Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C(F)=C(C=CC=1F)C(Cl)=O.C(OCC)(=O)CC(OCC)=O.[Cl:24][C:25]1[C:26]([F:45])=[C:27]([CH:41]=[CH:42][C:43]=1[F:44])[C:28]([CH:30]([C:36]([O:38][CH2:39][CH3:40])=O)[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:29].ClC1C(F)=C(C=CC=1F)C(CC(OCC)=O)=O.C([O-])([O-])OCC.C(OC(=O)C)(=O)C>>[Cl:24][C:25]1[C:26]([F:45])=[C:27]([CH:41]=[CH:42][C:43]=1[F:44])[C:28]([C:30](=[CH:36][O:38][CH2:39][CH3:40])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:29]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1ccc(F)c(Cl)c1F
Agent: CCOC(=O)CC(=O)c1ccc(F)c(Cl)c1F
Agent: CCOC([O-])[O-]
Agent: O=C(Cl)c1ccc(F)c(Cl)c1F
Solvent: CCOC(=O)CC(=O)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1ccc(F)c(Cl)c1F

Procedure:
Reaction of 3-chloro-2,4-difluoro-benzoyl chloride with diethyl malonate gives diethyl (3-chloro-2,4-difluoro-benzoyl)-malonate, and partial hydrolysis and decarboxylation lead to ethyl (3-chloro-2,4-difluoro-benzoyl)-acetate, which is reacted with ethyl orthoformate/acetic anhydride to give ethyl 2-(3-chloro-2,4-difluorobenzoyl)-3-ethoxy-acrylate; further reaction with cyclopropylamine leads to ethyl 2-(3-chloro-2,4-difluoro-benzoyl)-3-cyclopropylaminoacrylate, which is cyclized with potassium carbonate/dimethylformamide to give ethyl 8-chloro-1-cyclopropyl-7-fluoro-1,4-dihydro-4-oxo-3 -quinolinecarboxylate; hydrolysis then finally leads to the corresponding carboxylic acid. The reaction sequence described can be represented by the following equation: ##STR4##
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])[CH:5]=[CH:4][N:3]=[CH:2]1.[N:19]1[C:27]2[C:22]3[C:23](=[CH:28][CH:29]=[CH:30][C:21]=3[C:20]=1S)[CH:24]=[CH:25][CH:26]=2>C(O)C>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:20]2[C:21]3[CH:30]=[CH:29][CH:28]=[C:23]4[C:22]=3[C:27](=[CH:26][CH:25]=[CH:24]4)[N:19]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: SC1=Nc2cccc3cccc1c23
Reactant: NCCCCCCCCCCCCn1ccnc1
Solvent: CCO
Product: c1cc2c3c(cccc3c1)C(NCCCCCCCCCCCCn1ccnc1)=N2

