Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B.C1COCC1.[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:29][CH3:30])[CH:25]=3)[CH:20]2[CH3:31])=O)=[CH:12][CH:11]=1)([O-:9])=[O:8]>Cl>[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:29][CH3:30])[CH:25]=3)[CH:20]2[CH3:31])=[CH:12][CH:11]=1)([O-:9])=[O:8]
Reactant: COc1ccc2c(c1)CCN(C(=O)Cc1ccc([N+](=O)[O-])cc1)C2C
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCN(CCc1ccc([N+](=O)[O-])cc1)C2C
Temperature: 25 °C
Yield: 77.1 %

Procedure:
A stirred solution of 200 ml of 0.5 M borane/THF was treated with N-(4-nitrophenylacetyl)-1,2,3,4-tetrahydro-6-methoxy-1-methylisoquinoline (11.5 g, 0.03 m) portionwise, at room temperature, then warmed to reflux. After 30 min at reflux, the reaction was cooled and acidified with 60 ml of 20% HCl, added dropwise. The acidified reaction mixture was refluxed one hour, then concentrated on the rotovap at 40° C. to about 1/3 volume, then diluted with 600 ml water. The mixture was basified, then extracted with CH2Cl2 (2×400 ml). The CH2Cl2 was concentrated to an oil which crystallized when treated with 200 ml ether. The product was filtered off and air dried, giving 8.5 g N-(4-nitrophenethyl)-1,2,3,4-tetrahydro-6-methoxy-1-methylisoquinoline, m.p. 176°-178° (86%).
Reaction SMILES: CO[C:3](=O)[C:4]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])=[CH:5][O:6]CC.[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24]>C1(OC2C=CC=CC=2)C=CC=CC=1>[Cl:20][C:21]1[CH:22]=[C:23]2[C:25]([C:5]([OH:6])=[C:4]([S:9]([C:12]3[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=3)(=[O:10])=[O:11])[CH:3]=[N:24]2)=[CH:26][CH:27]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CCOC=C(C(=O)OC)S(=O)(=O)c1ccc(Cl)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=S(=O)(c1ccc(Cl)cc1)c1cnc2cc(Cl)ccc2c1O
Yield: 48 %

Procedure:
The mixture of 2-(4-chloro-benzenesulfonyl)-3-ethoxy-acrylic acid methyl ester (7.62 g, 25 mmol) and 3-chloroaniline (3.19 g, 25 mmol) in diphenyl ether (20 ml) was heated at near reflux for 1 h. After cooling the precipitate was filtered and washed with ether to obtain 4.25 g of the title compound in 48.0% yield.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:24])=[C:4]([C:8]2[N:9]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[S:33](Cl)(=[O:35])=[O:34]>>[NH2:19][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([C:20]([CH3:21])([CH3:23])[CH3:22])=[N:9][C:8]=2[C:4]2[C:3]([F:24])=[C:2]([NH:1][S:33]([C:27]3[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:26]=3[CH3:25])(=[O:34])=[O:35])[CH:7]=[CH:6][CH:5]=2)[CH:18]=[CH:17][N:16]=1
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Reactant: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(N)n2)s1
Product: Cc1ccc(F)cc1S(=O)(=O)Nc1cccc(-c2nc(C(C)(C)C)sc2-c2ccnc(N)n2)c1F
Yield: 46 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 4-[4-(3-amino-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinamine (0.082 g, 0.239 mmol) and 2-methyl 5-fluorobenzenesulfonyl chloride (0.055 g, 0.263 mmol) the title compound was obtained (57 mg, 0.11 mmol, 46% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.48 (s, 1H), 7.91 (d, J=5.3 Hz, 1H), 7.44 (dd, J=8.8, 2.6 Hz, 1H), 7.29-7.42 (m, 3H) 7.16-7.29 (m, 2H), 6.71 (s, 2H), 5.73 (d, J=5.1 Hz, 1H), 2.49 (s, 3H), 1.35 (s, 9H). MS (ES+): 516 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=O)[C:5]2=O.[CH3:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([NH2:21])=[C:16]([NH2:22])[CH:15]=1>C(O)(=O)C>[CH3:20][C:19]1[CH:18]=[C:17]2[C:16](=[CH:15][C:14]=1[CH3:13])[N:22]=[C:6]1[NH:7][C:8]3[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=3[C:5]1=[N:21]2
Reactant: Cc1cc(N)c(N)cc1C
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Solvent: CC(=O)O
Product: Cc1cc2nc3[nH]c4ccc(Br)cc4c3nc2cc1C

