Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([OH:19])=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:23])[C:6]=2[CH:24]=1.[CH:25](O)([CH3:27])[CH3:26]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([O:19][CH:25]([CH3:27])[CH3:26])=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:23])[C:6]=2[CH:24]=1
Reactant: CC(C)O
Reactant: Cc1c(S(=O)(=O)Nc2cccc(C(=O)O)c2)sc2ccc(Cl)cc12
Product: Cc1c(S(=O)(=O)Nc2cccc(C(=O)OC(C)C)c2)sc2ccc(Cl)cc12
Yield: 57 %

Procedure:
The product was prepared from 3-{[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]amino}benzoic acid (21 mg, 0.055 mmol) (Intermediate 19) and isopropyl alcohol (6.0 mg, 0.100 mmol) according to the General Procedure 7, described in Example 107, using a slightly modified reaction time (2 days). The title compound was obtained in 57% yield (13.3 mg). 1H NMR (500 MHz, CDCl3) δ ppm 1.30 (d, J=6.32 Hz, 6 H) 2.45 (s, 3 H) 5.18 (spt, J=6.32 Hz, 1 H) 6.89 (s, 1 H) 7.35 (dd, J=8.06, 7.65 Hz, 1 H) 7.41 (ddd, J=8.06, 2.35, 1.18 Hz, 1 H) 7.44 (dd, J=8.73, 1.94 Hz, 1 H) 7.68 (dd, J=2.35, 1.50 Hz, 1 H) 7.71 (dd, J=8.73, 0.61 Hz, 1 H) 7.71 (dd, J=1.94, 0.61 Hz, 1 H) 7.83 (ddd, J=7.65, 1.50, 1.18 Hz, 1 H). MS (ESI+) m/z 424 [M+H]+.
Reaction SMILES: [N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([NH:23][C:24]([NH2:26])=[NH:25])[CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1.CN(C)[CH:29]=[C:30]([CH3:41])[C:31](=O)[CH:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:33].C(N(CC)CC)C>CN1CCCC1=O>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([NH:23][C:24]2[N:26]=[C:31]([CH:32]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH3:33])[C:30]([CH3:41])=[CH:29][N:25]=2)[CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: CC(=CN(C)C)C(=O)C(C)c1ccccc1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Solvent: O=[N+]([O-])O
Product: COc1cc(Nc2ncc(C)c(C(C)c3ccccc3)n2)ccc1-n1cnc(C)c1
Reaction time: 0.5 h

Procedure:
The title compound was prepared in analogous manner described in example 4c) from N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate, 1-dimethylamino-2-methyl-4-phenyl-pent-1-en-3-one and triethylamine using 1-methyl-2-pyrrolidinone as the solvent. The reaction was performed in a microwave at 200° C. for 30 min. The title compound was isolated as a pale-yellow solid in 39% yield.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:9]2[C:14](=[O:15])[NH:13][CH:12]=[N:11][C:10]=2[NH:16][C:17]=1[CH3:18])=[O:6])([CH3:3])[CH3:2].[CH3:28][O+](C)C.F[B-](F)(F)F>ClCCCl>[CH:1]([O:4][C:5]([C:7]1[CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:9]2[C:14]([O:15][CH3:28])=[N:13][CH:12]=[N:11][C:10]=2[NH:16][C:17]=1[CH3:18])=[O:6])([CH3:3])[CH3:2]
Reactant: CC1=C(C(=O)OC(C)C)C(c2cccc([N+](=O)[O-])c2)c2c(nc[nH]c2=O)N1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCCl
Product: COc1ncnc2c1C(c1cccc([N+](=O)[O-])c1)C(C(=O)OC(C)C)=C(C)N2
Reaction time: 3 h