Procedure:
A mixture of 2.5 g of 12-(1H-imidazol-1-yl)dodecanamine, 1.9 g of benz[cd]indole-2-thiol, 3.4 g of mercuric acetate and 400 ml of ethanol was reacted as described in Example 1. The crude product was purified by dissolving it in chloroform and chromatographing it on a silica gel column, eluting with 10% methanol in chloroform giving 490 mg of the desired product, mp 95°-97° C.
Reaction SMILES: [CH:1]1([C@H:6]2[C:33](=[O:34])[N:32]3[CH2:35][C@@H:29]([CH2:30][C@H:31]3[C:36]([NH:38][C@:39]3([C:44](=[O:52])[NH:45][S:46]([CH:49]4[CH2:51][CH2:50]4)(=[O:48])=[O:47])[CH2:41][C@H:40]3[CH:42]=[CH2:43])=[O:37])[O:28][C:18]3=[N:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=4[C:26]([OH:27])=[C:17]3[CH2:16][CH:15]=[CH:14][CH2:13][CH2:12][C@@H:11]3[CH2:53][CH2:54][CH2:55][C@H:10]3[O:9][C:8](=[O:56])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[P:64](Cl)([O:69][CH2:70][CH3:71])([O:66][CH2:67][CH3:68])=[O:65]>ClCCl>[P:64]([O:69][CH2:70][CH3:71])([O:66][CH2:67][CH3:68])([O:27][C:26]1[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N:19]=[C:18]2[O:28][C@H:29]3[CH2:35][N:32]([C:33](=[O:34])[C@H:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[NH:7][C:8](=[O:56])[O:9][C@@H:10]4[CH2:55][CH2:54][CH2:53][C@H:11]4[CH2:12][CH2:13][CH:14]=[CH:15][CH2:16][C:17]=12)[C@H:31]([C:36](=[O:37])[NH:38][C@:39]1([C:44](=[O:52])[NH:45][S:46]([CH:49]2[CH2:50][CH2:51]2)(=[O:47])=[O:48])[CH2:41][C@H:40]1[CH:42]=[CH2:43])[CH2:30]3)=[O:65]
Reactant: CCOP(=O)(Cl)OCC
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CCC=CCc1c(nc3ccccc3c1O)O2)C(=O)NS(=O)(=O)C1CC1
Agent: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CC/C=C/Cc1c(nc3ccccc3c1O)O2)C(=O)NS(=O)(=O)C1CC1
Agent: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CC/C=C/Cc1c(nc3ccccc3c1OP(=O)(OCC)OCC)O2)C(=O)NS(=O)(=O)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CCC=CCc1c(nc3ccccc3c1OP(=O)(OCC)OCC)O2)C(=O)NS(=O)(=O)C1CC1
Temperature: 25 °C

Procedure:
To a solution of (3aR,7S,10S,12R,21E,24aS)-7-cyclopentyl-N-{(1R,2S)-1-[(cyclopropylsulfonyl)carbamoyl]-2-ethenylcyclopropyl}-19-hydroxy-5,8-dioxo-1,2,3,3a,5,6,7,8,11,12,20,23,24,24a-tetradecahydro-10H-9,12-methanocyclopenta[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoline-10-carboxamide (Example 17) (35 mg) in dichloromethane (0.44 mL) was added triethylamine (123 μl) followed by diethyl chlorophosphate (64 μl). The reaction mixture was stirred at room temperature until disappearance of the starting material. The reaction was quenched with water and extracted with ethyl acetate (3×). The combined organic fractions were dried over magnesium sulfate, filtered and concentrated. Purification by reverse phase HPLC (40-100% ACN/0.015% TFA-water) afforded the desired product (20 mg). LRMS (ES+) m/z 926.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=1>Cl>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([N:6]([CH3:7])[C:11]2[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1
Reactant: CNc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: Cl
Product: CN(c1ccc(Cl)cc1)c1ncccc1[N+](=O)[O-]

Procedure:
To 90 g (0.63 mole) of 4-chloro-N-methylaniline heated to 115°-120° C. under nitrogen atmosphere with stirring was added 66.3 g (0.42 mole) of 2-chloro-3-nitropyridine in four portions over a period of 80 minutes. After stirring the reaction mixture for an additional 20 minutes at 115°-120° C., the temperature was increased to 135°-140° C. for an additional 20 minute period. The hot melt was poured into 700 ml of 2N hydrochloric acid solution. Red precipitate weighing 96 g was collected and dissolved in hot acetic acid and converted to the hydrochloride salt by adding etheral hydrogen chloride. The yield of the yellow solid was 90 g (72%). A portion of the salt was recrystallized from ethyl acetate-ethyl alcohol. On drying at 80° C. in vacuo, the hydrochloride salt dissociated to the free base, the title compound, m.p. 107°-110° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+]([O-])=O)[CH:5]=[C:4]([CH3:11])[N:3]=1.[K].[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1)([O-:15])=[O:14]>CN1CCCC1=O>[Br:1][C:2]1[CH:7]=[C:6]([S:22][C:19]2[CH:20]=[CH:21][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][CH:18]=2)[CH:5]=[C:4]([CH3:11])[N:3]=1
Reactant: O=[N+]([O-])c1ccc(S)cc1
Reactant: Cc1cc([N+](=O)[O-])cc(Br)n1
Agent: [K]
Solvent: CN1CCCC1=O
Product: Cc1cc(Sc2ccc([N+](=O)[O-])cc2)cc(Br)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 63.5 %