Procedure:
A mixture of 22.6 g 5-bromoisatin (0.1 mole), 15.0 g 4,5-dimethyl-o-phenylene diamine (0.11 mole) and 400 ml acetic acid is boiled under reflux for 4 hours. After cooling the product is sucked, washed with ethanol and dried. Yield 29 g, 89%. Recrystallisation from pyridine gives needle shaped crystals with melting point 319°-322° C.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10]O)[CH:7]=[CH:6][C:5]=1[C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=1[F:20].C(N(CC)CC)C.CS([Cl:34])(=O)=O>ClCCl>[Cl:34][CH2:10][C:8]1[N:9]=[C:4]([CH2:3][C:2]([CH3:22])([CH3:21])[CH3:1])[C:5]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[F:20])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(F)c(-c2ccc(CO)nc2CC(C)(C)C)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(F)c(-c2ccc(CCl)nc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 64.8 %

Procedure:
To a solution of (6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methanol (4.00 g) and triethylamine (4.00 g) in dichloromethane (20 mL) was added dropwise methanesulfonyl chloride (3.00 g) at 0° C., and the mixture was stirred at room temperature for 15 hr. Dichloromethane (150 ml) was added to the reaction mixture, and the mixture was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.75 g) as a colorless oil.
Reaction SMILES: [C-:1]#[N:2].[Na+].Br[CH2:5][C:6]1[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([Cl:18])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(OC)(C)(C)C>O.CS(C)=O>[Cl:17][C:16]1[C:6]([CH2:5][C:1]#[N:2])=[C:7]([C:13]([Cl:18])=[CH:14][CH:15]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1c(Cl)ccc(Cl)c1CBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Solvent: CS(C)=O
Product: CCOC(=O)c1c(Cl)ccc(Cl)c1CC#N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 56.4 %

Procedure:
A solution of sodium cyanide (75.12 g, 1.53 mol) in water (300 mL) was added dropwise to a solution of ethyl 2-(bromomethyl)-3,6-dichlorobenzoate (253c, 320 g, 1.03 mol) in dimethylsulfoxide (2.4 L) at room temperature. The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was poured into a mixture of water (4 L) and methyl tert-butyl ether (2 L), and the layers separated. The organic layer was washed with water (2 L) and with saturated aqueous sodium chloride solution (2 L), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with 30:1 petroleum ether/ethyl acetate), affording ethyl 3,6-dichloro-2-(cyanomethyl)benzoate (253d, 150 g, ˜75% pure, 47% yield) as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:29]=[C:30]([S:34]([NH:37][CH2:38][CH3:39])(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[CH2:38]([NH:37][S:34]([C:30]1[CH:29]=[C:28]([NH:27][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])[CH:33]=[CH:32][CH:31]=1)(=[O:36])=[O:35])[CH3:39]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CCNS(=O)(=O)c1cccc(N)c1
Product: CCNS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) and 3-amino-N-ethyl-benzenesulfonamide [CAS 56445-08-0] according to general procedure II. Yellow solid. MS (ISP) 556.0 [(M+H)+]; mp 207° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.[Br:9]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Cl)cn1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(CBr)nc1
Reaction time: 5 h
Yield: 58.1 %

