Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].CC1[O:21][C:9]2[C:10]([O:19][CH3:20])=[C:11]3[O:18][CH:17]=[CH:16][C:12]3=[C:13]([O:14][CH3:15])[C:8]=2[C:6](=[O:7])[CH:5]=1.Cl>O>[CH3:5][C:6]([C:8]1[C:9]([OH:21])=[C:10]([O:19][CH3:20])[C:11]2[O:18][CH:17]=[CH:16][C:12]=2[C:13]=1[O:14][CH3:15])=[O:7]
Reactant: COc1c2occc2c(OC)c2c(=O)cc(C)oc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1c(C(C)=O)c(O)c(OC)c2occc12
Temperature: 25 °C
Yield: 92.2 %

Procedure:
To a stirred solution of potassium hydroxide (193.2 g) in 1.5 l of water, heated to 75° C., is added 300 g of khellin (formula XXI) in 50 g portions over a period of 30 minutes. When khellin addition is complete, the resulting mixture is then heated to reflux for 2 hr and thereafter cooled to ambient temperature. Concentrated hydrochloric acid (300 ml) is then added to the cooled solution and the resulting precipitate is collected by filtration and dried at ambient temperature in a vacuum for 18 hr. The resulting crude yellow solid is then recrystallized from one liter of methanol, yielding 251 g of pure title product. Melting point is 99°-100° C. Silica gel TLC Rf is 0.60 is hexane and ethyl acetate (1:1). Infrared absorptions are observed at 3160, 3140, 1700, 1695, 1680, 1620, 1590, 1550, 1300, 1265, 1150, 1075, and 1060 cm-1. NMR absorptions are observed at 7.52, 6.91, 4.15, 4.05, 2.72, and 13.06δ (deuterochloroform solvent). The mass spectrum exhibits peaks at 236, 221, 206, 203, 191, 175, 163, and 119. Carbon:hydrogen ratio is 60.65:5.15.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=O)[CH2:9][CH:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:6]=2[CH:20]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:30]2)=CC=1.O>CN(C)P(=O)(N(C)C)N(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[S:30])[CH2:9][CH:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:6]=2[CH:20]=1
Reactant: O=C1CC=C(c2ccccc2F)c2cc(Cl)ccc2N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: Fc1ccccc1C1=CCC(=S)Nc2ccc(Cl)cc21
Temperature: 25 °C

Procedure:
20.2 g of 7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1-benzazepin-2-one are dissolved in 110 ml of hexamethylphosphoric acid triamide and treated with 13.8 g of 2,4-bis-(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulphide. The mixture is warmed to 100° for 1 hour, again cooled to room temperature and poured into 2.2 l of water. The mixture is extracted three times with ethyl acetate and the organic extracts are washed with water, sodium hydrogen carbonate solution and with saturated sodium chloride solution. The ethyl acetate solutions are evaporated and the residue is chromatographed on 400 g of silica gel. By elution with toluene and toluene/chloroform (19:1) and recrystallization of the resulting material from diisopropyl ether there is obtained 7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1-benzazepine-2-thione of melting point 179°-181°.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]3C=CC(C#N)=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2.[OH-:25].[K+].[CH2:27]([OH:31])[CH2:28][CH2:29][CH3:30]>O>[CH3:1][C:2]1([CH3:24])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]3[CH:17]=[CH:18][C:28]([C:27]([OH:25])=[O:31])=[CH:29][CH:30]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C#Cc3ccc(C#N)cc3)ccc21
Reactant: CCCCO
Reactant: [OH-]
Agent: [K+]
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Yield: 44 %

Procedure:
2.6 g (8 millimoles) of 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphth-2-yl)-ethynyl]-benzonitrile (Example 1) and 4.6 g of 85% strength potassium hydroxide in 17 ml of n-butanol were refluxed for 1.5 hours. The cooled reaction mixture was dissolved in 100 ml of water and the solution was extracted three times with ether. The aqueous phase was freed from residual ether under reduced pressure and acidified with 2N HCl. The precipitate which had separated out was filtered off under suction, washed with water and dried in a stream of nitrogen. 2.1 g of crude product remained. Recrystallization from isopropanol gave 1.2 g (44%) of the title compound of melting point 252°-256° C., which had a purity of 99.9% according to HPLC (C18 reversed phase; 9:1 acetonitrile/ H2O+0.1% of acetic acid; 100 ml/min; tR : 7 min).
Reaction SMILES: [C:1]([O:5][C:6]([N:8](C(OC(C)(C)C)=O)[C:9]1[S:10][CH:11]=[C:12]([CH:19]([CH3:21])[CH3:20])[C:13]=1[C:14]([O:16]CC)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].C(O)(=O)C>CO.O>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([CH:19]([CH3:21])[CH3:20])[C:13]=1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1c(C(C)C)csc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CC(C)c1csc(NC(=O)OC(C)(C)C)c1C(=O)O
Temperature: 80 °C
Yield: 79 %

