Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([C:18]([F:21])([F:20])[F:19])=[O:17])=[CH:12][CH:11]=1)=[O:8].[F:29][C:30]1[CH:31]=[N:32][CH:33]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:35]=1>>[F:29][C:30]1[CH:35]=[C:34]([C:2]2[C:3]([N:23]3[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([S:16]([C:18]([F:21])([F:19])[F:20])=[O:17])=[CH:14][CH:15]=3)=[O:8])[CH:22]=2)[CH:33]=[N:32][CH:31]=1
Reactant: CC1(C)OB(c2cncc(F)c2)OC1(C)C
Reactant: O=C(Nc1ccc(S(=O)C(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Product: O=C(Nc1ccc(S(=O)C(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cncc(F)c2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 185 using 5-bromo-6-((R)-3-hydroxypyrrolidin-1-yl)-N-(4-((trifluoromethyl)sulfinyl)phenyl)nicotinamide (Stage 222.1) and 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine to afford an off-white foam. HPLC (Condition 4) tR=4.46 min, UPLC-MS (Condition 3) tR=0.87 min, m/z=495.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.65-1.78 (m, 1H) 1.79-1.88 (m, 1H) 2.88 (d, J=1.00 Hz, 1H) 3.22 (m, J=4.70 Hz, 2H) 3.34-3.44 (m, 1H) 4.14-4.23 (m, 1H) 4.86 (d, J=3.52 Hz, 1H) 7.86 (d, J=8.99 Hz, 3H) 8.01-8.14 (m, 3H) 8.50 (s, 1H) 8.59 (d, J=2.74 Hz, 1H) 8.79 (d, J=2.35 Hz, 1H) 10.40 (s, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:9]([CH2:10]O)=[C:8]([CH3:12])[N:7]=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)[N:5]=1.S(Cl)([Cl:26])=O>>[Cl:26][CH2:10][C:9]1[C:4]([CH2:3][O:2][CH3:1])=[N:5][C:6]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)=[N:7][C:8]=1[CH3:12]
Reactant: COCc1nc(-c2ccc(OC(F)(F)F)cc2)nc(C)c1CO
Reactant: O=S(Cl)Cl
Product: COCc1nc(-c2ccc(OC(F)(F)F)cc2)nc(C)c1CCl

Procedure:
In analogy to the procedure described in example 113H], [4-methoxymethyl-6-methyl-2-(4-trifluoromethoxy-phenyl)-pyrimidin-5-yl]-methanol and thionylchloride gave the title compound as a brown oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[C:24]([Cl:25])=[CH:23][C:12]2[C:13](=O)[CH2:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[S:17][C:11]=2[CH:10]=1.O>C1C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[Cl:8][C:9]1[C:24]([Cl:25])=[CH:23][C:12]2[C:13]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[CH:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[S:17][C:11]=2[CH:10]=1
Reactant: CN1CCNCC1
Reactant: O=C1Cc2ccccc2Sc2cc(Cl)c(Cl)cc21
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: c1ccccc1
Solvent: O
Product: CN1CCN(C2=Cc3ccccc3Sc3cc(Cl)c(Cl)cc32)CC1
Reaction time: 28 h

Procedure:
1-Methylpiperazine (15.0 g), followed by titanium tetrachloride (3.1 g) in benzene (45 ml), was added to a warm solution of 7,8-dichlorodibenzo(b,f)thiepine-10(11H)-one (8.85 g) (its preparation is described in Example 8) in benzene (75 ml). The mixture was refluxed while stirring for 28 hours, cooled and decomposed with water (100 ml). The resultant precipitate was filtered and washed with benzene and water. The benzene layer in the filtrate was separated, washed with water, dried over magnesium sulfate and taken down. The enamine base, obtained in nearly quantitative yield, was purified by crystallization from ethanol, m.p. 157°-159° C. Neutralization with maleic acid in ethanol yields the maleate, C23H22Cl2N2O4S, which is crystallized from ethanol; m.p. 229°-232° C.
Reaction SMILES: CS(C)=O.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1.[OH-].[K+].Cl[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-:25])=[O:24]>O>[N+:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[O:13][C:9]1[CH:8]=[C:7]([O:6][CH3:5])[CH:12]=[CH:11][CH:10]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: COc1cccc(O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COc1cccc(Oc2ccccc2[N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 97.1 %