Procedure:
1.0 g (0.00458 mol) of 2-bromo-6-methyl-4-nitropyridine and 0.885 g (0.00458 mol) of 4-nitrothiophenol potassium salt were dissolved in 10 ml of 1-methyl-pyrrolidone and stirred at 50° C. for 1 hr. The solvent was removed in a high vacuum and the residue was partitioned in water and ethyl acetate. The combined organic phases were washed with sat. sodium chloride solution and dried over MgSO4. After filtration and removal of the solvent the residue was chromatographed on silica gel with ethyl acetate/hexane 1:4 and 1:3 and subsequently dried in a high vacuum. There was obtained 0.945 g (63%) of 2-bromo-6-methyl-4-(4-nitrophenylsulphanyl)-pyridine as yellow crystals; m.p.: 124-126° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][N+:4]=1[O-])#N.Cl.O.C(=O)(O)[O-:14].[Na+]>C(Cl)Cl>[CH3:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([CH:1]=[O:14])[CH:8]=1
Reactant: O=C([O-])O
Reactant: Cc1cc[n+]([O-])c(C#N)c1
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1ccnc(C=O)c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 14.8 %

Procedure:
To a solution of 2-cyano-4-methylpyridine-N-oxide (3.29 g, 0.0279 mol) in 164 mL of methylene chloride at -78° C. was added 27.6 mL of DIBAL(H) and the mixture was stirred at -78° C. for 2 h. To the above mixture was added 13 mL of HCl (conc.) and 52 mL of water, and the mixture was warmed to room temperature. To the aqueous layer was added sodium bicarbonate solution, the solution was extracted with ether, and the combined organic layer was concentrated in vacuo. The residue was purified by chromatography on silica (ether) to afford 0.5 g (14.8%) of 4-methylpyridine-2-carboxaldehyde, as an oil.
Reaction SMILES: [CH:1]12[CH2:6][CH:5]1[CH2:4][N:3]([C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=3)[C:10]([C:24](O)=[O:25])=[CH:9][N:8]=1)[CH2:2]2.[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[CH:1]12[CH2:6][CH:5]1[CH2:4][N:3]([C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=3)[C:10]([C:24]([NH:33][CH2:32][C:31]3[CH:34]=[CH:35][C:28]([F:27])=[CH:29][CH:30]=3)=[O:25])=[CH:9][N:8]=1)[CH2:2]2
Reactant: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)O)cc1Cl
Reactant: NCc1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)NCc2ccc(F)cc2)cc1Cl
Reaction time: 18 h
Yield: 15.6 %

Procedure:
In THF (10 mL) were dissolved 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-chloro-4-methoxybenzyl)amino)-pyrimidine-5-carboxylic acid (150 mg, 0.40 mmol), 4-fluorobenzylamine (56 mg, 0.45 mmol) and triethylamine (101 mg, 1 mmol). The reaction mixture was cooled in an ice bath and HATU (266 mg, 0.70 mmol) was added. The reaction was conducted at ambient temperature for 18 h. The reaction mixture was concentrated, followed by addition of water and extraction with ethyl acetate. The organic phase was dried, concentrated, and purified by silica gel column chromatography (DCM/methanol=20/1) to give 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-chloro-4-methoxybenzyl)amino)-N-(4-fluorobenzyl)pyrimidine-5-formamide (30 mg, 16% yield).
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)=[CH:22][CH:21]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[C:36]1([CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[N:11]=[C:7]([CH2:6][C:5]2[CH:34]=[CH:35][C:2]([N:45]3[CH2:46][CH2:47][CH:42]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH2:43][CH2:44]3)=[CH:3][CH:4]=2)[N:8]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]3)=[CH:22][CH:21]=2)[CH:9]=1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)cc2)S(=O)(=O)N1
Reactant: c1ccc(C2CCNCC2)cc1
Product: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(N4CCC(c5ccccc5)CC4)cc3)cc2)S(=O)(=O)N1