Procedure:
A solution of ethyl 2-bis(t-butoxycarbonyl)amino-4-isopropylthiophene-3-carboxylate (22.5 g, 55 mmol) in methanol (425 ml) was stirred and a solution of potassium hydroxide (14.5 g, 259 ml) in water (145 ml) was added. The mixture was heated at 80° C. for 16 h, cooled to 0° C. and acidified (pH=5) with glacial acetic acid. The precipitate was filtered off and recrystallized from ethyl acetate/petroleum ether to afford 12.4 g (80%) of 2-t-butoxycarbonylamino-4-isopropylthiophene-3-carboxylic acid. M.p. 205°-206° C. 1H-NMR (CDCl3, δ): 1.25 (d, 6H) 1.55 (s, 9H), 3.6 (m, 1H) 6.45 (s, 1H), 7.25 (s, 1H), 10.2 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([OH:26])[CH2:24][CH3:25])=[CH:4][CH:3]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[F:58][C:59]([F:63])([F:62])[CH2:60]O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([O:26][CH2:60][C:59]([F:63])([F:62])[F:58])[CH2:24][CH3:25])=[CH:4][CH:3]=1
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: OCC(F)(F)F
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCC(OCC(F)(F)F)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 35 %

Procedure:
To a solution of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (100 mg, 0.243 mmol) and 1,1′-(azodicarbonyl)dipiperdine (123 mg, 0.49 mmol) in tetrahydrofuran (5.0 mL) was added tri(n-butyl)phosphine (0.122 mL, 0.49 mmol) at room temperature. After the mixture was stirred at room temperature for 10 min under nitrogen atmosphere, 2,2,2-trifluoroethanol (0.177 mL, 2.32 mmol) was added to the reaction mixture. The mixture was stirred at 60° C. for 8 hr under nitrogen atmosphere. The mixture was concentrated in vacuo and diethyl ether was added to the residue. The solid was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 10-40% ethyl acetate/n-hexane gradient mixture and recrystallization from 2-propanol/n-hexane to give the title compound (41.8 mg, 0.085 mmol, 35%) as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:19])[CH2:12][CH2:13][CH2:14][CH2:15][C:16](O)=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:22])=O>ClCCl>[CH2:1]([O:8][C:9](=[O:10])[N:11]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([Cl:22])=[O:17])[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(CCCCC(=O)O)C(=O)OCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CN(CCCCC(=O)Cl)C(=O)OCc1ccccc1

Procedure:
1.97 g (7.43 mmol) of 5-[[(benzyloxy)carbonyl](methyl)amino]valeric acid are dissolved in 30 ml of dichloromethane, and 4.9 ml (67.3 mmol) of thionyl chloride are added. The mixture is heated under reflux for 1 h. It is then concentrated in vacuo, and the residue is again mixed with dichloromethane and concentrated once again. A viscous oil remains and is dried under high vacuum. 2 g (95% of theory) of the target compound are obtained and are reacted further without further purification and characterization.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:33]=[CH:32][C:12]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH:24]=[C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:22][CH2:21]3)=[O:14])=[C:11]([N+:34]([O-])=O)[CH:10]=2)[CH2:4][CH2:3]1.C(O)C.[Sn](Cl)Cl.[OH-].[Na+]>C(Cl)(Cl)Cl.O1CCCC1>[NH2:34][C:11]1[CH:10]=[C:9]([CH2:8][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:33]=[CH:32][C:12]=1[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:21][CH:22]=[C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:24][CH2:25]1)=[O:14]
Reactant: CN1CCN(Cc2ccc(C(=O)NCCCCN3CC=C(c4ccccc4)CC3)c([N+](=O)[O-])c2)CC1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CN1CCN(Cc2ccc(C(=O)NCCCCN3CC=C(c4ccccc4)CC3)c(N)c2)CC1
Yield: 126.8 %