Procedure:
To 150 ml of dimethyl sulfoxide were added 19.9 g of 3-methoxyphenol and 9.1 g of potassium hydroxide and the mixture was heated to 70°-80° C. to prepare a homogeneous solution. To this solution was added 21.1 g of 2-chloronitrobenzene and the mixture was stirred at 100° C. for 4 hours. The reaction mixture was then diluted with water and extracted with ether and the ether extract was washed succesively with 10% sodium hydroxide solution and saturated sodium chloride solution. The washed extract was dried over magnesium sulfate and the ether was distilled off to give 31.9 g of the title compound as a light yellow solid.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16](O)=[O:17])(=[O:12])=[O:11])=[CH:5][CH:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:48]12[CH2:57][CH2:56][CH2:55][CH2:54][CH:53]1[CH2:52][NH:51][CH2:50][CH2:49]2>CN(C)C(=O)C.CC1CCCO1>[CH2:52]1[N:51]([C:16]([C:15]2[CH:14]=[C:13]([S:10]([NH:9][C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:22])([F:23])[F:1])=[CH:4][CH:5]=3)(=[O:11])=[O:12])[CH:21]=[CH:20][CH:19]=2)=[O:17])[CH2:50][CH2:49][N:48]2[CH2:57][CH2:56][CH2:55][CH2:54][CH:53]12
Reactant: C1CCN2CCNCC2C1
Reactant: O=C(O)c1cccc(S(=O)(=O)Nc2ccc(C(F)(F)F)cc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC1CCCO1
Solvent: CC(=O)N(C)C
Product: O=C(c1cccc(S(=O)(=O)Nc2ccc(C(F)(F)F)cc2)c1)N1CCN2CCCCC2C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To 3-({[4-(trifluoromethyl)phenyl]amino}sulfonyl)benzoic acid (4.35 g, 12.6 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (5.27 g, 13.9 mmol) in N,N-dimethylacetamide (30 mL) and 2-methyltetrahydrofuran (90 mL) was added 1,4-diazabicyclo[4.4.0]decane (2.47 g, 17.6 mmol). The reaction was stirred at ambient temperature for 2.5 hours, and then it was diluted with 2-methyltetrahydrofuran (57 mL). The organic solution was washed with 6% NaHCO3/6% NaCl (35 mL), and the aqueous layer was extracted with 2-methyltetrahydrofuran (50 mL). The organic layer was washed with 6% NaHCO3/6% NaCl (50 mL) and 1:1 saturated NaCl/water (6×50 mL), and then it was concentrated. The residue was concentrated from ethanol (2×50 mL) to give the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[C:6]2[CH2:15][CH2:16]O)#[N:2].[Br:18]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.ClCCl>C(OCC)C>[Br:18][CH2:16][CH2:15][C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:1]#[N:2])[CH:4]=2)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=1
Reactant: Cn1c(=O)cc(CCO)c2cc(C#N)ccc21
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: ClCCl
Product: Cn1c(=O)cc(CCBr)c2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
0.24 g (1.05 mmol) of 6- cyano-4-(2-hydroxyethyl)-1-methyl-2(1H)-quinolone is added in small amounts to 0.48 g (1.14 mmol) of dibromotriphenylphosphorane in 14 ml of dichdoromethane at room temperature. After 75 minutes of stirring at room temperature, the reaction medium is poured into 200 ml of dichloromethane and the mixture is washed with water. The organic phase is dried over sodium sulphate, filtered and condensed under vacuum. The white residue is ground in diethylether. The solid obtained is taken up in a minimum of dichloromethane, the mixture is filtered rapidly through a layer of silica, eluting with ether, and the filtrate is evaporated.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C@@H:4]([C:18]([O-:20])=O)[CH2:3]1.[Li+].Cl.[NH2:23][C:24]1([C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)C[CH2:25]1>>[OH:1][C@H:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=2)[C@@H:4]([C:18]([NH:23][C@H:24]([C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)[CH3:25])=[O:20])[CH2:3]1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Reactant: O=C([O-])[C@H]1C[C@@H](O)CN1Cc1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [Li+]
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2C[C@@H](O)CN2Cc2cccc(C(F)(F)F)c2)cc1
Yield: 42.3 %

