Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[N:18]([CH3:19])[C:17]([C:20]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)=[CH:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:16][CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].[H][H]>CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[N:18]([CH3:19])[C:17]([CH:20]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:16][CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: Cn1c(CCNS(=O)(=O)c2ccc(F)cc2)ccc1C(=CCCCC(=O)O)c1cccnc1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1c(CCNS(=O)(=O)c2ccc(F)cc2)ccc1C(CCCCC(=O)O)c1cccnc1

Procedure:
A mixture of 2.36 g of 6-(5-(2-(4-fluorobenzenesulphonylamino)ethyl)-N-methyl-pyrrol-2-yl)-6-(3-pyridyl)hex-5-enoic acid, 0.4 g of sodium hydroxide and 1 g of 10% palladium/charcoal in 50 ml of methanol is hydrogenated under 5 bar of hydrogen pressure. Then the catalyst is filtered off, the filtrate is evaporated down, the residue is diluted with water, acidified and extracted with ethylene chloride. The organic extract is evaporated down and the residue recrystallised from ethyl acetate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH3:10].[Mg].II.C[Mg]Br.[CH2:17]([Sn:21](Cl)([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20]>C1COCC1.CCOCC>[CH3:10][O:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[Sn:21]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: COc1cc(C)ccc1Br
Agent: C[Mg]Br
Agent: II
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(C)cc1OC
Temperature: 50 °C
Reaction time: 18 h
Yield: 67.8 %

Procedure:
A solution of 2-bromo-5-methylanisole (3.8 g) [obtained as described in J. Gen. Chem. U.S.S.R., 1932, 2, 455 (Chemical Abstracts, 1933, 27, 962)] in THF (50 ml) was added to magnesium turnings (0.47 g) and a catalytic amount of iodine under an atmosphere of argon. A catalytic volume of 1M methyl magnesium bromide in ether was added and the mixture was heated 50° C. for 1 hour, and then cooled to 0° C. Tributyltin chloride (5.6 g) was added dropwise over 5 minutes and the mixture was stirred for 18 hours. Volatile material was removed by evaporation and the residue partitioned between ether (50 ml) and saturated ammonium chloride solution (50 ml). The organic phase was separated and washed with saturated ammonium chloride solution (2×20 ml). The ether layer was separated, diluted with ethyl acetate (50 ml), and washed with water (25 ml), followed by saturated sodium chloride solution (50 ml). Volatile material was removed by evaporation and the residue purified by distillation to give (2-methoxy-4-methylphenyl)tributyl tin (B) (4.8 g), as an oil, b.p. 190° C. at 0.05 torr; NMR: 0.75-1.7 (complex m,27H), 2.4(s,3H), 3.8(s,3H), 6.6(t,1H), 6.8(d,1H), 7.2(d,1H).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)=[O:7].[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(CC1C=C(CN(C)C)C(O)=C(CN(C)C)C=1)C>[CH2:23]([NH:30][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][CH:17]=[C:9]([NH:8][C:6](=[O:7])[CH2:5][O:4][C:3]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:2]=2[Cl:1])[CH:10]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(COc1ccc(Cl)cc1Cl)Nc1cccc(C(=O)O)c1
Reactant: NCc1ccccc1
Agent: CN(C)Cc1cc(CN(C)C)c(O)c(CN(C)C)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(COc1ccc(Cl)cc1Cl)Nc1cccc(C(=O)NCc2ccccc2)c1
Temperature: 25 °C
Yield: 14 %

Procedure:
To solution of 3-[2-(2,4-dichloro-phenoxy)-acetylamino]-benzoic acid (68 mg, 0.2 mmol), benzylamine (0.032 ml, 0.3 mmol) in DMF 3.0 mL was added EDC (57.5 mg, 0.3 mmol), HOBt (40.6 mg, 0.3 mmol) and DIPEA (0.052 ml, 0.3 mmol). Reaction mixture was stirred at room temperature, and separated by EtoAC and brine. The organic phase was dried (MgSO4 anh) and concentrated. The residue was purified by silica gel column chromatography (n-Hexane:EtoAC:MeOH=15:3:1) to give N-benzyl-3-[2-(2,4-dichloro-phenoxy)-acetylamino]-benzamide as a white solid (12 mg, 14% yield).
Reaction SMILES: C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C.[F:17][C:18]1[CH:19]=[N:20][C:21](=[O:24])[NH:22][CH:23]=1.O[CH2:26][C:27]1[S:28][CH:29]=[CH:30][CH:31]=1>CN(C)C=O>[F:17][C:18]1[CH:19]=[N:20][C:21](=[O:24])[N:22]([CH2:26][C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)[CH:23]=1
Reactant: OCc1cccs1
Reactant: O=c1ncc(F)c[nH]1
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Solvent: CN(C)C=O
Product: O=c1ncc(F)cn1Cc1cccs1
Temperature: 80 °C