Procedure:
To a stirred mixture of 4-(4-methylpiperazin-1-ylmethyl)-2-nitro-N-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]benzamide (0.21 g), ethanol (5 ml) and dry tetrahydrofuran (10 ml) was added tin (II) chloride (0.33 g) and the mixture was refluxed for 1 hour. After cooling, chloroform (15 ml) and 1N sodium hydroxide (25 ml) were added and the mixture was stirred. The organic layer was separated and the remained aqueous layer was extracted with chloroform. The organic layer and extract were combined and dried over magnesium sulfate and evaporated to give 2-amino-4-(4-methylpiperazin-1-ylmethyl)-N-[4-(4-phenyl-1,2,3,6-tetrahydropyridin 1-yl)butyl]benzamide (0.25 g).
Reaction SMILES: CC1(C)[O:9][CH:8]2[CH:4]([CH:5]([CH2:18][OH:19])[O:6][CH:7]2[N:10]2[C:16](=[O:17])[NH:15][C:13](=[O:14])[CH:12]=[CH:11]2)[O:3]1.[CH2:21]([O:23][C:24](Cl)=[O:25])[CH3:22].C(Cl)(Cl)Cl.CO>N1C=CC=CC=1>[CH2:21]([O:23][C:24]([C@@:7]1([N:10]2[CH:11]=[CH:12][C:13](=[O:14])[NH:15][C:16]2=[O:17])[O:6][C@H:5]([CH2:18][OH:19])[C@@H:4]([OH:3])[C@H:8]1[OH:9])=[O:25])[CH3:22]
Reactant: CC1(C)OC2C(CO)OC(n3ccc(=O)[nH]c3=O)C2O1
Reactant: CCOC(=O)Cl
Solvent: CO
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@@]1(n2ccc(=O)[nH]c2=O)O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C

Procedure:
To an ice cold solution of 0.5 grams (1.76 millimoles) grams of 2′, 3′-isopropylidene uridine in 10 ml pyridine, 2.64 mmoles (1.5 equivalents) of ethylchloroformate was added dropwise while stirring. The reaction was allowed to warm up to room temperature (25° C.) and stirred overnight (18 hours), at which point TLC (9:1 chloroform/methanol) showed complete conversion of starting material to a single product. The solvent was removed by rotary evaporation under high vacuum, giving a light beige syrup which was carried over into the subsequent deprotection step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:15]([OH:17])=O)[N:5]([C:8]2[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[C:6]=1[Cl:7].[NH2:18][C:19]1[C:20]([C:31](O)=[O:32])=[CH:21][C:22]2[C:27]([C:28]=1[Cl:29])=[CH:26][CH:25]=[C:24](Br)[CH:23]=2.BrC1C=C(C(O)=O)N(C2C(Cl)=CC=CN=2)C=1.NC1C(C)=CC(Cl)=CC=1C(O)=O>>[Cl:29][C:28]1[C:19]2[N:18]=[C:15]([C:4]3[N:5]([C:8]4[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][N:9]=4)[C:6]([Cl:7])=[C:2]([Cl:1])[CH:3]=3)[O:17][C:31](=[O:32])[C:20]=2[CH:21]=[C:22]2[C:27]=1[CH:26]=[CH:25][CH:24]=[CH:23]2
Reactant: Nc1c(C(=O)O)cc2cc(Br)ccc2c1Cl
Reactant: O=C(O)c1cc(Cl)c(Cl)n1-c1ncccc1Cl
Agent: Cc1cc(Cl)cc(C(=O)O)c1N
Agent: O=C(O)c1cc(Br)cn1-c1ncccc1Cl
Product: O=c1oc(-c2cc(Cl)c(Cl)n2-c2ncccc2Cl)nc2c(Cl)c3ccccc3cc12