Procedure:
The title compound (D35) (10.3 mg) was prepared according to the general procedure for amides preparation starting from lithium (2R,4R)-4-hydroxy-1-(3-(trifluoromethyl)benzyl)pyrrolidine-2-carboxylate (D15) (11.7 mg, 0.054 mmol) and methyl 4-(1-aminocyclopropyl)benzoate hydrochloride (27.2 mg, 0.054 mmol).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([O:16][CH3:17])=[CH:11][C:10]=2[CH:18]([CH3:20])[CH3:19])=[CH:6][N:5]=[C:4]([NH2:21])[N:3]=1.C(Cl)Cl.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH:18]([C:10]1[CH:11]=[C:12]([O:16][CH3:17])[C:13]([CH3:15])=[CH:14][C:9]=1[O:8][C:7]1[C:2]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:3][C:4]([NH2:21])=[N:5][CH:6]=1)([CH3:20])[CH3:19]
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2Cl)cc1C
Reactant: Nc1ccccc1
Solvent: ClCCl
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2Nc2ccccc2)cc1C
Temperature: 100 °C

Procedure:
A suspension of 4-chloro-5-(2-isopropyl-4-methoxy-5-methyl-phenoxy)-pyrimidin-2-ylamine (0.043 g, 0.14 mmol) in aniline (4 ml) was placed in a sealed tube and heated at 100 ° C. over night. Methylene chloride was added and insoluble solid was removed by filtration through celite. The combined methylene chloride filtrate was washed with water and dried over anhydrous sodium sulfate. After removal of the drying agent, the organic phase was concentrated under reduced pressure. The residue was purified with silica gel chromatography (2% methanol in methylene chloride) to yield a yellow oily residue, which was further purified with preparative TLC and HPLC (5 to 100% acetonitrile in water with 0.1% trifluoroacetic acid to yield 5-(2-Isopropyl-4-methoxy-5-methyl-phenoxy)-N4-phenyl-pyrimidine-2,4-diamine, M+H: 365.
Reaction SMILES: [O:1]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH2:13][OH:14].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>N1C=CC=CC=1>[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21]([O:14][CH2:13][CH:2]2[CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:1]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: OCC1COCCOCCOCCO1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2COCCOCCOCCO2)cc1
Yield: 91.6 %

Procedure:
Reaction in pyridine (13 ml) of 1,4,7,10-tetraoxacyclo-dodecane-2-methanol (5 g) with p-toluenesulphonyl chloride (5 g) produces 1,4,7,10-tetraoxacyclododecane-2-methanol p-toluenesulphonate (8 g; m.p. 49°-51° C. from diethyl ether). Subsequent reaction with diethyl malonate (3.36 ml) and potassium tert-butoxide (3.47 g) in N-methyl pyrrolidone (30 ml) yields [(1,4,7,10-tetraoxacyclododecane-2-yl)methyl]-malonate diethyl ester as a viscous oil that is treated with aqueous lithium hydroxide 0.8 g) to obtain pure [(1,4,7,10-tetraoxacyclododecane-2-yl)methyl]-malonic acid N.M.R. (CDCl3): 2.08-2.19; 3.48-3.82; 9.38].
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:12]2[S:13][CH:14]=[C:15]([CH3:16])[C:11]=2[C:10](=[O:17])[N:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[C:8]1=[O:27])=[O:5])[CH3:2].[Br:28]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:12]2[S:13][C:14]([Br:28])=[C:15]([CH3:16])[C:11]=2[C:10](=[O:17])[N:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[C:8]1=[O:27])=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)Cn1c(=O)n(Cc2ccc(Cl)c(Cl)c2)c(=O)c2c(C)csc21
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)Cn1c(=O)n(Cc2ccc(Cl)c(Cl)c2)c(=O)c2c(C)c(Br)sc21
Yield: 85 %