Procedure:
N,N-Dimethylformamide dineopentyl acetal (1.76 ml) was added to a stirred suspension of 5-fluoropyrimidin-2-one (456 mg) and 2-hydroxymethyl thiophene (0.7 ml) in dry N,N-dimethylformamide (8 ml) under nitrogen and the mixture was then heated at 80° C. After 1 h the reaction mixture was evaporated to a brown solid which was crystallised twice from ethyl acetate to give white crystals of the title pyrimidinone (230 mg), m.p. 161°-163° C., λmax (EtOH) 222.5 nm (ε 10,890), 333.5 nm (ε 3,660).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[C:21]4[C:16](=[N:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[C:14]3[C:22](O)=[O:23])[CH:8]=2)=[CH:4][CH:3]=1.Cl.[CH:26]([N:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1)([CH3:28])[CH3:27].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl.C(N(CC)CC)C>[CH:26]([N:29]1[CH2:34][CH2:33][CH:32]([NH:35][C:22]([C:14]2[N:13]([CH2:12][C:9]3[CH:8]=[C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)[O:11][N:10]=3)[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)=[O:23])[CH2:31][CH2:30]1)([CH3:28])[CH3:27]
Reactant: O=C(O)c1cc2ncccc2n1Cc1cc(-c2ccc(Cl)s2)on1
Reactant: CC(C)N1CCC(N)CC1
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)N1CCC(NC(=O)c2cc3ncccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Reaction time: 16 h

Procedure:
To a suspension of 50 mg 1-[5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid, 36 mg 1-isopropyl-piperidin-4-ylamine hydrochloride and 35 mg bis(2-oxo-3-oxazolidinyl)phosphinic chloride in 1 mL dichloromethane, 77 μl triethylamine were added at room temperature and the mixture was stirred for 16 hours. After removing of the solvent under reduced pressure, the residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/acetonitrile gradient with 0.1% trifluoroacetic acid). The fractions containing the product were evaporated and lyophilized to yield a white residue which was partitioned between 5 mL aqueous 0.1 N sodium hydroxide solution and 5 mL ethyl acetate. The organic layer was washed with additional water and then dried over sodium sulphate. After filtration and removal of the solvent under reduced pressure, a white solid was obtained.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([NH2:7])[CH:3]=1.[CH:8]1([CH2:12][N:13]([CH2:27][CH3:28])[C:14]2[N:19]=[C:18]3[N:20]([CH3:24])[N:21]=[C:22]([CH3:23])[C:17]3=[CH:16][C:15]=2[CH:25]=O)[CH2:11][CH2:10][CH2:9]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C>[CH:8]1([CH2:12][N:13]([C:14]2[N:19]=[C:18]3[N:20]([CH3:24])[N:21]=[C:22]([CH3:23])[C:17]3=[CH:16][C:15]=2[CH2:25][NH:7][C:4]2[CH:3]=[C:2]([CH3:1])[O:6][N:5]=2)[CH2:27][CH3:28])[CH2:11][CH2:10][CH2:9]1
Reactant: CCN(CC1CCC1)c1nc2c(cc1C=O)c(C)nn2C
Reactant: Cc1cc(N)no1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCN(CC1CCC1)c1nc2c(cc1CNc1cc(C)on1)c(C)nn2C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
5-Methyl-isoxazol-3-ylamine (0.37 g, 3.8 mmol) was added to a solution of 6-(cyclobutylmethyl-ethyl-amino)-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (0.54 g, 1.9 mmol) in anhydrous chloroform (20 mL) and acetic acid (0.2 mL) under nitrogen. After stirring for 15 min at RT, sodium triacetoxyborohydride (1.20 g, 5.7 mmol) was added slowly and this mixture was stirred at RT overnight. After evaporation of chloroform in vacuo, water (30 mL) and ethyl acetate (30 mL) were added to the residue. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated to give title compound, which was taken on without further purification.
Reaction SMILES: O[C:2]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[OH:13])=O.C([O-])(=O)C.[Na+].Cl.[CH3:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([NH:35][NH2:36])=[CH:31][CH:30]=1)(=[O:28])=[O:27]>>[OH:18][C:16]1[CH:17]=[C:2]2[C:3]([C:4]([C:6]3[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=3[OH:13])=[N:36][N:35]2[C:32]2[CH:31]=[CH:30][C:29]([S:26]([CH3:25])(=[O:28])=[O:27])=[CH:34][CH:33]=2)=[CH:14][CH:15]=1
Reactant: CS(=O)(=O)c1ccc(NN)cc1
Reactant: O=C(c1ccc(O)cc1O)c1ccc(O)cc1O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: CS(=O)(=O)c1ccc(-n2nc(-c3ccc(O)cc3O)c3ccc(O)cc32)cc1
Yield: 59.6 %

