Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:39])([F:38])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[C:40]([OH:48])(=[O:47])[C@H:41]([CH2:43][C:44]([OH:46])=[O:45])[OH:42]>CC(OC)(C)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:38])([F:39])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[C:40]([O-:48])(=[O:47])[C@H:41]([CH2:43][C:44]([O-:46])=[O:45])[OH:42]
Reactant: O=C(O)C[C@H](O)C(=O)O
Agent: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc(C(F)(F)F)c2)cn1
Solvent: COC(C)(C)C
Product: O=C([O-])C[C@H](O)C(=O)[O-]
Temperature: 5 °C
Reaction time: 8 h

Procedure:
Nilotinib base (0.300 g, 0.57 mmol) was dissolved in TFE (2 mL) at 40° C. to obtain a mixture. The mixture was stirred and added to a solution of L-malic acid (0.038 g, 0.28 mmol) in TFE (1 mL) at 40° C. The resulting clear solution was stirred for about 4 h at 40° C. and subsequently cooled to 5° C. The mixture was kept at 5° C. overnight and then MTBE (1.5 v/v) was added to the mixture at room temperature leading to precipitation. The precipitate was filtered and the filter cake was dried at 40° C. in a vacuum oven over night to give Nilotinib L-malate form I.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Br:8])=[N:6][CH:7]=1.[C:9]([N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>>[C:12]([O:11][C:9]([N:16]1[CH2:21][CH2:20][CH:19]([NH:1][C:2]2[CH:7]=[N:6][C:5]([Br:8])=[CH:4][CH:3]=2)[CH2:18][CH2:17]1)=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1ccc(Br)nc1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Br)nc2)CC1
Yield: 57.6 %

Procedure:
Using general procedure A, 5-amino-2-bromopyridine (Binz; v, Schickh, Chem. Ber., 68, 1935, 315-321) (308 mg, 1.78 mmol) and 1-Boc-4-piperidone (317 mg, 1.59 mmol) gave 4-(6-bromo-pyridin-3-ylamino)-piperidine-1-carboxylic acid tert-butyl ester as a yellow solid (326 mg, 58%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH2:10]([NH2:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:10]([NH:16][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: COc1ccc(Cl)cc1
Reactant: CCCCCCN
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CCCCCCNc1ccc(OC)cc1

Procedure:
According to the general procedure B, 4-chloroanisole (72 mg, 0.50 mmol) reacted with n-hexylamine (80 μl, 0.60 mmol) using 2 mol % of Pd(OAc)2, 4 mol % of Ph5FcP(t-Bu)2, and sodium tert-butoxide (59 mg, 0.60 mmol) in toluene at 70° C. for 8 h to give the title compound (96 mg, 92%as a colorless oil: 1H-NMR (400 MHz, CDCl3): δ 6.79 (d, 2H, J=8.0 Hz), 6.60 (d, 2H, J=8.0 Hz), 3.76 (s, 3H, ArOMe), 3.07 (t, 2H, J=6.8 Hz), 1.61 (m, 2H), 1.39 (m, 2H), 1.33 (m, 2H), 0.91 (t, 3H, J=6.4 and 6.8 Hz). 13C{1H}-NMR (100 MHz, CDCl3): δ 151.92, 142.77, 114.83, 114.02, 55.80, 45.04, 31.66, 29.61, 26.87, 22.62, 14.05. GC/MS(EI): m/z 207 (M+), 136. Anal. Calcd for C13H21NO: C, 75.32; H, 10.21; N, 6.76. Found: C, 75.56; H, 10.37; N, 6.78.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([B:6]2[O:14][C:11]([CH3:13])([CH3:12])[C:8]([CH3:10])([CH3:9])[O:7]2)[CH:3]=[N:2]1.[CH2:15](Br)[CH:16]=[CH2:17].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>>[CH2:17]([N:2]1[CH:3]=[C:4]([B:6]2[O:7][C:8]([CH3:9])([CH3:10])[C:11]([CH3:13])([CH3:12])[O:14]2)[CH:5]=[N:1]1)[CH:16]=[CH2:15]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: C=CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The title compound was prepared from pyrazole-4-boronic acid pinacol ester and allyl bromide according to Method AC (after initial stirring at r.t. for 16 h, an additional 0.3 equivalent of sodium bis(trimethylsilyl)amide was added and the reaction mixture was stirred at 90° C. for 16 h) and was isolated as an amber oil (quantitative) that was used without further purification. LCMS (ES+) 235.0 (M+H)+, RT 3.09 minutes (Method 1).
Reaction SMILES: O[C:2]1([C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][O:30][C:24]=3[CH:23]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:3]1[C:17]([O:19]CC)=[O:18].O=C1C2C(=CC=CC=2)C(C2C=CC=CC=2)=C1C(OCC)=O.C1OC2C=CC([Mg]Br)=CC=2O1>C1COCC1>[CH2:29]1[O:28][C:25]2[CH:26]=[CH:27][C:22]([CH:2]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH:3]3[C:17]([OH:19])=[O:18])=[CH:23][C:24]=2[O:30]1
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccccc2C1(O)c1ccc2c(c1)OCO2
Agent: Br[Mg]c1ccc2c(c1)OCO2
Agent: CCOC(=O)C1=C(c2ccccc2)c2ccccc2C1=O
Solvent: C1CCOC1
Product: O=C(O)C1C(c2ccccc2)c2ccccc2C1c1ccc2c(c1)OCO2
Reaction time: 0.5 h
Yield: 72 %