Procedure:
A suspension of 5-chloro-2-methylpyridine (Reference Example 66, Step A, 6.4 g, 50 mmol) and N-bromosuccinimide (12.5 g, 70 mmol) in 100 mL carbon tetrachloride was heated to gentle reflux (bath temperature 90° C.), and 2,2′-azobisisobutyronitrile (0.74 g) was added in several portions over 30 min. After stirring at this temperature for 5 h, the reaction mixture was concentrated. The resulting slurry was diluted with EtOAc (100 mL) and was washed with water (100 mL), saturated aqueous sodium bicarbonate/saturated aqueous sodium thiosulfate, and brine. The organic solution was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel eluted with 2 to 15% ether in CH2Cl2/hexane (1:1) to afford 2-bromomethyl-5-chloropyridine (6.0 g, 60%), which was used immediately for the ensuing reaction. Thus, to a vigorously stirred solution of 2-bromomethyl-5-chloropyridine (6.0 g, 29 mmol) and 3-bromophenyl acetone (Step A, 6.0 g, 28 mmol) and tetrabutylammonium iodide (20 mg) in 30 mL CH2Cl2 at −78° C. was added cesium hydroxide monohydrate (10 g, 60 mmol), and the reaction was allowed to slowly warm to room temperate overnight. The reaction mixture was partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (2×100 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel eluted with 5 to 40% EtOAc in hexane to afford the title compound. 1H NMR (500 MHz, CD3OD): δ 8.44 (d, 1H), 7.66 (dd, 1H), 7.46-7.41 (m, 2H), 7.24 (t, 1H), 7.22 (d, 1H), 7.15 (d, 1 h), 4.42 (dd, 1H), 3.54 (dd, 1H), 3.07 (dd, 1H), 2.12 (s, 3H). LC-MS: m/e 338 (M+H)+ (3.0 min).
Reaction SMILES: O([C@H]1CC[C@H](C[NH:12][C:13](=[O:19])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])CC1)[N+]([O-])=O.[O:20]([C@H:24]1[CH2:29][CH2:28][C@H:27](CN)[CH2:26][CH2:25]1)[N+:21]([O-:23])=[O:22].C1(=O)OC(=O)CC1>>[O:20]([C@H:24]1[CH2:25][CH2:26][C@H:27]([NH:12][C:13](=[O:19])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:28][CH2:29]1)[N+:21]([O-:23])=[O:22]
Reactant: NC[C@H]1CC[C@H](O[N+](=O)[O-])CC1
Reactant: O=C(O)CCC(=O)NC[C@H]1CC[C@H](O[N+](=O)[O-])CC1
Agent: O=C1CCC(=O)O1
Product: O=C(O)CCC(=O)N[C@H]1CC[C@H](O[N+](=O)[O-])CC1

Procedure:
N-(trans-4-nitroxycyclohexylmethyl)-succinic acid monoamide from trans-4-nitroxycyclohexylmethylamine and succinic acid anhydride melting point: 79°-81° C. (ether), yield: 80%.
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12][CH2:13][CH3:14])=[N:10][C:9](F)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])([O-])=O.[K+].[K+].CN(C=O)C.[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34][SH:35]>O>[Br:1][C:2]1[C:11]([O:12][CH2:13][CH3:14])=[N:10][C:9]([S:35][CH2:34][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[Cl:27])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CCOc1nc(F)c2ncccc2c1Br
Reactant: SCc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1nc(SCc2ccccc2Cl)c2ncccc2c1Br
Temperature: 100 °C
Yield: 64.9 %

Procedure:
To a 5 mL microwave reactor vial was added 5-bromo-6-ethoxy-8-fluoro-1,7-naphthyridine (100 mg, 0.37 mmol), a large excess of K2CO3, followed by DMF (5 mL). (2-chlorophenyl)methanethiol (70 mg, 0.44 mmol) was then added to the mixture, the vessel was capped and heated under microwave irradiation for 20 min at 100° C. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The resultant residue was purified by silica gel to yield 5-bromo-8-(2-chlorobenzylthio)-6-ethoxy-1,7-naphthyridine as a pale yellow solid (100 mg, 0.24 mmol, 66%). 1H NMR (400 MHz, CDCl3): δ ppm 8.74 (d, J=2.64 Hz, 1H), 8.34 (d, J=7.47 Hz, 1H), 7.50-7.68 (m, 2H), 7.35-7.48 (m, 1H), 7.11-7.22 (m, 2H), 4.67 (s, 2H), 4.53 (q, J=7.03 Hz, 2H), 1.41 (t, J=7.03 Hz, 3H). LC/MS m/z 411 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:33][C:34]2[CH:45]=[CH:44][C:37]([C:38]([NH:40][CH:41]3[CH2:43][CH2:42]3)=[O:39])=[CH:36][CH:35]=2)[CH:12]2[C:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][CH2:15][N:14](CC3C=CC(OC)=CC=3OC)[C:13]2=[O:32])(=[O:10])=[O:9])=[CH:4][CH:3]=1>FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([C:38]([NH:40][CH:41]3[CH2:43][CH2:42]3)=[O:39])=[CH:44][CH:45]=2)[CH:12]2[C:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][CH2:15][NH:14][C:13]2=[O:32])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: COc1ccc(CN2CCCC(C)(C)C(N(Cc3ccc(C(=O)NC4CC4)cc3)S(=O)(=O)c3ccc(Cl)cc3)C2=O)c(OC)c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CCCNC(=O)C1N(Cc1ccc(C(=O)NC2CC2)cc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.8 %