Procedure:
Prepared according to Method B from 2,2′,4,4′-tetrahydroxybenzophenone (0.400 g, 1.60 mmol), sodium acetate (0.267 g, 3.3 mmol) and (4-methanesulfonyl)phenylhydrazine hydrochloride (0.454 g, 2.5 mmol) to give 0.378 g of product as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]=2[C:10](=O)[CH2:9]1.[C:24]([NH:27][NH2:28])([NH2:26])=[NH:25].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]=2[C:10](=[N:28][NH:27][C:24]([NH2:26])=[NH:25])[CH2:9]1
Reactant: O=C1CC(c2ccccc2Cl)Cc2[nH]nc(-c3ccccc3)c21
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: N=C(N)NN=C1CC(c2ccccc2Cl)Cc2[nH]nc(-c3ccccc3)c21
Yield: 124.4 %

Procedure:
A mixture of 6-(2-chlorophenyl)-3-phenyl-4,5,6,7-tetrahydroindazol-4-one (0.05 g), aminoguanidine hydrochloride (0.021 g), concentrated hydrochloric acid (0.039 ml), water (0.039 ml) and ethanol (5 ml) was refluxed for 5 hours. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethanol to give 6-(2-chlorophenyl)-4-guanidinoimino-3-phenyl-4,5,6,7-tetrahydroindazole hydrochloride (Compound 147) (0.04 g) as colorless crystals.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]#[N:20])[CH:18]=[C:13]3[C:12]([C:21]3[CH:22]=[C:23]([CH:44]=[CH:45][CH:46]=3)[CH2:24][NH:25][C:26]([C:28]3[C:29](=[O:43])[N:30]([CH2:34][C:35]4[CH:40]=[CH:39][C:38]([F:41])=[C:37]([F:42])[CH:36]=4)[CH:31]=[CH:32][CH:33]=3)=[O:27])=[CH:11]2)(=O)=O)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[C:19]([C:17]1[CH:18]=[C:13]2[C:12]([C:21]3[CH:22]=[C:23]([CH:44]=[CH:45][CH:46]=3)[CH2:24][NH:25][C:26]([C:28]3[C:29](=[O:43])[N:30]([CH2:34][C:35]4[CH:40]=[CH:39][C:38]([F:41])=[C:37]([F:42])[CH:36]=4)[CH:31]=[CH:32][CH:33]=3)=[O:27])=[CH:11][NH:10][C:14]2=[N:15][CH:16]=1)#[N:20]
Reactant: N#Cc1cnc2c(c1)c(-c1cccc(CNC(=O)c3cccn(Cc4ccc(F)c(F)c4)c3=O)c1)cn2S(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: N#Cc1cnc2[nH]cc(-c3cccc(CNC(=O)c4cccn(Cc5ccc(F)c(F)c5)c4=O)c3)c2c1