Procedure:
Three and 0.7 g (10 mmol) (±)-3,4,5,8-tetrahydro-7-methyl-5-(3-nitrophenyl)-4-oxo-pyrido[2,3-d]-pyrimidine-6-carboxylic acid isopropyl ester and 3.0 g (20 mmol) trimethyloxonium-tetrafluoroborate are stirred in 150 ml 1,2-dichloroethane in nitrogen atmosphere and at room temperature for three hours. The product is extracted twice with 50 ml saturated sodium hydrogen carbonate solution, the organic phase is separated, dried over sodium sulfate and reduced under vacuum. Twice recrystallizing the residue from diisopropyl ether/isopropanol yields the product in the form of colorless crystals with a mp of 212°-213° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[I:7][C:8]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O.C(N(CC)CC)C.[CH2:27]([NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:28]>ClCCl.CN(C1C=CN=CC=1)C.O.CN(C)C=O>[CH2:27]([N:29]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:10](=[O:12])[C:9]1[CH:13]=[CH:14][C:15]([N+:17]([O-:19])=[O:18])=[CH:16][C:8]=1[I:7])[CH3:28]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1I
Reactant: CCNc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(C(=O)c1ccc([N+](=O)[O-])cc1I)c1ccccc1
Temperature: 23 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
Oxalyl chloride (12 ml, 17.3 g, 0.14 mol) was added dropwise to a solution of 2-iodo-4-nitrobenzoic acid I-1 b (20 g, 68.3 mmol) in dichloromethane (137 ml). N,N-Dimethylformamide (0.1 ml) was added to the reaction mixture via syringe, the reaction mixture was stirred at 23° C. for 1 hour, and another portion of N,N-dimethylformamide (0.1 ml) was added. After stirring the reaction mixture another 2 hours, the reaction mixture was concentrated in vacuo. The residue was taken up in dichloromethane (137 ml), and DMAP (50 mg) and triethylamine (14.3 ml, 10.3 g, 0.102 mol) were added. The mixture was cooled to 0° C. and N-ethylaniline (10.1 ml, 9.9 g, 82 mmol) was added over a 10 min period. The reaction mixture was warmed to 23° C. After 16 hours at this temperature, water (150 ml) was added, and the layers were separated. The organics were washed with 1 N HCl (2 100-ml portions), dried over anhydrous sodium sulfate, and were concentrated. Purification of the residue by flash column chromatography (dichloromethane) afforded N-ethyl-2-iodo-4-nitro-N-phenyl-benzamide I-1c (24.3 g, 93%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[F:12].[F:13][C:14]([F:35])([F:34])[C:15]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:23][CH:22]=1)([OH:20])[C:16]([F:19])([F:18])[F:17].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.C(=O)([O-])O.[Na+]>ClCCl>[NH2:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([C:6]([N:31]2[CH2:32][CH2:33][N:28]([CH2:27][C:24]3[CH:25]=[CH:26][C:21]([C:15]([OH:20])([C:16]([F:17])([F:18])[F:19])[C:14]([F:35])([F:13])[F:34])=[CH:22][CH:23]=3)[CH2:29][CH2:30]2)=[O:8])=[CH:9][C:10]=1[F:11]
Reactant: OC(c1ccc(CN2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Reactant: Nc1c(F)cc(C(=O)O)cc1F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Nc1c(F)cc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Reaction time: 2 h
Yield: 36 %

Procedure:
4-Amino-3,5-difluorobenzoic acid (1.899 mmol, 329 mg), 1,1,1,3,3,3-hexafluoro-2-(4-(piperazin-1-ylmethyl)phenyl)propan-2-ol (1.899 mmol, 650 mg) and triethylamine (5.70 mmol, 0.792 mL, 576 mg) were combined and stirred at room temperature in dichloromethane (5 mL). 1-Propanephosphonic acid cyclic anhydride (2.85 mmol, 1.696 mL, 1813 mg; 50% solution in ethyl acetate) was added and the reaction stirred for 2 hours. Saturated sodium hydrogen carbonate solution was added to the reaction mixture and the layers separated. The organic layer was dried over magnesium sulfate and concentrated under vacuum to afford the title compound (340 mg) as a pale pink solid. MS (ESI) m/z 498.7 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.Cl.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([F:28])=[C:17]([C@@:19]2([CH3:27])[NH:25][C:24](=[O:26])[CH2:23][CH2:22][O:21][CH2:20]2)[CH:18]=1>>[F:28][C:16]1[CH:15]=[CH:14][C:13]([NH:12][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[O:10])=[CH:18][C:17]=1[C@@:19]1([CH3:27])[NH:25][C:24](=[O:26])[CH2:23][CH2:22][O:21][CH2:20]1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: C[C@@]1(c2cc(N)ccc2F)COCCC(=O)N1
Agent: Cl
Product: C[C@@]1(c2cc(NC(=O)c3ccc(Cl)cn3)ccc2F)COCCC(=O)N1