Procedure:
4-({(4-Chloro-benzenesulfonyl)-[1-(2,4-dimethoxy-benzyl)-4,4-dimethyl-2-oxo-azepan-3-yl]-amino}-methyl)-N-cyclopropyl-benzamide (95 mg) was dissolved in a mixture of trifluoroacetic acid/trifluoromethanesulfonic acid/dichloromethane=40:1:59 (2 ml) and stirred at room temperature for 15 minutes. After evaporation flash chromatography (heptane/ethyl acetate gradient) yielded 65 mg (90%) of 4-{[(4-chloro-benzenesulfonyl)-(4,4-dimethyl-2-oxo-azepan-3-yl)-amino]-methyl}-N-cyclopropyl-benzamide as a foam; MS: m/e=504.2 (MH+), 521.3 (M+NH4+).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[N:5][S:6][C:7]=1[NH:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C:15](OC)=[O:16])=[O:10])#[N:2].S(=O)(=O)(O)[OH:29]>>[N+:25]([C:22]1[CH:21]=[CH:20][C:19]([C:4]2[C:3]([C:1]([NH2:2])=[O:29])=[C:7]([NH:8][C:9]([N:11]3[CH2:12][CH2:13][CH2:14][C:15]3=[O:16])=[O:10])[S:6][N:5]=2)=[CH:24][CH:23]=1)([O-:27])=[O:26]
Reactant: COC(=O)CCCNC(=O)Nc1snc(-c2ccc([N+](=O)[O-])cc2)c1C#N
Reactant: O=S(=O)(O)O
Product: NC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)nsc1NC(=O)N1CCCC1=O
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
Methyl 4-[({[4-cyano-3-(4-nitrophenyl)isothiazol-5-yl]amino}carbonyl)amino]butanoate (10.0 g) was added portion wise to concentrated sulfuric acid (50.0 mL) at ambient temperature over 20 min. The resulting suspension was heated to 45° C. over 90 min. The reaction mixture was cooled to ambient temperature. The reaction mixture was poured into ice water (600 ml), stirred for 30 min. The solid which formed was collected and washed with water then dried in vacuo to give the titlee compound as off white solid (10.2 g, 99%).
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]([CH3:12])[C:5](=[O:11])[C:6]([O:8]CC)=[O:7].[Li+].[OH-]>CO.O>[F:1][CH2:2][CH2:3][N:4]([CH3:12])[C:5](=[O:11])[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)C(=O)N(C)CCF
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(CCF)C(=O)C(=O)O
Reaction time: 2 h
Yield: 56 %

Procedure:
To a solution of ethyl 2-((2-fluoroethyl)(methyl)amino)-2-oxoacetate (1.2 g, 7.36 mmol) in methanol/water (30 mL, 1:1) was added LiOH (0.352 g, 14.71 mmol). The solution was stirred for 2 h. The methanol was removed by concentration and concentrated HCl (2 mL) was added. The solvent was removed and the residue dissolved in CH2Cl2 and filtered. The filtrate was concentrated to give the title compound as an off-white crystalline powder (0.615 g, 56% yield). 1H NMR (400 MHz, CDCl3) δ: 4.47-4.89 (2 H, m) 3.67-4.39 (2 H, m) 3.07-3.60 (3 H, m).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][OH:7].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl>[S:16]([O:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:18])(=[O:17])[CH3:15]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cccs1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1cccs1
Temperature: 0 °C