Procedure:
According to the same manner as that of Reference Preparation Example 71-(5), 4,5-dichloro-1-(3-chloro-2-pyridinyl)-1H-pyrrole-2-carboxylic acid and 3-amino-7-bromo-4-chloro-2-naphthoic acid were used in place of 4-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrrole-2-carboxylic acid and 2-amino-5-chloro-3-methylbenzoic acid respectively to obtain 10-chloro-2-[4,5-dichloro-1-(3-chloro-2-pyridinyl)-1H-pyrrol-2-yl]-4H-naphtho[2,3-d][1,3]oxazine-4-one of the formula:
Reaction SMILES: [C:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13](B(O)O)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([O:3][C:4]([CH3:7])(C)C)=[O:2].N1C=CC=CC=1.[C:26]([C:30]1[CH:34]=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[NH:32][N:31]=1)([CH3:29])([CH3:28])[CH3:27].B(O)O>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[C:26]([C:30]1[CH:34]=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[N:32]([C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([C:1]([O:3][CH2:4][CH3:7])=[O:2])[CH:9]=[CH:10]3)[N:31]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CCOC(=O)c1cc(C(C)(C)C)n[nH]1
Reactant: CC(C)(C)OC(=O)n1ccc2cc(B(O)O)ccc21
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: OBO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(C(C)(C)C)nn1-c1ccc2c(ccn2C(=O)OCC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
Commercially available N-Boc-5-indoleboronic acid (0.30 g, 1.1 mmol) was dissolved in CH2Cl2 (20 mL) and pyridine (1 mL) with molecular sieves (activated 4 A) and stirred overnight at RT. Commercially available ethyl 3-t-butyl-1 H-pyrazole-5-carboxylate, Cu(OAc)2 and molecular sieves (4 A activated, powder) were added to the boronic acid solution and the whole stirred at RT open to the atmosphere for 2d. The reaction mixture was filtered through a pad of Celite®, concentrated and purified by column chromatography to yield ethyl 5-(3-t-butyl-5-(ethoxycarbonyl)-1H-pyrazol-1-yl)-1H-indole-1-carboxylate (0.18 g, 38% yield). LC-MS (EI) m/z: 412.3 (M+H+).
Reaction SMILES: [F:1][CH2:2][C:3]([N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21])([CH2:6][CH2:7][CH2:8][CH2:9]I)[C:4]#[N:5].CN(C=O)C.[C:27]1(=[O:37])[NH:31][C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12.[K]>CC(C)=O>[F:1][CH2:2][C:3]([N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21])([CH2:6][CH2:7][CH2:8][CH2:9][N:31]1[C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]2[C:27]1=[O:37])[C:4]#[N:5]
Reactant: N#CC(CF)(CCCCI)N1C(=O)c2ccccc2C1=O
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: N#CC(CF)(CCCCN1C(=O)c2ccccc2C1=O)N1C(=O)c2ccccc2C1=O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 2-fluoromethyl-2-phthalimido-6-iodohexanenitrile (9.0 g, 22.5 mmol), dry DMF (30 ml), and potassium phthalimide (4.2 g, 1 equivalent) is stirred and heated at 80° C. for 4 hours. The DMF is removed under reduced pressure (0.1 mm Hg), and the residue is taken up in chloroform. The chloroform mixture is filtered and the filtrate is washed with 2N NaOH, 2N HCl, and water. Evaporation of solvent gives a residue which, when dissolved in the minimum amount of acetone, crystallizes upon addition of ether. After standing at 5° C. overnight, the colourless crystals of 2-fluoromethyl-2,6-diphthalimidohexanenitrile are collected (7.0 g), m.p. (Kofler) 136° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[C:10](=[O:23])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21]#[N:22])[CH:14]=1.[H-].[Na+].Br[CH2:27][C:28]#[N:29].CN(C)P(N(C)C)(N(C)C)=[O:33]>>[C:28]([CH2:27][O:33][N:5]1[C:6]([CH3:8])=[CH:7][C:2]([OH:1])=[C:3]([C:10](=[O:23])[CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21]#[N:22])[CH:14]=2)[C:4]1=[O:9])#[N:29]
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: N#CCBr
Reactant: Cc1cc(O)c(C(=O)C=Cc2cccc(OCC#N)c2)c(=O)[nH]1
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(O)c(C(=O)C=Cc2cccc(OCC#N)c2)c(=O)n1OCC#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 0.50 g of 4-hydroxy-3-[3-[3-(cyanomethoxy)phenyl]-1-oxo-2-propenyl]-6-methyl-2(1H)-pyridinone in 6 ml of hexamethylphosphoramide was added 46 mg of sodium hydride (60% oily) under ice-cooling, and this was stirred at room temperature for 1 hour. To the reaction mixture was added 0.33 ml of bromoacetonitrile under ice-cooling, and this was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and precipitated crystals were filtered, washed with t-butyl methyl ether, and dried to obtain 0.14 g of 1-(cyanomethoxy)-3-[3-[3-(cyanomethoxy)phenyl]-1-oxo-2-propenyl]-4-hydroxy-6-methyl-2(1H)-pyridinone [Compound No. (6c)] as a yellow crystal.
Reaction SMILES: [CH3:1][C:2]12[CH2:11][CH2:10][C@@H:9]([C:12]([OH:15])([CH3:14])[CH3:13])[CH2:8][C:7]1=[CH:6][C:5](=O)[CH2:4][CH2:3]2.[CH:17](Cl)(Cl)Cl>>[CH3:17][C:5]1[CH2:4][CH2:3][C@@:2]2([CH3:1])[CH2:11][CH2:10][C@@H:9]3[CH2:8][C@:7]2([O:15][C:12]3([CH3:14])[CH3:13])[CH:6]=1
Reactant: ClC(Cl)Cl
Reactant: CC12CCC(=O)C=C1C[C@H](C(C)(C)O)CC2
Product: CC1=C[C@@]23C[C@@H](CC[C@]2(C)CC1)C(C)(C)O3