Procedure:
5-{-4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (119 mg, 0.2 mmol) was treated as described in general procedure R using 4-phenylpiperidine (162 mg, 1 mmol) to give 5-(4-{4-(2,4-dichloro-phenyl)-2-[4-(4-phenyl-piperidin-1-yl)-benzyl]-imidazol-1-yl}-phenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)=[CH:5][CH:4]=1.[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[C:33]([CH3:34])=[C:32]([CH:35]=O)[NH:31][C:30]=2[CH3:37])=[O:28])[CH:23]=[CH:22][N:21]=[N:20]1>C(O)C.N1CCCCC1>[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[C:33]([CH3:34])=[C:32]([CH:35]=[C:11]3[C:10]4[C:14](=[CH:15][CH:16]=[CH:17][C:9]=4[C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[NH:13][C:12]3=[O:18])[NH:31][C:30]=2[CH3:37])=[O:28])[CH:23]=[CH:22][N:21]=[N:20]1
Reactant: COc1ccc(-c2cccc3c2CC(=O)N3)cc1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCn1ccnn1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc(-c2cccc3c2C(=Cc2[nH]c(C)c(C(=O)NCCn4ccnn4)c2C)C(=O)N3)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 44.8 %

Procedure:
To a solution of 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (67.9 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(4-methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as a yellow solid (54 mg, 45%).
Reaction SMILES: Br[C:2]1[C:7]([Cl:8])=[CH:6][C:5](O)=[C:4]([Cl:10])[CH:3]=1.[Cl:11]C1C=CC(Cl)=CC=1O.ClC1C=C(Cl)C=CC=1O>>[Cl:10][C:4]1[CH:3]=[CH:2][C:7]([Cl:8])=[CH:6][C:5]=1[Cl:11]
Reactant: Oc1cc(Cl)ccc1Cl
Reactant: Oc1cc(Cl)c(Br)cc1Cl
Agent: Oc1ccc(Cl)cc1Cl
Product: Clc1ccc(Cl)c(Cl)c1

Procedure:
A process for the preparation of 4-bromo-2,5-dichlorophenol which comprises reacting a mixture of 2,5-dichlorophenol and 2,4-dichlorophenol obtained by saponifying 1,2,4-trichlorobenzene and distilling 3,4-dichlorophenol from the resulting mixture, with an equimolar amount of bromine in a glacial acetic acid reaction medium at a temperature of about 30° C. and thereafter recovering the 4-bromo-2,5-dichlorophenol.
Reaction SMILES: O[C:2]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH2:24][CH2:25][F:26])[CH2:7][CH2:6][CH:5]([CH:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH3:16])[CH2:10][CH2:9]2)[CH2:4][CH2:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH2:14]([CH:11]1[CH2:10][CH2:9][CH:8]([CH:5]2[CH2:6][CH2:7][C:2]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH2:24][CH2:25][F:26])=[CH:3][CH2:4]2)[CH2:13][CH2:12]1)[CH2:15][CH3:16]
Reactant: CCCC1CCC(C2CCC(O)(c3ccccc3OCCF)CC2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCC1CCC(C2CC=C(c3ccccc3OCCF)CC2)CC1

Procedure:
The crude 1-hydroxy-4-(4-propylcyclohexyl)cyclohexyl-2-fluoroethoxybenzene obtained in the first step was dissolved in toluene. p-Toluene sulfonic acid monohydrate was added and refluxed while heating for two hours under dewatering by using a Dean-Stark apparatus. The reaction mixture was poured into an aqueous saturated sodium hydrogen carbonate solution and extracted with toluene. The organic layer was washed with water and then with an aqueous saturated sodium chloride solution successively and, after dying over anhydrous magnesium sulfate, concentrated under a reduced pressure. The residue was purified by silica gel column chromatography to obtain 4-(4-propylcyclohexyl)cyclohexenyl-2-fluoroethoxybenzene.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]2[N:9]([CH:13]([C:15]3[O:16][C:17](=[O:37])[C:18]4[C:23]([C:24]=3[C:25]3[S:26][C:27]([CH2:30][N:31]5[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]5)=[CH:28][CH:29]=3)=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH3:14])[N:10]=[C:11](I)[C:4]=12.[F:38][C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[C:43]([OH:45])[CH:44]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>C1COCC1>[ClH:1].[NH2:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]2[N:9]([CH:13]([C:15]3[O:16][C:17](=[O:37])[C:18]4[C:23]([C:24]=3[C:25]3[S:26][C:27]([CH2:30][N:31]5[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]5)=[CH:28][CH:29]=3)=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH3:14])[N:10]=[C:11]([C:41]3[CH:42]=[C:43]([OH:45])[CH:44]=[C:39]([F:38])[CH:40]=3)[C:4]=12
Reactant: CC(c1oc(=O)c2ccccc2c1-c1ccc(CN2CCCCC2)s1)n1nc(I)c2c(N)ncnc21
Reactant: OB(O)c1cc(O)cc(F)c1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(c1oc(=O)c2ccccc2c1-c1ccc(CN2CCCCC2)s1)n1nc(-c2cc(O)cc(F)c2)c2c(N)ncnc21
Yield: 71.8 %