Procedure:
Starting from 5-chloro-pyridine-2-carboxylic acid and (R)-3-(5-amino-2-fluoro-phenyl)-3-methyl-[1,4]oxazepan-5-one hydrochloride, the 5-chloro-pyridine-2-carboxylic acid [4-fluoro-3-((R)-3-methyl-5-oxo-[1,4]oxazepan-3-yl)-phenyl]-amide was obtained as a white solid. MS (ISP): m/z=378.3 [M+H]+.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([Cl:29])=[N:23][C:24]=2Cl)(=[O:3])[CH3:2].[CH2:30]([C:34]1[NH:35][CH:36]=[CH:37][N:38]=1)[CH2:31][CH2:32][CH3:33]>CC#N>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([Cl:29])=[N:23][C:24]=2[N:35]1[CH:36]=[CH:37][N:38]=[C:34]1[CH2:30][CH2:31][CH2:32][CH3:33])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCCCc1ncc[nH]1
Solvent: CC#N
Product: CCCCc1nccn1-c1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Yield: 115.3 %

Procedure:
A solution of 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2,6-dichloropurine (2.41 g, 5.4 mmol) and 2-butylimidazole (6.68 g, 54 mmol) in CH3CN (60 mL) was stirred at 65° C. under N2 for 32 h (reaction complete, TLC). Volatiles were evaporated in vacuo, and the residue was chromatographed (MeOH/CH2Cl2, 1:90) to give crude 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-6-(2-butylimidazol-1-yl)-2-chloropurine (3.33 g, contaminated with 2-butylimidazole): 1H NMR (500 MHz, CDCl3) δ 8.56 (s, 1H), 8.24 (s, 1H), 7.10 (s, 1H), 6.26 (d, J=5.8 Hz, 1H), 5.83 (t, J=5.6 Hz, 1H), 5.61 (t, J=5.6 Hz, 1H), 4.43-4.51 (m, 3H), 3.31 (t, J=7.9 Hz, 2H), 2.18 (s, 3H), 2.16 (s, 3H), 2.11 (s, 3H), 1.81 (quint, J=7.7 Hz, 2H), 1.50 (sext, J=7.7 Hz, 2H), 0.98 (t, J=7.3 Hz, 3H); HRMS m/z 535.1702 (MH+[C23H28ClN6O7]=535.1708).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH3:10])[CH:6]=[C:5]([CH2:11][CH3:12])[C:4]=1[C:13]1[C:14](=[O:27])[N:15]([CH3:26])[N:16]=[C:17]([C:22]([F:25])([F:24])[F:23])[C:18]=1S(C)=O)[CH3:2].CN1CCCC1=[O:34].[OH-].[Na+].Cl>O>[CH2:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH3:10])[CH:6]=[C:5]([CH2:11][CH3:12])[C:4]=1[C:13]1[C:14](=[O:27])[N:15]([CH3:26])[N:16]=[C:17]([C:22]([F:25])([F:24])[F:23])[C:18]=1[OH:34])[CH3:2]
Reactant: CN1CCCC1=O
Reactant: CCc1cc(CC)c(-c2c(S(C)=O)c(C(F)(F)F)nn(C)c2=O)c(CC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1cc(CC)c(-c2c(O)c(C(F)(F)F)nn(C)c2=O)c(CC)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 54.1 %