Procedure:
1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid 3-(1-benzenesulfonyl-5-cyano-1H-pyrrolo[2,3-b]pyridin-3-yl)-benzylamide (128 mg, 0.000201 mol) was dissolved in methanol (4.5 mL; Fisher) and water (1.5 mL, Fisher). To this was added potassium carbonate (129 mg, 0.000933 mol; Fisher) and the reaction was heated at reflux for 1 hour. The reaction was evaporated, taken up in N,N-dimethylformamide, neutralized with TFA (200 uL) and purified by preparative HPLC chromatography to yield the product in 26.9 mg yield (22%). 1H NMR (400 MHz, DMSO-d6) d ppm 12.582 (s (br), 1H) 10.078 (t, J=5.7 Hz, 1H) 8.804 (s, 1H) 8.648 (s, 1H) 8.405 (d, J=7.2 Hz, 1H) 8.224 (d, J=6.4 Hz, 1H) 8.098 (d, J=1.8 Hz, 1H) 7.750 (s, 1H) 7.639 (d, J=8.0 Hz, 1H) 7.470-7.334 (m, 3H) 7.236 (d, J=7.4 Hz, 1H) 7.183-7.128 (m, 1H) 6.589 (t, J=7.2 Hz, 1H) 5.212 (s, 2H) 4.596 (d, J=6.0 Hz, 2H); MS m/z=496.02 M+H.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N+:6]([O-])=[CH:5][CH:4]=1)#[N:2].P(Cl)(Cl)([Cl:12])=O>>[Cl:12][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][N:6]=1)[C:1]#[N:2]
Reactant: N#Cc1cc[n+]([O-])cc1
Reactant: O=P(Cl)(Cl)Cl
Product: N#Cc1ccnc(Cl)c1
Temperature: 110 °C

Procedure:
4-cyanopyridine-N-oxide (10.0 g) was added to phosphorus oxychloride (85 mL) and heated to 110° C. for 2.5 h. The mixture was cooled to room temperature and the excess phosphorus oxychloride removed under reduced pressure. The residue was dissolved in water and made basic with concentrated ammonia. The product was extracted into methylene chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Column chromatography on silica gel (100 mL) using methylene chloride as eluent to give 7.19 g of the title compound: 1H NMR (CDCl3) δ 7.48, 7.6, 8.6.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1[O:7][C:6]([NH2:8])=[N:5][CH:4]=1.[F:11][C:12]1[CH:13]=[CH:14][C:15]2[CH:16]([C:27](O)=[O:28])[C:17]3[C:22]([O:23][C:24]=2[CH:25]=1)=[CH:21][C:20]([F:26])=[CH:19][CH:18]=3>>[F:1][C:2]([F:10])([F:9])[C:3]1[O:7][C:6]([NH:8][C:27]([CH:16]2[C:17]3[CH:18]=[CH:19][C:20]([F:26])=[CH:21][C:22]=3[O:23][C:24]3[C:15]2=[CH:14][CH:13]=[C:12]([F:11])[CH:25]=3)=[O:28])=[N:5][CH:4]=1
Reactant: O=C(O)C1c2ccc(F)cc2Oc2cc(F)ccc21
Reactant: Nc1ncc(C(F)(F)F)o1
Product: O=C(Nc1ncc(C(F)(F)F)o1)C1c2ccc(F)cc2Oc2cc(F)ccc21

Procedure:
The title compound, white solid, m.p. 249° C. and MS: m/e=379.2 (M+H+), is prepared in accordance with the general method of example 3c from 5-trifluoromethyl-oxazol-2-ylamine and 3,6-difluoro-9H-xanthene-9-carboxylic acid.
Reaction SMILES: C(O)C.[N+:4]([C:7]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][S:22]([C:24]2[N:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[CH:26]=[CH:27][N:28]=2)=[O:23])=[CH:14][C:8]=1[CH:9]=[CH:10][C:11](O)=[O:12])([O-])=O.[H][H]>[C].[Pd].C(N(CC)CC)C>[CH3:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[N:25]1[CH:26]=[CH:27][N:28]=[C:24]1[S:22]([CH2:21][CH2:20][CH2:19][O:18][C:15]1[CH:14]=[C:8]2[C:7](=[CH:17][CH:16]=1)[NH:4][C:11](=[O:12])[CH2:10][CH2:9]2)=[O:23]
Reactant: Cc1ccccc1-n1ccnc1S(=O)CCCOc1ccc([N+](=O)[O-])c(C=CC(=O)O)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1ccccc1-n1ccnc1S(=O)CCCOc1ccc2c(c1)CCC(=O)N2
Temperature: 25 °C
Reaction time: 6 h
Yield: 26 %