Procedure:
2-thienylmethanol mesylate is prepared by treating a solution of 2-thienylmethanol (5.57 g; 50 mmol) in methylene chloride (100 ml) and triethylamine (15.05 g, 150 mmol) at 0° C. with methanesulfonyl chloride (11.45 g, 100 mmol) dropwise and at RT 1 hr after the addition. The reaction mixture is poured into ice-water and the organic layer is separated, dried (MgSO4), and evaporated.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:7]([NH:23][C:24]([NH:26][C:27]2[C:32]([CH:33]([CH3:35])[CH3:34])=[CH:31][C:30]([CH2:36]Br)=[CH:29][C:28]=2[CH:38]([CH3:40])[CH3:39])=[O:25])[C:6]1=[O:41])[CH2:2][CH2:3][CH3:4].C1(=O)[NH:46]C(=O)C2=CC=CC=C12.[K].O>CN(C)C=O>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:7]([NH:23][C:24]([NH:26][C:27]2[C:32]([CH:33]([CH3:35])[CH3:34])=[CH:31][C:30]([CH2:36][NH2:46])=[CH:29][C:28]=2[CH:38]([CH3:40])[CH3:39])=[O:25])[C:6]1=[O:41])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cc(CBr)cc2C(C)C)c(-c2cccc(OC)c2)c2cccnc21
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cc(CN)cc2C(C)C)c(-c2cccc(OC)c2)c2cccnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.7 %

Procedure:
To a solution of N-[1-butyl-4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N′-(2,6-diisopropyl-4-bromomethylphenyl)urea (400 mg, 0.65 mmol) in dimethylformamide (10 ml) is added potassium phthalimide (144 mg, 0.78 mmol) at room temperature, and the mixture is stirred at room temperature for 3 hours. To the mixture is added water, and the mixture is extracted with ethyl acetate. The organic layer is washed twice with water, and dried over anhydrous magnesium sulfate. The solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give the title compound (393 mg, 0.57 mmol) as colorless amorphous.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=1>>[CH3:18][C:14]1[N:13]=[C:12]([O:10][C:7]2[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][OH:1])=[CH:5][CH:6]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cccc(Cl)n1
Reactant: OCCc1ccc(O)cc1
Product: Cc1cccc(Oc2ccc(CCO)cc2)n1

Procedure:
The title compound was prepared by a procedure similar to that described for D1 starting from 4-(2-hydroxyethyl)phenol and 2-chloro-6-methylpyridine. LC-MS (ESI): m/z 230 [M+H]+; 3.08 min (ret time).
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]([C:12]1[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[N:13]=1)[CH2:6][C:7]([O:9]CC)=[O:8])#[N:2].[Li+].[OH-].O.Cl>C1COCC1>[C:1]([CH2:3][CH2:4][N:5]([C:12]1[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[N:13]=1)[CH2:6][C:7]([OH:9])=[O:8])#[N:2]
Reactant: CCOC(=O)CN(CCC#N)c1cc(C)nc(-n2ccnc2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(N(CCC#N)CC(=O)O)nc(-n2ccnc2)n1
Reaction time: 18 h
Yield: 76.9 %