Procedure:
3-(1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-(5-(piperidin-1-ylmethyl)thiophen-2-yl)-1H-isochromen-1-one hydrochloride (Intermediate D9, 100 mg, 0.154 mmol), 3-fluoro-5-hydroxyphenylboronic acid (48.1 mg, 0.308 mmol), S-Phos-Pd-G2 (11.10 mg, 0.015 mmol) and K3PO4 (151 mg, 0.462 mmol) were reacted in THF (1.2 ml) and water (0.3 ml) under argon at 80° C. under mw irradiation for 30 min The reaction was quenched by the addition of 1M HClaqueous (2 ml) and the mixture purified via reverse phase chromatography using a Biotage C18 60 g SNAP with a gradient of water and acetonitrile to give (prior to drying a small amount of 1M HCl aqueous was added) the title compound (70 mg, 71.7% yield) as yellowish solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[CH3:21][N:22]([CH3:32])[C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[CH3:21][N:22]([CH3:32])[C:23]1[CH:28]=[CH:27][C:26]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[C:4](=[O:19])[CH2:3][C:2]3([CH3:20])[CH3:1])=[CH:25][CH:24]=1
Reactant: CN(C)c1ccc(B(O)O)cc1
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Product: CN(C)c1ccc(-c2ccc3c(c2)C(C)(C)CC3=O)cc1

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester and 4-(dimethylamino)phenyl boronic acid according to the procedure described in example 21. MS m/z 280; HRMS: calcd for C19H21NO+H+, 280.16959; found (ESI, [M+H]+), 280.1691.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][C:11]([CH3:18])([C:14](OC)=[O:15])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:19][CH3:20].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][C:11]([CH2:14][OH:15])([CH3:18])[CH2:12][CH2:13]2)=[CH:4][C:3]=1[O:19][CH3:20]
Reactant: COC(=O)C1(C)CCN(c2ccc(Cl)c(OC)c2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(N2CCC(C)(CO)CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.6 %

Procedure:
A solution of methyl 1-(4-chloro-3-methoxyphenyl)-4-methylpiperidine-4-carboxylate (500 mg, 1.679 mmol) in anhydrous THF (5 mL) and Et2O (10 mL) was treated dropwise with lithium aluminum hydride (3.36 mL of a 1.0 M solution in THF, 3.36 mmol) while the reaction temperature was controlled with a water bath. The mixture was then stirred at RT for 1 h, treated with Na2SO4.10H2O (1 g), stirred vigorously for 30 min and then dried with anhydrous MgSO4. The mixture was filtered and concentrated to give (1-(4-chloro-3-methoxyphenyl)-4-methylpiperidin-4-yl)methanol as a pale yellow oil (460 mg). The product was used without further purification in the subsequent step.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([S:15]([C:18]3[S:22][C:21](C4CCN(C(OC(C)(C)C)=O)CC4=O)=[CH:20][CH:19]=3)(=[O:17])=[O:16])[C@H:11]([CH3:37])[CH2:10]2)=[C:5]([C:38]([F:41])([F:40])[F:39])[CH:4]=1.BrC1SC(S(N2CCN(C3C=CC(F)=CC=3C(F)(F)F)C[C@H]2C)(=O)=O)=CC=1.[O:69]=[C:70]1[NH:75][CH2:74][CH2:73][N:72](C(OC(C)(C)C)=O)[CH2:71]1>CCOC(C)=O>[F:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([S:15]([C:18]3[S:22][C:21]([N:75]4[CH2:74][CH2:73][NH:72][CH2:71][C:70]4=[O:69])=[CH:20][CH:19]=3)(=[O:16])=[O:17])[C@H:11]([CH3:37])[CH2:10]2)=[C:5]([C:38]([F:41])([F:40])[F:39])[CH:4]=1
Reactant: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2=O)s1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1ccc(Br)s1
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1ccc(N2CCNCC2=O)s1