Procedure:
Ethyl (1RS)-1-Hydroxy-1-(3,4-methylenedioxyphenyl)-3-phenylindene-2-carboxylate. To a solution of ethyl 1-oxo-3-phenylindene-2-carboxylate (1.0 g, 3.6 mmol) in THF (35 ml) under an argon atmosphere at 0° C. was added a solution of freshly prepared 3,4-methylenedioxyphenyl magnesium bromide (5.4 mmol). After stirring for 30 min, the mixture was partitioned between 3 M HCl and EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3 and saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with 10% EtOAc/hexanes to afford the title compound (1.03 g, 72%).
Reaction SMILES: [C:1]1([C:7]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:11][C:10](=[O:12])[N:9]([CH2:13][OH:14])[C:8]2=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:22][CH:23]([CH3:27])[C:24](Cl)=[O:25]>C(OCC)C>[Br:22][CH:23]([CH3:27])[C:24]([O:14][CH2:13][N:9]1[C:8](=[O:15])[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:11][C:10]1=[O:12])=[O:25]
Reactant: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1CO
Reactant: CC(Br)C(=O)Cl
Solvent: CCOCC
Product: CC(Br)C(=O)OCN1C(=O)NC(c2ccccc2)(c2ccccc2)C1=O

Procedure:
5,5-Diphenyl-3-hydroxymethyl-2,4-imidazolidinedione (2 g, 0.0071 mol) was dissolved in 2-bromopropionyl chloride (8.5 g, 5 mL, 0.05 mol) by heating for 30 minutes on a 100°-110° C. oil bath. The reaction mixture was cooled, 20 mL of ethyl ether were added, and the resultant solution was extracted with aqueous potassium carbonate, dried and then crystallized. The product was obtained as a solid white substance (1 g, 34%), m.p. 112°-115° C. Anal. calc. for C19H17N2O4Br: C, 54.69; H, 4.11; N, 6.72; Br, 19.15. Found: C, 54.77; H, 4.15; N, 6.69; Br, 19.25. The product had the formula: ##STR76##
Reaction SMILES: C1(C)C=CC(C([C@@](C(O)=O)(O)[C@@](C(C2C=CC(C)=CC=2)=O)(O)C(O)=O)=O)=CC=1.[CH3:29][N:30]([CH3:50])[CH2:31][CH2:32][C@H:33]([O:39][C:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=[CH:42][CH:41]=1)[C:34]1[S:35][CH:36]=[CH:37][CH:38]=1.CN(C)CC[C@@H](OC1C2C(=CC=CC=2)C=CC=1)C1SC=CC=1>>[CH3:50][N:30]([CH3:29])[CH2:31][CH2:32][CH:33]([O:39][C:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=[CH:42][CH:41]=1)[C:34]1[S:35][CH:36]=[CH:37][CH:38]=1
Reactant: CN(C)CC[C@H](Oc1cccc2ccccc12)c1cccs1
Agent: CN(C)CC[C@@H](Oc1cccc2ccccc12)c1cccs1
Agent: Cc1ccc(C(=O)[C@](O)(C(=O)O)[C@@](O)(C(=O)O)C(=O)c2ccc(C)cc2)cc1
Product: CN(C)CCC(Oc1cccc2ccccc12)c1cccs1