Procedure:
To 2-[(2-cyanoethyl)[2-(1H-imidazol-1-yl)-6-methyl-4-pyrimidinyl]amino]acetic acid, ethyl ester (4.51 g, 14.4 mmol) dissolved in THF (250 mL) was added LiOH (0.91 g, 21.7 mmol) and water (30 mL). After stirring for 18 hours, most of the solvent was removed in vacuo and 1 N HCl (21.7 mL, 21.7 mmol) was added. The solid that formed was suction filtered and collected on paper to give 3.17 g of 2-[(2-cyanoethyl)[2-(1H-imidazol-1-yl)-6-methyl-4-pyrimidinyl]amino]acetic acid (a compound of formula (Yc2)).
Reaction SMILES: [CH:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:7]=2)([CH3:3])[CH3:2].O=P(Cl)(Cl)Cl.CN([CH:26]=[O:27])C>>[CH:26]([C:12]1[C:11]2[C:6](=[CH:7][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][CH:10]=2)[NH:5][C:4]=1[CH:1]([CH3:3])[CH3:2])=[O:27]
Reactant: CCOC(=O)c1ccc2cc(C(C)C)[nH]c2c1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc2c(C=O)c(C(C)C)[nH]c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 2-isopropyl-1H-indole-6-carboxylate (Compound 33, 2.00 g, 8.66 mmol) in DMF (12 ml) at 0° C. under argon then added dropwise POCl3 (1.58 ml, 17.3 mmol) was added dropwise. The reaction was stirred for 30 minutes at 25° C. then cooled to 0° C., quenched with saturated NaHCO3, diluted with EtOAc, washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→50% EtOAc-hexanes) to yield the title compound as a light tan solid.
Reaction SMILES: [OH:1][NH:2]/[C:3](=[N:14]\[H])/[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1.[O:16]=[C:17]1[C:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][CH2:20][CH2:19][N:18]1[CH2:35][C:36](O)=O.Cl.C(N=C=NCCCN(C)C)C>ClC(Cl)C>[C:29]1([C:22]2([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:21][CH2:20][CH2:19][N:18]([CH2:35][C:36]3[O:1][N:2]=[C:3]([C:4]4[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=4)[N:14]=3)[C:17]2=[O:16])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: [H]/N=C(\NO)c1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(Cl)Cl
Product: O=C1N(Cc2nc(-c3cccc(C(F)(F)F)c3)no2)CCCC1(c1ccccc1)c1ccccc1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
A solution of (Z)—N-hydroxy-3-(trifluoromethyl)benzimidamide (0.155 g, 0.761 mmol), 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (0.214 g, 0.692 mmol; Example 68E) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.172 g, 0.899 mmol) were stirred together in dichloroethane (0.5 mL) at room temperature for 3 hours. The reaction was then heated to 85° C. and stirred overnight. The reaction was cooled, loaded onto a SF15-12 column (Analogix®) and the product eluted using a gradient of 5% ethyl acetate/hexanes to 35% ethyl acetate over 30 minutes (Flow=30 mL/minute) to supply the title compound. 1H NMR (300 MHz, CDCl3) δ 8.40 (s, 1H), 8.31 (d, J=7.7, 1H), 7.80 (d, J=7.9, 1H), 7.64 (dd, J=6.4, 14.3, 1H), 7.39-7.10 (m, 10H), 4.89 (d, J=20.0, 2H), 3.70-3.56 (m, 2H), 2.70 (dt, J=11.5, 25.9, 2H), 1.92 (dtd, J=3.1, 6.4, 9.4, 2H).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:7]=[C:8]([CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:25]4=[C:26]([C:28](=[O:38])[C:29]([CH2:31][C:32]5[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=5)=[CH:30][N:24]4[C:23]4[CH:22]=[C:21]([Br:39])[CH:20]=[CH:19][C:18]=4[S:17]3)[CH:27]=2)[CH:9]=[N:10][CH:11]=1)(=O)C.[OH-].[Na+]>CO.O>[Br:39][C:21]1[CH:20]=[CH:19][C:18]2[S:17][C:16]3[C:25]4=[C:26]([C:28](=[O:38])[C:29]([CH2:31][C:32]5[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=5)=[CH:30][N:24]4[C:23]=2[CH:22]=1)[CH:27]=[C:14]([O:13][CH2:12][C:8]1[CH:9]=[N:10][CH:11]=[C:6]([CH2:5][OH:4])[CH:7]=1)[CH:15]=3
Reactant: CC(=O)OCc1cncc(COc2cc3c4c(c2)c(=O)c(Cc2cccnc2)cn4-c2cc(Br)ccc2S3)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=c1c(Cc2cccnc2)cn2c3c(cc(OCc4cncc(CO)c4)cc13)Sc1ccc(Br)cc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
The compound (220 mg) obtained in Example 41 was suspended in methanol(10 mL) and to the suspension was added dropwise a solution of sodium hydroxide (90 mg) in water (1 mL). The mixture was stirred at room temperature overnight. After the end of reaction, the precipitate crystals were collected by filtration and washed with methanol and ether in turns to obtain the title compound (180 mg; 91%).