3:24])=[CH:19][C:18]=1[CH3:28].BrC1C=CC([C@@H](N2CC[C@](CC(C)=C)(C3C=CC=CC=3)OC2=O)C)=CC=1>>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([C@@H:23]([N:25]2[CH2:2][CH2:3][C@:4]([CH2:5][C:6]([CH3:8])=[CH2:7])([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[O:9][C:26]2=[O:27])[CH3:24])=[CH:19][C:18]=1[CH3:28]
Reactant: C=C(C)CC(O)(CCCl)c1ccccc1
Reactant: Cc1cc([C@H](C)N=C=O)ccc1Br
Agent: C=C(C)C[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Product: C=C(C)C[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)c(C)c2)C(=O)O1

Procedure:
The title compound was prepared from 1-chloro-5-methyl-3-phenyl-hex-5-en-3-ol and (S)-1-bromo-4-(1-isocyanato-ethyl)-2-methyl-benzene following a procedure analogous to that described in Step 1 of Example 96. Mass spectrum (ESI+): m/z=428/430 (Br) [M+H]+; 1H NMR (400 MHz, DMSO-d6) 1.40 (d, J=6.9 Hz, 3H), 1.55 (s, 3H), 2.13 (s, 3H) superimposed on 2.07-2.18 (m, 2H), 2.42-2.47 (m, 1H), 2.53 (broad s, 2H), 2.92-3.03 (m, 1H), 4.60 (hardly resolved m, 1H), 4.77 (hardly resolved m, 1H), 5.33 (q, J=6.9 Hz, 1H), 6.62 (dd, J=8.2 Hz, 2.0 Hz, 1H), 6.76 (hardly resolved d, 1H), 7.26-7.33 (m, 4H), 7.34-7.40 (m, 2H). The assignment of the stereogenic centers of the title compound is based on the comparison of the 1H NMR data with the data of the known analog 3-[(S)-1-(4-bromo-phenyl)-ethyl]-(R)-6-(2-methyl-allyl)-6-phenyl-[1,3]oxazinan-2-one.
Reaction SMILES: [C:1]([CH2:5][C:6]([NH:8][N:9]1[CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][CH:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:12][CH:11]([N:28]=[N+]=[N-])[C:10]1=[O:31])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.C(Cl)Cl.CO.C(OCC)(=O)C.[Pd].[H+].[H+].[Cl-].[Cl-].[Cl-].[Cl-].[Cl-].[Cl-].[K+].[I-].[Pt]>[C:1]([CH2:5][C:6]([NH:8][N:9]1[CH:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:14][CH:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:12][CH:11]([NH2:28])[C:10]1=[O:31])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)CC(=O)NN1C(=O)C(N=[N+]=[N-])CC(c2ccccc2)CC1c1ccccc1
Agent: [Pd]
Agent: [Pt]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCO
Solvent: CO
Product: CC(C)(C)CC(=O)NN1C(=O)C(N)CC(c2ccccc2)CC1c1ccccc1

Procedure:
A solution of 1.09 g (2.60 mmol) 1-(t-butylacetamido)-3-azido-5,7-diphenylhexahydroazepin-2-one in 30 mL ethanol and 15 mL methylene chloride was hydrogenated at 42 psi in the presence of 0.40 g 10% palladium-on-carbon for 36 hours. The reaction showed Rf =0.30/0.15 iodoplatinate positive, in 30% methanol in ethyl acetate. It was filtered through Celite with ethanol and methylene chloride, evaporated, and chromatographed on silica gel using 30% methanol in ethyl acetate as eluant to afford 300 mg (29%) of the less polar diastereomer as an oil and 420 mg (41%) of the more polar diastereomer as an oil.