Procedure:
Di-para-toluoyl-L-tartaric acid works as an efficient resolving agent for preparation of (S)-isomer of compound of formula 4, for example, (S)-(+)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine. The R-isomer enriched mother liquor containing (R)-(−)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine can be racemized to obtain (±)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine by treatment with a base, which can be further recycled and subjected to resolution process with DPTTA, thereby increasing the yield of desired enantiomer, (S)-(+)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine.
Reaction SMILES: [H-].[Na+].[Si](OC[C@@H]1NC(=O)CCC1)(C(C)(C)C)(C)C.I[CH2:20][C:21]#[C:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27]>CN(C=O)C>[CH3:29][O:28][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][C:22]#[C:21][CH3:20]
Reactant: COC(=O)CCCC#CCI
Agent: CC(C)(C)[Si](C)(C)OC[C@H]1CCCC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC#CCCCC(=O)OC
Reaction time: 1 h

Procedure:
Sodium hydride (60% dispersion in oil, 195 mg, 4.87 mmol) was added to a solution of (R)-6-(tert-butyldimethylsilanyloxymethyl)-piperidin-2-one (1.13 g, 4.64 mmol) in DMF (8 mL) at rt. After 1 h, methyl 7-iodohept-5-ynoate (1.35 g, 5.07 mmol) in DMF (2 mL) was added via cannula. After 18 h at rt, the reaction was quenched by the addition of aqueous HCl (0.5 M, 25 mL) and the mixture was extracted with EtOAc (3×50 mL). The combined organic phase was washed with saturated aqueous NaHCO3 (50 mL) and brine (3×50 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→50% EtOAc/CH2Cl2, gradient) afforded 713 mg (40%) of 7-[(R)-2-tert-butyldimethylsilanyloxymethyl)-6-oxo-piperidin-1-yl]-hept-5-ynoic acid methyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.C([Li])CCC.[CH3:16][Sn:17](Cl)([CH3:19])[CH3:18].[Cl-].[NH4+]>CCOCC.CCCCCC>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][C:7]([Sn:17]([CH3:19])([CH3:18])[CH3:16])=[CH:8][C:4]=2[CH:3]=1
Reactant: Cc1ccc2sccc2c1
Reactant: C[Sn](C)(C)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1ccc2sc([Sn](C)(C)C)cc2c1
Reaction time: 0.5 h

Procedure:
A solution of 7.411 g of 5-methylbenzo[b]thiophene (Maybridge, Chemical Co. Ltd., 11-78) in 35 ml of ether is added dropwise at 0° to a mixture of 40 ml of 1.5N butyllithium in hexane and 40 ml of ether. After 30 minutes, a solution of 9.963 g of trimethyltin chloride in 50 ml of ether is also added dropwise at 0°. After stirring for 1 hour at 0°, 50 ml of 5% ammonium chloride solution are added. The product is obtained by extracting with 100 ml and 150 ml of ether. Distillation at 0.15 mbar and 100°-106° yields 5-methyl-2-trimethylstannylbenzo[b]thiophene.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][C@H:9]([NH:14]C(=O)C3C=CC=CC=3CO)[C@H:10]2[OH:13])=[CH:6][CH:5]=1)[CH3:2].C(OC1C=C2C(C[C@H](NC(=O)C3C=CC=CC=3CO)[C@@H]2O)=CC=1)C>C(O)(=O)C>[NH2:14][C@H:9]1[CH2:8][C:7]2[C:11](=[CH:12][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=2)[C@@H:10]1[OH:13]
Reactant: CCOc1ccc2c(c1)[C@H](O)[C@@H](NC(=O)c1ccccc1CO)C2
Agent: CCOc1ccc2c(c1)[C@@H](O)[C@@H](NC(=O)c1ccccc1CO)C2
Solvent: CC(=O)O
Product: CCOc1ccc2c(c1)[C@H](O)[C@@H](N)C2
Reaction time: 18 h