Procedure:
White solid,: mp 38-39° C., [α]D1045.8° (c=0.47, chloroform). MS: 220 (M+, 15), 205 (50), 187 (14), 162 (31), 147 (50), 31 (100); 1H NMR (CDCl3, δ): 0.90 (s, 3 H, 6-CH3), 1.21 (s, 3 H, 10-CH3), 1.33 (s, 3 H, 10-CH3), 1.37 (s, 3 H, 3-CH3), 5.16 (s, 1 H, 2-H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[N:5]=[N:4][C:3]=1[C:16]([NH2:18])=[O:17].CI.[C:21](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:15][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][C:11]=1[Cl:14])[CH2:7][N:6]1[C:2]([NH:1][CH3:21])=[C:3]([C:16]([NH2:18])=[O:17])[N:4]=[N:5]1
Reactant: O=C([O-])[O-]
Reactant: NC(=O)c1nnn(Cc2ccc(Cl)c(Cl)c2)c1N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CNc1c(C(N)=O)nnn1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5-amino-1-(3,4-dichlorobenzyl)-1,2,3-triazole-4-carboxamide (2.86 g, 10.0 mmol), methyl iodide (1.42 g, 10.0 mmol), and potassium carbonate (1.38 g, 10 0 mmol) in N,N-dimethylformamide (20 ml) is stirred 48 hours at ambient temperature, poured into water (150 ml), and filtered. Chromatography provides 1-(3,4-dichloro- benzyl)-5-methylamino-1,2,3-triazole-4-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH2:10][C:9]([Cl:15])(S(Cl)(=O)=O)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+].[S:18]([O-])([O-:20])=[O:19].[Na+].[Na+].O>>[Cl:15][C:9]1[CH:10]=[C:2]([Cl:1])[C:3]([C:4]([OH:6])=[O:5])=[CH:7][C:8]=1[S:18]([OH:20])=[O:19]
Reactant: O=S([O-])[O-]
Reactant: O=C(O)C1=C(Cl)CC(Cl)(S(=O)(=O)Cl)C=C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(S(=O)O)c(Cl)cc1Cl

Procedure:
This compound is prepared following substantially the same procedure described in Example 1, Step A, using the following substances:2,4-dichloro-4-chlorosulfonylbenzoic acid 145 g. (0.5 mole)10N sodium hydroxide 145 ml.sodium sulfite 189 g. (1.5 mole)water 0.5 liter
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4](Cl)=[O:5].[CH2:12]([NH:14][CH2:15][C:16]([CH2:22][NH:23][C:24]1[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]2[C:25]=1[CH:26]=[N:27][N:28]2[C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)([OH:21])[C:17]([F:20])([F:19])[F:18])[CH3:13]>>[CH2:12]([N:14]([CH2:15][C:16]([CH2:22][NH:23][C:24]1[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]2[C:25]=1[CH:26]=[N:27][N:28]2[C:34]1[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=1)([OH:21])[C:17]([F:19])([F:20])[F:18])[C:4](=[O:5])[C:3]1[C:2]([CH3:1])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:11])[CH3:13]
Reactant: Cc1cccc(C)c1C(=O)Cl
Reactant: CCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Product: CCN(CC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1c(C)cccc1C

Procedure:
Prepared similarly to Example 48 from 2,6-dimethylbenzoyl chloride and 3-(ethylamino)-1,1,1-trifluoro-2-({[1-(4-fluorophenyl)-6-methyl-1H-indazol-4-yl]amino}methyl)-2-propanol.
Reaction SMILES: N([O-])=O.[Na+].S(=O)(=O)(O)O.[Br:10][C:11]1[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[C:12]=1N.[ClH:20]>C(O)(=O)C>[Cl:20][C:12]1[C:14]([Cl:19])=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=1[Br:10]
Reactant: Nc1c(Cl)cc(Cl)cc1Br
Reactant: Cl
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: Clc1cc(Cl)c(Cl)c(Br)c1