Procedure:
To 50 ml of ethanol were added 300 mg of 2-nitro-5-{3-[1-(2-methylphenyl)-2-imidazolylsulfinyl]-propoxy}cinnamic acid, 100 mg of 10% palladium carbon and 0.6 ml of triethylamine. Hydrogenation was conducted at a hydrogen pressure of 4 atm. at 60° C. for 3 hours. The reaction mixture was cooled to room temperature and filtered to remove the catalyst. To the filtrate was added 200 mg of 10% palladium carbon, and hydrogenation was conducted at a hydrogen pressure of 4 atm. at 60° C. for 6 hours. Ethanol was removed by distillation. The residue was made acidic with hydrochloric acid, followed by extraction with methylene chloride. The extract was washed with an aqueous solution saturated with sodium chloride, dried with anhydrous magnesium sulfate, and subjected to distillation to remove the solvent. The residue was purified by a silica gel column chromatography (eluant: dichloromethane/methanol=50/1→20/1). The crude crystals were recrystallized from ethanol-n-hexane to obtain 70 mg of 6-{3-[1-(2-methylphenyl)-2-imidazolylsulfinyl]propoxy}-3,4-dihydrocarbostyril.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:7]#[N:8])=[N:4][NH:5][CH:6]=1.[CH2:9]([O:11][C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16](F)=[CH:15][CH:14]=1)[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH2:9]([O:11][C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([N:5]2[CH:6]=[C:2]([Br:1])[C:3]([C:7]#[N:8])=[N:4]2)=[CH:15][CH:14]=1)[CH3:10]
Reactant: N#Cc1n[nH]cc1Br
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-n2cc(Br)c(C#N)n2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 25.8 %

Procedure:
A suspension of 4-bromo-1H-pyrazole-3-carbonitrile (0.52 g), 4-fluoro-benzoic acid ethyl ester (0.56 g) and cesium carbonate (1.5 g) in N,N-dimethylformamide (10 mL) was stirred at 100° C. for 2 hours. After cooling to ambient temperature, this reaction mixture was poured into water, and this mixture was extracted with ethyl acetate. This organic layer was washed with brine, dried over anhydrous magnesium sulfate. The organic layer was through an aminopropyl silica gel, and this filtrate was concentrated under reduced pressure. This obtained residue was washed with a mixed solvent of n-hexane/diethyl ether=5/1 to give the title compound (0.25 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]([CH3:19])([CH3:18])[C:16]#N)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.[O:30]1CCCC1>CCCCCC>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]([CH3:19])([CH3:18])[CH:16]=[O:30])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: CC(C)(C#N)c1cccc(OCc2ccccc2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Product: CC(C)(C=O)c1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a 15° C. solution of 325 g. (1.25 mole) of 2-(3-benzyloxyphenyl)-2-methylpropionitrile in 1.85 liters of tetrahydrofuran is added 1.6 moles of diisobutylaluminum hydride as a 1.3 M solution in hexane (reaction temperature is maintained at 15°-18° C.). The reaction mixture is allowed to warm to room temperaure and is stirred 2 hours longer. It is then quenched by addition to a solution of 170 ml. of concentrated sulfuric acid in 670 ml. of water (temperature ≤30° C.). The resultant mixture is allowed to warm to room temperature and is then stirred an additional 2 hours. The organic layer is separated and the aqueous phase extracted once with one liter of ether. The combined organic phase is washed with 500 ml. of water and 500 ml. of saturated sodium chloride, dried over magnesium sulfate and evaporated to yield 315 g. (99%) of the title product.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[C:22]([C:26]1[CH:36]=[CH:35][C:29]([O:30][CH2:31][C@H:32]2[CH2:34][O:33]2)=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23]>>[C:22]([C:26]1[CH:36]=[CH:35][C:29]([O:30][CH2:31][C@H:32]([OH:33])[CH2:34][N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)=[CH:28][CH:27]=1)([CH3:23])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1ccc(OC[C@H]2CO2)cc1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: CC(C)(C)c1ccc(OC[C@H](O)CN2CCC3(CC2)CSC2=C(O3)c3ccccc3C(=O)C2=O)cc1