Procedure:
N-[(1S,2S)-6-ethoxy-2,3-dihydro-1-hydroxy-1H-inden-2-yl]-2-(hydroxymethyl)benzamide and N-[(1R,2S)-6-ethoxy-2,3-dihydro-1-hydroxy-1H-inden-2-yl]-2-(hydroxymethyl)benzamide (XVII, Example 16, 200 mg, 0.61 mmol) is dissolved in acetic acid (2.5 mL). The reaction mixture is stirred for 18 hr at 80°. Then the mixture is partitioned between methylene chloride and water. The aqueous phase is separated and adjusted to pH=10 using aqueous ammonium. The product is extracted with methylene chloride. The organic layers are concentrated to give the same title compound (VII) as EXAMPLE 6 and its cis-diastereomer.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[CH:14]3)=[C:6]([CH:9]=1)[C:7]#[N:8].Br[CH2:21][CH:22]([O:25][CH3:26])[O:23][CH3:24].[H-].[Na+]>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH3:24][O:23][CH:22]([O:25][CH3:26])[CH2:21][N:16]1[C:17]2[C:13](=[CH:12][C:11]([O:10][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:9][C:6]=3[C:7]#[N:8])=[CH:19][CH:18]=2)[CH:14]=[N:15]1
Reactant: N#Cc1cc(F)ccc1Oc1ccc2[nH]ncc2c1
Reactant: COC(CBr)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(Cn1ncc2cc(Oc3ccc(F)cc3C#N)ccc21)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
To a cooled (0° C.) solution of 5-fluoro-2-(1H-indazol-5-yloxy)-benzonitrile (0.100 g, 0.395 mmol) and 2-bromo-1,1-dimethoxyethane (0.114 g, 0.671 mmol) in DMF (4 mL) was added NaH (0.024 g of 60%, 0.59 mmol). The reaction mixture was warmed to room temperature and stirred for 1 hour. Tetrabutyl ammonium iodide (0.029 g, 0.079 mmol) was added to the mixture and it was heated to 60° C. for 3 hours. The mixture was cooled to room temperature, diluted with water (4 mL), and extracted with ether (3×30 mL). The combined extracts were washed with water (2×5 mL) and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was chromatographed eluting with ethyl acetate/hexanes (1:2) to afford 0.066 g of product (49% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][C:5]([N:9]2[C:13](=[O:14])[N:12]([CH:15]([F:17])[F:16])[C:11]([CH3:18])=[N:10]2)=[C:4]([F:19])[CH:3]=1.[OH:20][CH:21]([CH3:29])[C:22](=[CH2:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24].C(N(CCCC)CCCC)CCC>[Pd+2]>[C:21]([CH:22]([CH2:28][C:7]1[CH:6]=[C:5]([N:9]2[C:13](=[O:14])[N:12]([CH:15]([F:17])[F:16])[C:11]([CH3:18])=[N:10]2)[C:4]([F:19])=[CH:3][C:2]=1[Cl:1])[C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:20])[CH3:29]
Reactant: C=C(C(=O)OCC)C(C)O
Reactant: Cc1nn(-c2cc(I)c(Cl)cc2F)c(=O)n1C(F)F
Agent: [Pd+2]
Solvent: CCCCN(CCCC)CCCC
Product: CCOC(=O)C(Cc1cc(-n2nc(C)n(C(F)F)c2=O)c(F)cc1Cl)C(C)=O
Yield: 48.9 %

Procedure:
This compound was prepared in the manner of Example 6, with 1.03 grams (0.0025 mole--1.0 equiv.) of 1-(4-chloro-2-fluoro-5-iodophenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazole, 0.365 gram (0.0025 mole--1.0 equiv.) of ethyl 3-hydroxy-2-methylenebutanoate, 1.6 grams (0.0084 mole--3.36 equiv.) of tributylamine, and 0.062 gram (0.000029 mole--0.01 equiv.) of 5% palladium(II) on carbon as reagents. A yield of 0.52 gram of 98% pure ethyl α-acetyl-2-chloro-5-[4-(difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl]-4-fluorobenzenepropanoate (49.6% yield) was obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].Cl>O1CCOCC1>[F:18][C:12]1[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[C:8]1[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(-c2ccc(F)cc2F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1ccc(-c2ccc(F)cc2F)cc1
Temperature: 50 °C
Reaction time: 15 h
Yield: 24.7 %