Procedure:
To a 50 ml volume three-necked flask, 4-(2,4,6-triethylphenyl)-2-methyl-5-methylsulfinyl-6-trifluoromethyl-2,3-dihydro-3-pyridazinone ((2-49)-(1)-40) (0.692 g), N-methylpyrrolidone (6.40 g), water (3.11 g), and sodium hydroxide (0.626 g) were added at room temperature. The resulting mixture was stirred at 50° C. for 4 hours. The reaction mixture was cooled to room temperature, added 12N hydrochloric acid (3 ml) and water (15 ml), and extracted with ethyl acetate (30 ml) 3 times. The combined organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and subjected to silica gel column chromatography (hexane: ethyl acetate=8:1 to hexane: ethyl acetate=5:1 to hexane: ethyl acetate=3:1). Then, the resulting fraction was concentrated under reduced pressure, recrystallized from hexane to give 0.331 g of 4-(2,4,6-triethylphenyl)-5-hydroxy-2-methyl-6-trifluoromethyl-2,3-dihydro-3-pyridazinone ((1-16)-(1)-40) on the filter paper.
Reaction SMILES: [F:1][C:2]1[C:16](I)=[CH:15][C:5]([O:6][C:7]2[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=2)=[C:4]([CH:18]([CH3:20])[CH3:19])[CH:3]=1.[C:21]([C:23]1C(F)=CC(C(C)C)=C(C=1)OC1C(N)=NC(N)=NC=1)#[CH:22]>>[F:1][C:2]1[C:16]([C:22]#[C:21][CH3:23])=[CH:15][C:5]([O:6][C:7]2[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=2)=[C:4]([CH:18]([CH3:20])[CH3:19])[CH:3]=1
Reactant: CC(C)c1cc(F)c(I)cc1Oc1cnc(N)nc1N
Reactant: C#Cc1cc(Oc2cnc(N)nc2N)c(C(C)C)cc1F
Product: CC#Cc1cc(Oc2cnc(N)nc2N)c(C(C)C)cc1F

Procedure:
Similarly prepared from 5-(4-fluoro-5-iodo-2-isopropyl-phenoxy)-pyrimidine -2,4-diamine using the procedure of step 8 of example 1 was 5-(5-Ethynyl-4-fluoro-2-isopropyl-phenoxy)-pyrimidine -2,4-diamine, MS (M+H)=289.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[N:19][S:16]([C:13]2[CH:12]=[CH:11][C:10]([Cl:9])=[CH:15][CH:14]=2)(=[O:18])=[O:17])[CH:2]=1
Reactant: O=Cc1cccnc1
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=S(=O)(N=Cc1cccnc1)c1ccc(Cl)cc1
Yield: 65 %

Procedure:
In a similar manner to Example 2, 18.5 mmol of 3-pyridinecarboxaldehyde, 18.5 mmol of 4-chlorobenzenesulfonamide and 20 mg of TsOH in 100 mL of toluene reacted under reflux conditions to afford SULF-12 in 65% yield and high purity: 1H NMR (DSMO-d6, TMS ext std) δ 9.3 (s,1), 9.2 (d, 1), 8.9 (m, 1), 8.4 (m, 1), 8.0-7.8 (AB. 4).
Reaction SMILES: [Cl-].[F:2][C:3]1[CH:8]=[CH:7][C:6]([S+:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.O.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29]([OH:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1>>[C:23]1([CH3:33])[CH:24]=[CH:25][C:26]([S:29]([O-:32])(=[O:30])=[O:31])=[CH:27][CH:28]=1.[F:2][C:3]1[CH:8]=[CH:7][C:6]([S+:9]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: Fc1ccc([S+](c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: O
Product: Cc1ccc(S(=O)(=O)[O-])cc1

Procedure:
The 4-fluorophenyldiphenylsulfonium chloride aqueous solution in Synthesis Example 1 was combined with 4-toluenesulfonic acid monohydrate, followed by extraction with dichloromethane. The organic layer was washed with water, after which the solvent was distilled off in vacuum. Isopropyl ether was added to the residue for crystallization. Filtration and drying yielded the target compound.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[OH:9].C(=O)([O-])[O-].[K+].[K+].[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([Cl:24])=[CH:19][N:18]=1>O1CCCC1>[Cl:16][C:17]1[N:22]=[C:21]([NH:2][C@@H:3]2[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]2[OH:9])[C:20]([Cl:24])=[CH:19][N:18]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: N[C@@H]1CCCC[C@H]1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reaction time: 3 h
Yield: 49.8 %