Procedure:
A 0.3 g quantity of 1-ethoxycarbonylmethyl-3-(3,4-dichlorobenzyl)-5-methylthieno[2,3-d]pyrimidin-2,4(1H,3H)-dione (compound IV-5) synthesized in Reference Example 6 and 0.137 g of N-bromosuccinimide were dissolved in 30 ml of anhydrous tetrachloromethane, and the mixture was refluxed for 2 hours. The solvent was distilled off under reduced pressure and the residual solid obtained was purified by silica gel column chromatography (eluent:chloroform:n-hexane=2:1) to afford 0.30 g of 1-ethoxycarbonylmethyl-3-(3,4-dichlorobenzyl)-6-bromo-5-methylthieno[2,3-d]pyrimidin-2,4(1H,3H)-dione having m.p. of 165.5° to 167° C. in a yield of 85%.
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[OH:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=[O:14].N1C=CN=C1>C(Cl)(Cl)Cl>[Si:5]([O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=[O:14])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7]
Reactant: O=Cc1cccc(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.1 %

Procedure:
t-Butyldimethylchlorosilane (26.01 g; 172.56 mmol) was added to a solution of 3-hydroxybenzaldehyde (20.7 g; 164.35 mmol) and imidazole (27.97 g; 410.9 mmol) in chloroform (300 mL) under nitrogen at 0° C. The reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was washed with water (100 mL×3) and brine (100 mL), dried over anhydrous sodium sulfate and concentrated to give crude product (29.56 g), which was purified by column chromatography on silica gel eluting with (i) pentane and (ii) 3% ethyl acetate in pentane to give 3-(t-butyl-dimethylsilanyloxy)benzaldehyde (21.0 g; 54%). 1H NMR (300 MHz, CDCl3) δ 9.93 (s, 1H), 7.45 (d, 1H, J=7.5 Hz), 7.38 (dd, 1H, J=7.5, 7.5 Hz), 7.31 (d, 1H, J=1.0 Hz), 7.09 (1H, dd, J=7.5, 1.0 Hz), 0.98 (s, 9H), 0.20 (s, 6H).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:10][C@@H:11]([CH3:32])[C:12]([NH:14][CH:15]1[C:21](=[O:22])[N:20]([CH3:23])[C:19]2[CH:24]=[CH:25][CH:26]=[CH:27][C:18]=2[C:17]2[CH:28]=[CH:29][CH:30]=[CH:31][C:16]1=2)=[O:13]>>[CH3:23][N:20]1[C:21](=[O:22])[CH:15]([NH:14][C:12]([C@@H:11]([O:10][C:8](=[O:9])[NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:32])=[O:13])[C:16]2[CH:31]=[CH:30][CH:29]=[CH:28][C:17]=2[C:18]2[CH:27]=[CH:26][CH:25]=[CH:24][C:19]1=2
Reactant: O=C=Nc1ccccc1
Reactant: C[C@H](O)C(=O)NC1C(=O)N(C)c2ccccc2-c2ccccc21
Product: C[C@H](OC(=O)Nc1ccccc1)C(=O)NC1C(=O)N(C)c2ccccc2-c2ccccc21

Procedure:
The title compound, MS: m/e=430.3 (M+H+), was prepared in analogy to example 1 from phenylisocyanate and (S)-2-hydroxy-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-propionamide.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7](Br)[CH:6]=[C:5]([F:10])[C:3]=1[NH2:4].[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O>>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:7]1[CH:8]=[C:2]([F:1])[C:3]([NH2:4])=[C:5]([F:10])[CH:6]=1
Reactant: Nc1c(F)cc(Br)cc1F
Reactant: OB(O)c1ccccc1Cl
Product: Nc1c(F)cc(-c2ccccc2Cl)cc1F
Yield: 55.1 %

Procedure:
The title compound (0.140 g) was prepared from 2,6-difluoro-4-bromo aniline (0.22 g, 1.06 mmol) and 2-chlorophenylboronic acid (0.21 g, 1.38 mmol) as a white solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.52-7.50 (m, 1H), 7.40-7.35 (m, 3H), 7.00 (d, J 2.1, 7.6, 2H), 5.39 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]([CH2:11][CH2:12][CH2:13]O)[C:8](=[O:15])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:18])=O>ClC(Cl)Cl>[Cl:1][C:2]1[C:10]2[N:9]([CH2:11][CH2:12][CH2:13][Cl:18])[C:8](=[O:15])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=c1[nH]c2cccc(Cl)c2n1CCCO
Solvent: ClC(Cl)Cl
Product: O=c1[nH]c2cccc(Cl)c2n1CCCCl
Reaction time: 3 h