Procedure:
Prepared by acid treatment (1N HCl in EtOAc) of tert-butyl 4-(5-((R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-ylsulfonyl)thiophen-2-yl)-3-oxopiperidine-1-carboxylate, as a white solid [tert-butyl 4-(5-((R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-ylsulfonyl)thiophen-2-yl)-3-oxopiperidine-1-carboxylate was prepared according to procedures similar to those described in Example 29FH from (R)-1-(5-bromothiophen-2-ylsulfonyl)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazine (292 mg, 0.6 mmol), and tert-butyl 3-oxopiperazine-1-carboxylate (181 mg, 0.9 mmol) as a white solid (major product, 89.4 mg, 86%)]. HRMS: calcd for C20H22F4N4O3S2+H+, 507.11422. found (ESI-FTMS, [M+H]1+), 507.11461.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][S:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:21])=[O:20])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Nc1ccc(Cl)c2cccnc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Product: O=S(=O)(Nc1ccc(Cl)c2cccnc12)c1ccccc1
Yield: 64.3 %

Procedure:
In the similar fashion using route 14 general procedure 27, 5-chloroquinolin-8-amine (Intermediate 27) (70 mg, 0.39 mmol), benzenesulfonyl chloride (83 mg, 0.42 mmol) and DMAP (cat.) gave the title compound (80 mg, 64%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [Cl:1][C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.O.[NH2:16][NH2:17]>C(O)C>[Cl:1][C:2]1[C:11]([NH:16][NH2:17])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: COc1ccc2nc(Cl)c(Cl)nc2c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: COc1ccc2nc(Cl)c(NN)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
2,3-Dichloro-6-methoxyquinoxaline (4.2 g., 0.018 mole), the product of Preparation E(b), and 2.7 ml. of hydrazine hydrate in 100 ml. of ethanol were heated under reflux for 4 hours and stirred at room temperature overnight. The precipitate was removed by filtration and washed with ethanol to afford 3.9 g. (97% yield) of 2-chloro-3-hydrazino-6-methoxyquinoxaline, m.p. <250° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8]CC)=O)=[CH:2]1.O.[NH2:12][NH2:13]>C(O)C>[O:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:12][NH2:13])=[O:8])=[CH:2]1
Reactant: CCOC(=O)c1ccoc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ccoc1
Reaction time: 6 h

Procedure:
Ethyl 3-furancarboxylate (7.0 g) and hydrazine monohydrate (4.8 ml) in ethanol (10 ml) were heated at reflux while stirring for 6 hours. The solvent was evaporated under reduced pressure, and the thus-precipitated crystals were recrystallized from ethanol, thereby giving 3.2 g of the desire compound.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:36]2[C:37]([C:43]([F:46])([F:45])[F:44])=[N:38][C:39]([NH2:42])=[N:40][CH:41]=2)O1>>[CH3:21][S:18]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[N:3][C:2]([C:36]4[C:37]([C:43]([F:46])([F:45])[F:44])=[N:38][C:39]([NH2:42])=[N:40][CH:41]=4)=[N:7][C:6]=3[CH:8]=2)[CH2:13][CH2:14]1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CC1(C)OB(c2cnc(N)nc2C(F)(F)F)OC1(C)C
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4cnc(N)nc4C(F)(F)F)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (200 mg), prepared via General Procedure B-3, was coupled to 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-4-trifluoromethyl-pyrimidin-2-ylamine via General Procedure A to yield 20 mg of 327. MS (Q1) 559.2 (M)+.