Procedure:
A Sodium nitrite (3.88 g, 0.056 mole) was added in portions to concentrated sulphuric acid (28.16 ml) stirred below 10° C. A solution of 2-bromo-4,6-dichloroaniline (12 g, 0.05 mole, Lancaster) in glacial acetic acid (126 ml) was added maintaining the temperature below 10° C. The mixture was stirred below 10° C. for 1 hr and then slowly added to a stirred solution of cuprous chloride (10.11 g, 0.10 mole) in concentrated hydrochloric acid (101.05 ml) at room temperature. The mixture was then stirred at room temperature for 17 hrs. The product was filtered, washed with water (3×50 ml), dissolved in chloroform (150 ml), dried over anhydrous magnesium sulphate, filtered and the filtrate evaporated in vacuo to give the desired product. Yield 10 g (77%), M.p. 55-57° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11](Cl)=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:15][CH2:16][CH:17]1[NH:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]([N:22]2[CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:18][CH:17]2[CH2:16][OH:15])=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNC(CO)C1
Reactant: Clc1ncc(Cc2ccccc2)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Cc3ccccc3)cn2)C(CO)C1
Temperature: 25 °C
Yield: 22.5 %

Procedure:
A solution of 5-benzyl-2-chloropyrimidine (944 mg, 4.626 mmol), tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (1.0 g, 6.939 mmol) and diisopropylethylamine (1.8 g, 13.878 mmol) in dioxane (100 mL) was stirred at 110° C. for two days. The reaction mixture was cooled to room temperature, concentrated and directly purified by silica gel chromatography eluting with petroleum ether:ethyl acetate=1:1, to afford tert-butyl 4-(5-benzylpyrimidin-2-yl)-3-(hydroxymethyl)piperazine-1-carboxylate (400 mg, 15%) as a white solid. MS (ES+) C21H28N4O3 requires: 384, found: 385 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C@@H:13]1[CH2:18][CH2:17][C@H:16]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:26]=[C:27]([CH:35]=[O:36])[CH:28]=[C:29]4[C:34]=3[N:33]=[CH:32][CH:31]=[CH:30]4)[CH2:21][CH2:20]2)[CH2:15][CH2:14]1)#[N:2].[O-:37]Cl=O.[Na+]>CC(O)(C)C.O.CCO>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C@@H:13]1[CH2:18][CH2:17][C@H:16]([N:19]2[CH2:20][CH2:21][N:22]([C:25]3[CH:26]=[C:27]([C:35]([OH:37])=[O:36])[CH:28]=[C:29]4[C:34]=3[N:33]=[CH:32][CH:31]=[CH:30]4)[CH2:23][CH2:24]2)[CH2:15][CH2:14]1)#[N:2]
Reactant: Cn1cc([C@H]2CC[C@@H](N3CCN(c4cc(C=O)cc5cccnc45)CC3)CC2)c2cc(C#N)ccc21
Reactant: [O-][Cl+][O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(C)(C)O
Product: Cn1cc([C@H]2CC[C@@H](N3CCN(c4cc(C(=O)O)cc5cccnc45)CC3)CC2)c2cc(C#N)ccc21
Temperature: 23 °C
Reaction time: 12 h
Yield: 38 %

Procedure:
To 750 mg (1.6 mmol) of 8-[4-[(cis)-4-(5-cyano-1-methyl-1H-indole-3-yl)cyclohexyl]-1-piperazinyl]-6-quinolinecarbaldehyde in 60 mL of t-BuOH and 8 mL of CH3CHC(CH3)2 at 23° C. was added a solution of 1.3 mg (14.4 mmol) NaClO2, 1.3 g (10.8 mmol) NaH2PO4 in 3 ml water. After stirring at 23° C. for 12 hours, the volatiles were removed by rotary evaporation. The reaction mixture was transferred to a separatory funnel and partitioned between water and CH2Cl2. The organics were washed with brine, dried over MsSO4, and chromatographed on silica gel eluting with 20:1 CH2Cl2:MeOH containing 5% glacial HOAc. The product fractions were pooled, stripped, and treated with 75 mg (0.83 mmol) of (CO2H)2 in absolute EtOH to give 390 mg (0.6 mmol, a 38% yield) of the oxalate salt of the title compound as a tan crystalline solid. mp: 230° C.; MS (ES) m/z: 494 (MH)+.