Procedure:
Tetrahydrofuran (100 mL) was added to racemic trans-2-amino-cyclohexanol hydrochloride (4.28 g, 28.2 mmol) and potassium carbonate (12.1 g, 88 mmol). The mixture was cooled at 0° C. before 2,4,5-trichloropyrimidine (2 mL, 17.4 mmol) was added. After 3 hours, the mixture was partitioned between water and ethyl acetate, the aq. layer was extracted and the combined extracts were dried and conc. in vacuo. The crude product was taken up in ethyl acetate and washed with 10% w/v citric acid, then with sodium bicarbonate, dried over sodium sulfate and conc. in vacuo to give rel-(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexanol (2.27 g, 50%) as a white solid. m.p.=139-142° C.; LCMS (m/e) 262 (M+1); 1H-NMR (DMSO-d6, 400 MHz) δ 8.12 (s, 1H), 7.45 (m, 1H), 68 (m, 1H), 3.81 (m, 1H), 3.55 (m, 1H), 1.92 (m, 1H), 1.81 (m, 1H), 1.67 (m, 2H), 1.41 (m, 1H), 1.26 (m, 3H).
Reaction SMILES: [CH3:1][S:2][C:3](=O)[NH:4][CH:5]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:14]=1)[C:6]1[C:11]([Cl:12])=[N:10][CH:9]=[CH:8][N:7]=1.CN(C=O)C.O=P(Cl)(Cl)Cl>CC#N>[CH2:20]([O:19][C:15]1[CH:14]=[C:13]([C:5]2[N:4]=[C:3]([S:2][CH3:1])[N:7]3[CH:8]=[CH:9][N:10]=[C:11]([Cl:12])[C:6]=23)[CH:18]=[CH:17][CH:16]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CSC(=O)NC(c1cccc(OCc2ccccc2)c1)c1nccnc1Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CN(C)C=O
Product: CSc1nc(-c2cccc(OCc3ccccc3)c2)c2c(Cl)nccn12
Temperature: 55 °C
Reaction time: 8 h

Procedure:
To a solution of [(3-benzyloxy-phenyl)-(3-chloro-pyrazin-2-yl)-methyl]-thiocarbamic acid S-methyl ester (200 mg, 0.0005 mol) in MeCN (10 mL) and DMF (0.12 mL, 0.0015 mol) was added POCl3 (0.14 mL, 0.0015 mol); the resulting mixture was stirred at 55° C. overnight. The mixture was quenched with 2N NH3/iPrOH, then diluted with EtOAc, washed with brine and dried over anhydrous sodium sulfate. The residue was purified by silica gel chromatography (Hex.: EtOAc=80:20→70:30) to give a yellow solid. 1H-NMR (CDCl3) confirmed a mixture of the desired product and starting material in ca. 1:1 ratio, which was taken on to next step.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[C:15]([F:23])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[F:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([C:35](O)=[O:36])=[CH:27][CH:26]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:35]([C:28]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:25]([F:24])=[CH:26][CH:27]=2)=[O:36])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[C:15]([F:23])[CH:14]=2)=[CH:6][CH:7]=1
Reactant: NC(Cc1ccc(C(F)(F)F)c(F)c1)C(O)c1ccc(F)cc1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1ccc(C(F)(F)F)c(F)c1)C(O)c1ccc(F)cc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(3-fluoro-4-(trifluoromethyl)phenyl)-1-propanol (400 mg, 1.21 mmol) in acetonitrile (30 ml) were added 4-fluoronaphthalenecarboxylic acid (230 mg, 1.21 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (347 mg, 1.81 mmol) and 1-hydroxy-1H-benzotriazole (185 mg, 1.21 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (525 mg, 86%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][C:19]=1[Cl:20])[N:16]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[N:15]=[C:14]2[NH:29][C:30](=[O:34])[CH2:31][CH2:32][CH3:33].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C(OCC)(=O)C>[Cl:20][C:19]1[CH:18]=[C:17]2[C:13]([C:14]([NH:29][C:30](=[O:34])[CH2:31][CH2:32][CH3:33])=[N:15][N:16]2[CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:26])[CH3:27])=[CH:12][C:11]=1[C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: OB(O)c1ccncc1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)c(Br)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)c(-c3ccncc3)cc12
Yield: 77.3 %