Procedure:
Compound 185 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2R)-2-[(4-tert-butylphenoxy)methyl]oxirane and conditions outlined in procedure Y. M.p.=150-152° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.89 (d, J=7.2 Hz, 1H), 7.79 (m, 2H), 7.56 (m, 1H), 7.28 (d, J=8 Hz, 2H), 6.85 (d, J=8 Hz, 2H), 4.84 (s, 1H), 3.94 (m, 2H), 3.85 (m, 1H), 3.07 (s, 2H), 2.80 (m, 2H), 2.45 (m, 4H), 1.99 (m, 2H), 1.82 (m, 2H); LCMS: 508 [M+H]; enantiomeric excess determined from chiral HPLC: 98%; Chiral HPLC Rt=35.55 min.
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[N:10]=[C:9]([Cl:11])[CH:8]=[C:7](Cl)[N:6]=1.O.[C:14](OCC)(=[O:16])C>CO>[Cl:4][C:5]1[N:10]=[C:9]([Cl:11])[CH:8]=[C:7]([O:16][CH3:14])[N:6]=1
Reactant: CCOC(C)=O
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(Cl)nc(Cl)n1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
3.24 g of sodium methoxide dissolved beforehand in 13 ml of methanol are added dropwise to a solution of 11 g of 2,4,6-trichloropyrimidine in 140 ml of methanol cooled to 0° C. in an ice bath. The ice bath is withdrawn. The reaction medium is stirred at 0° C. for 45 minutes, and then the cooling bath is removed so as to allow the temperature to rise to ambient temperature. The reaction medium is concentrated under reduced pressure. The residue obtained is taken up with 30 ml of water and 100 ml of ethyl acetate. After settling out, the organic phase is dried over magnesium sulfate, filtered, and concentrated under reduced pressure so as to give an oil which is left to crystallize for 24 hours at ambient temperature. The product crystallizes in the form of needles in the middle of an oil. The needles are separated so as to give 3.94 g of 2,4-dichloro-6-methoxypyrimidine, the characteristics of which are the following:
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=4)[N:20]=[CH:19][CH:18]=3)=[C:12]([F:31])[CH:11]=2)=[CH:4][N:3]=1.[F:32][C:33]1[CH:34]=[C:35]([CH:37]=[CH:38][CH:39]=1)[NH2:36]>O1CCOCC1.Cl>[CH3:28][O:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][C:23]=1[O:29][CH3:30])[N:20]=[CH:19][CH:18]=[C:17]2[O:16][C:13]1[CH:14]=[CH:15][C:10]([C:5]2[C:6](=[O:9])[N:7]([CH3:8])[C:2]([NH:36][C:35]3[CH:37]=[CH:38][CH:39]=[C:33]([F:32])[CH:34]=3)=[N:3][CH:4]=2)=[CH:11][C:12]=1[F:31]
Reactant: COc1cc2nccc(Oc3ccc(-c4cnc(Cl)n(C)c4=O)cc3F)c2cc1OC
Reactant: Nc1cccc(F)c1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc2nccc(Oc3ccc(-c4cnc(Nc5cccc(F)c5)n(C)c4=O)cc3F)c2cc1OC
Temperature: 60 °C

Procedure:
The crude 2-chloro-5-(4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl)-3-methylpyrimidin-4(3H)-one from Step 3 was dissolved in 15 mL 1,4-dioxane. To 5 mL of this solution was added m-fluoroaniline (0.2 mL) and concentrated HCl (1 drop). The reaction was heated in the microwave at 60° C. and 60 W for 5 min before being cooled to RT. The mixture was concentrated and filtered through a 1 inch plug of silica gel with EtOAc→2:1 EtOAc/MeOH→3:2 MeOH/EtOAc. The filtrate was concentrated and purified using reverse phase HPLC (10%→95% MeCN/H2O with 0.1% TFA). Finally, the compound was filtered again through a 1-inch plug of silica gel in a pipette column with EtOAc to give the title compound. MS (ESI pos. ion) m/z: 517. Calc'd for C28H22F2N4O4: 516.16.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11](OS(C(F)(F)F)(=O)=O)[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[C:21]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])(=[O:24])[CH:22]=[CH2:23].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])[CH:23]=[CH:22][C:21]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)cc1OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C=CC(=O)OC(C)(C)C)cc1OC
Temperature: 75 °C
Reaction time: 16 h

Procedure:
To a solution of methyl 2-methoxy-4-trifluoromethanesulfonyloxybenzoate (26.8 g), t-butyl acrylate (62.5 ml), triethylamine (25 ml) in anhydrous dimethylformamide (100 ml) are added palladium acetate (0.4 g) and 1,3-bis(diphenylphosphino)propane (0.74 g) under argon atmosphere, and the mixture is heated with stirring at 75° C. for 16 hours. The reaction solution is concentrated under reduced pressure to remove the solvent, and thereto is added water. The mixture is extracted with ethyl acetate, and the extract is washed with water, dried, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; ethyl acetate:n-hexane=1:5) to give t-butyl 3-methoxy-4-methoxycarbonylcinnamate (23.5 g).