Procedure:
To a stirred mixture of 5 parts of 4-chloro-1,3-dihydro-3-(3-hydroxypropyl)-2H-benzimidazol-2-one and 75 parts of trichloromethane are added dropwise 8 parts of sulfinyl chloride. Upon completion, stirring is continued for 3 hours at reflux temperature. The reaction mixture is cooled and evaporated. The residue is stirred in a small amount of 4-methyl-2-pentanone. The product is filtered off and dried, yielding 4-chloro-3-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]=1[C:21]1[O:22][CH:23]=[CH:24][N:25]=1.[NH2:26][C:27]([C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1)=[O:28]>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:33](=[O:34])[C:32]3[CH:36]=[CH:37][C:29]([C:27]([NH2:26])=[O:28])=[CH:30][CH:31]=3)=[C:4]([C:21]3[O:22][CH:23]=[CH:24][N:25]=3)[N:5]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1
Reactant: NC(=O)c1ccc(C(=O)O)cc1
Reactant: NCc1c(-c2ncco2)n(-c2ccccc2)c2cc(Cl)ccc2c1=O
Product: NC(=O)c1ccc(C(=O)NCc2c(-c3ncco3)n(-c3ccccc3)c3cc(Cl)ccc3c2=O)cc1

Procedure:
N-(7-Chloro-2-oxazol-2-yl-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-terephthal-amide was prepared starting from intermediate A and 4-(aminocarbonyl)benzoic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.40 (t, J=4.50 Hz, 1H) 8.31 (d, J=8.59 Hz, 1H) 8.02 (br. s, 1H) 7.97 (d, J=0.78 Hz, 1H) 7.83-7.87 (m, 2H) 7.73-7.78 (m, 2H) 7.37-7.54 (m, 7H) 7.16 (d, J=0.78 Hz, 1H) 6.72 (d, J=1.56 Hz, 1H) 4.25 (d, J=4.30 Hz, 2H). MS calcd. for C27H19ClN4O4 [(M+H)+] 499.1, obsd. 499.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:33][CH:34]=[CH2:35])[CH:8]=[C:9]([C:11]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[N:21]=[CH:20]3)([OH:16])[C:12]([F:15])([F:14])[F:13])[CH:10]=1)=[O:5])C.[Cl-].[NH4+]>CCO.[OH-].[Na+].O>[CH2:33]([N:7]1[CH:8]=[C:9]([C:11]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[N:21]=[CH:20]3)([OH:16])[C:12]([F:14])([F:15])[F:13])[CH:10]=[C:6]1[C:4]([OH:5])=[O:3])[CH:34]=[CH2:35]
Reactant: C=CCn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)cc1C(=O)OCC
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C=CCn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)cc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.8 %

Procedure:
A mixture of 1-allyl-4-{2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-1-hydroxyethyl}-1H-pyrrole-2-carboxylic acid ethyl ester (728 mg, 1.5 mmol) in 5 mL of EtOH and 30 mL of 3 M NaOH was stirred at room temperature. After 18 hours, the mixture was neutralized with saturated aqueous ammonium chloride, diluted with water, and extracted with EtOAc. The combined organic layers were dried, filtered, and concentrated in vacuo to provide 660 mg (96%) of the title compound as a beige solid. MS m/z 460.25 (MH+).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[C:15]([O:16][CH3:17])=[C:14]2[C:10]([CH:11]=[N:12][NH:13]2)=[CH:9][CH:8]=1)=[O:6].[CH3:18][N:19]([CH3:24])[S:20](Cl)(=[O:22])=[O:21]>C1COCC1>[CH3:3][O:4][C:5]([C:7]1[C:15]([O:16][CH3:17])=[C:14]2[C:10]([CH:11]=[N:12][N:13]2[S:20](=[O:22])(=[O:21])[N:19]([CH3:24])[CH3:18])=[CH:9][CH:8]=1)=[O:6]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: COC(=O)c1ccc2cn[nH]c2c1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2cnn(S(=O)(=O)N(C)C)c2c1OC
Reaction time: 0.08 h
Yield: 75.4 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 1.27 g, 31.66 mmol) was added to anhydrous THF (100 mL) with stirring under an atmosphere of nitrogen. After 5 min, a solution of 7-methoxy-1H-indazole-6-carboxylic acid methyl ester (5.44 g, 26.38 mmol, prepared as described in J. Med. Chem. 2006, 49, 4762-4766) in anhydrous THF (50 mL) was added dropwise over 15 min. After stirring for 30 min, a solution of dimethylsulfamoyl chloride (3.68 mL, 34.3 mmol) in anhydrous THF (20 mL) was added dropwise over 10 min. After stirring for 2 h, the reaction mixture was quenched by addition of water (50 mL) and transferred to a separating funnel using EtOAc. The organic layer was washed with water. The aqueous layers were combined and extracted using EtOAc. The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 20% EtOAc in DCM) to afford the title compound as a yellow solid (6.23 g, 75%). 1H NMR (400 MHz, DMSO-d6): δ 8.98 (s, 1H), 7.47 (d, J=8.8 Hz, 1H), 7.33 (d, J=8.8 Hz, 1H), 4.29 (s, 3H), 3.85 (s, 3H), 2.97 (s, 6H).
Reaction SMILES: C(S[C:4]1[N:9]=[C:8]([OH:10])[CH:7]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=1)C.[Cl:17][C:18]1[CH:19]=[C:20]([NH2:26])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]>C1(OC2C=CC=CC=2)C=CC=CC=1>[Cl:17][C:18]1[CH:19]=[C:20]([NH:26][C:4]2[N:9]=[C:8]([OH:10])[CH:7]=[C:6]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:5]=2)[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: COc1ccc(N)cc1Cl
Reactant: CCSc1nc(O)cc(-c2ccccc2)n1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1ccc(Nc2nc(O)cc(-c3ccccc3)n2)cc1Cl