Procedure:
415 mg of 4-pyridylboronic acid are added to 1 g of N-[[5-bromo-6-chloro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]]butanamide, described previously, in Example 58, in 90 cm3 of dioxane, followed by addition of a solution of 570 mg of sodium carbonate in 18 cm3 of water and finally 173 mg of tetrakis-(triphenylphosphine)palladium, and the mixture is refluxed for 18 hours. The reaction medium is diluted with 75 cm3 of ethyl acetate and 50 cm3 of water. The organic phase is separated out after settling of the phases has taken place, washed with 50 cm3 of water and 50 cm3 of saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 50° C.). The crude product obtained is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with a cyclohexane/ethyl acetate mixture (60/40 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.); 770 mg of N-[6-chloro-5-(4-pyridyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide are obtained in the form of white crystals.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]1=[O:11].[Br:12]Br>C(O)(=O)C>[Br:12][C:8]1[CH:9]=[C:10]2[C:5]([N:4]=[CH:3][C:2](=[O:11])[NH:1]2)=[CH:6][CH:7]=1
Reactant: O=c1cnc2ccccc2[nH]1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=c1cnc2ccc(Br)cc2[nH]1
Reaction time: 1 h

Procedure:
Heat benzene-1,2-diamine (7.5 g, 69 mmol) and oxo-acetic acid ethyl ester (20 mL) in ethanol (100 mL) at 120° C. for 18 h. Cool, filter the resulting precipitate, and wash with dry ether to give 1H-quinoxalin-2-one (6.7 g). Dissolve 1H-quinoxalin-2-one in acetic acid (300 mL), add bromine (5 mL), and stir the reaction mixture for 1 h. Filter the resulting crystals and wash with ether to afford 7-bromo-1H-quinoxalin-2-one (7.2 g). Reflux 7-bromo-1H-quinoxalin-2-one in POCl3 (30 mL) for 18 h. Remove POCl3 in vacuo, dissolve the product in 3:1 chloroform/isopropyl alcohol, and wash the organic phase with saturated sodium bicarbonate. Dry over sodium sulfate and purify by silica gel flash chromatography eluting with dichloromethane to 10% methanol/90% dichloromethane to afford the title compound as a yellow solid (4.5 g, 58%). MS (electrospray, m/z) 243.0 and 245.0 (M+1).
Reaction SMILES: Cl.[CH2:2]([N:9]([CH2:11][C:12]([OH:14])=O)[CH3:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(Cl)CCl.Cl.[CH3:20][NH:21][O:22][CH3:23].CN1CCOCC1>CN(C=O)C>[CH2:2]([N:9]([CH3:10])[CH2:11][C:12]([N:21]([O:22][CH3:23])[CH3:20])=[O:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN(CC(=O)O)Cc1ccccc1
Reactant: CNOC
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)CN(C)Cc1ccccc1
Reaction time: 16 h
Yield: 101.2 %

Procedure:
(Benzyl-methyl-amino)-acetic acid hydrochloride salt (12 g, 56 mmol, 1.0 equiv) was mixed in DMF (200 mL) along with EDC (10.6 g, 56 mmol, 1.0 equiv) for 15 min. N,O-Dimethylhydroxylamine hydrochloride (6.52 g, 67 mmol, 1.2 equiv) was added to the reaction followed by N-methylmorpholine (34 mL, 334 mmol, 6.0 equiv). The reaction was stirred for 16 h. The DMF was removed in vacuo and the residue was redissolved in 200 mL of EtOAc. The solution was washed once with 200 mL brine. The organic layer was dried over Na2SO4, decanted and concentrated to yield the desired product as a free-flowing oil (12.6 g, 80%) that was used in the next step without further purification; MS, m/z 223=M+1.
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:21])=[CH:10][CH2:11][CH2:12][C:13]([CH3:20])=[CH:14][CH2:15][CH2:16][C:17](=[O:19])[CH3:18])[C:3]([OH:5])=O.[CH:22]([NH:25][CH:26]([CH3:28])[CH3:27])([CH3:24])[CH3:23]>>[CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:21])=[CH:10][CH2:11][CH2:12][C:13]([CH3:20])=[CH:14][CH2:15][CH2:16][C:17](=[O:19])[CH3:18])[C:3]([N:25]([CH:26]([CH3:28])[CH3:27])[CH:22]([CH3:24])[CH3:23])=[O:5]
Reactant: CC(C)NC(C)C
Reactant: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Product: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)N(C(C)C)C(C)C

Procedure:
Starting materials: 2,6,10-trimethyl-14-oxo-2,6,10-pentadecatrienoic acid and diisopropylamine.