Procedure:
2-Ethylsulfanyl-6-phenyl-pyrimidin-4-ol (3.0 g, 12.8 mmol) was treated with 3-chloro-4-methoxy-phenylamine (2.0 g, 12.8 mmol) in diphenyl ether at 180° C. for 16 hours to give 2-(3-chloro-4-methoxy-phenylamino)-6-phenyl-pyrimidin-4-ol.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[CH:6][C:5]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:4]([Cl:20])[N:3]=1.O1CCOCC1.[OH-].[Na+].C(O)(=O)C>O>[NH2:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[C:4]([Cl:20])[N:3]=1
Reactant: CCOC(=O)c1cc(-c2ccc(Cl)cc2)c(Cl)nc1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: Nc1nc(Cl)c(-c2ccc(Cl)cc2)cc1C(=O)O

Procedure:
2-Amino-6-chloro-5-(4-chlorophenyl)-3-pyridinecarboxylic acid, ethyl ester (0.3 gram) was partially dissolved in 3 ml water and 3 ml dioxane and then 0.2 gram of sodium hydroxide was added. The reaction mixture was refluxed for 11/2-2 hours and, after the mixture was neutralized with glacial acetic acid, a precipitate formed which was collected and washed with water, yield approximately 250 mg, m.p. 280°-284° C. dec.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:11])[N:7]=2)[C:3]=1[CH:12]1[CH2:14][CH:13]1[CH2:15][NH:16][C:17](=[O:19])[CH3:18].[CH:20]1(B(O)O)[CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+].COCCOC>C(OCC)(=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:20]1([C:2]2[CH:10]=[CH:9][C:8]3[C:4](=[CH:5][N:6]([CH3:11])[N:7]=3)[C:3]=2[CH:12]2[CH2:14][CH:13]2[CH2:15][NH:16][C:17](=[O:19])[CH3:18])[CH2:22][CH2:21]1
Reactant: OB(O)C1CC1
Reactant: CC(=O)NCC1CC1c1c(Br)ccc2nn(C)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)NCC1CC1c1c(C2CC2)ccc2nn(C)cc12
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 38.6 %

Procedure:
N-{[2-(5-bromo-2-methyl-2H-indazol-4-yl)cyclopropyl]methyl}acetamide (200 mg, 0.621 mmol) obtained in Example 29, cyclopropylboronic acid (80 mg, 0.931 mmol), potassium carbonate (85.8 mg, 0.621 mmol) and tetrakis(triphenylphosphine)palladium(0) (71.8 mg, 0.062 mmol) were added to a mixed solution of water (0.25 mL) and 1,2-dimethoxyethane (2.75 mL), and the mixture was stirred at 120° C. for 20 min using microwave, thereafter at 130° C. for 40 min. The reaction solution was diluted with ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→10/90) and HPLC to give the title compound (68 mg, yield 39%).