Procedure:
Combine 4-carbomethoxyphenylboronic acid (1.021 g, 5.67 mmol), 1-bromo-2,4-difluorobenzene (1.000 g, 5.181 mmol.), Pd(OAc)2 (0.113 g, 0.50 mmol), triphenylphosphine (0.149 g, 0.505 mmol), and sodium carbonate (1.664 g, 0.568 mmol). Purge the reaction vessel with argon. Add DMF (20 mL) and water (2.0 mL) with stirring. Place sealed reaction in an 80° C. oil bath and allow to stir for 24 hours. Cool reaction to room temperature, dilute with ethyl acetate, and filter through a short plug of celite with additional ethyl acetate. Wash organics with water, dry over MgSO4, filter, and evaporate. Purification by flash column chromatography yields 2′,4′-difluorobiphenyl-4-carboxylic acid methyl ester as a yellow solid. Dissolve the purified ester in dioxane (5 mL) and add 5M NaOH (1 mL). Stir vigorously at 50° C. for 15 hours. Upon completion, acidify the reaction with conc. HCl and extract with ethyl acetate. Evaporation of the solvent yields 300 mg (24.7%) of the title compound. MS (ES): m/z 233.0 (M−H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.[CH2:14]([S:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20])[CH3:15].C(=O)([O-])O.[Na+]>O>[CH3:1][NH:2][C:3]1[C:8]([NH:9][C:19](=[O:20])[C:18]2[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=2[S:16][CH2:14][CH3:15])=[CH:7][C:6]([C:10]([F:13])([F:11])[F:12])=[CH:5][N:4]=1
Reactant: CNc1ncc(C(F)(F)F)cc1N
Reactant: CCSc1ccccc1C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCSc1ccccc1C(=O)Nc1cc(C(F)(F)F)cnc1NC
Temperature: 50 °C
Reaction time: 2 h
Yield: 100.7 %

Procedure:
To a mixture of N2-methyl-5-trifluoromethylpyridine-2,3-diamine (3.82 g) and THE (40 ml), 2-ethylsulfanylbenzoic acid chloride (4.42 g) was added, stirred at 50° C. for 2 hours, then stirred under reflux for 2 hours. After the mixture was allowed to cool to room temperature, sodium hydrogen carbonate (1.85 g) was added thereto, and stirred at 50° C. for 2 hours. After the mixture was allowed to cool to room temperature, water was poured thereinto, and then the precipitated solid was collected by the filtration. The resulting solid was washed with water and hexane, and dried to give 7.15 g of N-(2-methylamino-5-trifluoromethylpyridine-3-yl)-2-ethylsulfanyl-benzamide (Compound ((1B)-19).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][CH2:6][C:7](Cl)=[O:8].[NH:10]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][C:11]1=[O:12]>C(=S)=S>[Cl:5][CH2:6][C:7]([C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[NH:10][C:11](=[O:12])[CH2:13][CH2:14]2)=[O:8]
Reactant: O=C(Cl)CCl
Reactant: O=C1CCc2ccccc2N1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: O=C1CCc2cc(C(=O)CCl)ccc2N1
Temperature: 0 °C
Yield: 89.5 %

Procedure:
To a solution of aluminum chloride (80 g) and chloroacetyl chloride (72 g) in carbon disulfide (200 ml) was added portionwise in 20 minutes a suspension of 3,4-dihydrocarbostyril (14.7 g) in carbon disulfide (100 ml) while refluxing with stirring. After completion of addition, the mixture was refluxed with stirring for 2 hours. After cooling, the reaction mixture was poured into ice water, and crystals which precipitated were collected by filtration, washed with water and recrystallized from ethanol to give 20 g of 6-chloroacetyl-3,4-dihydrocarbostyril.
Reaction SMILES: [CH:1]1([C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:5]=2[O-:6])[CH2:3][CH2:2]1.[Na+].C(C(CCCC)CO)C.[OH:22][C:23]1[CH:28]=[C:27]([Cl:29])[N:26]=[N:25][C:24]=1Cl.C1(C2C=CC=C(C)C=2O)CC1>C1(C)C=CC=CC=1.O>[Cl:29][C:27]1[N:26]=[N:25][C:24]([O:6][C:5]2[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:4]=2[CH:1]2[CH2:3][CH2:2]2)=[C:23]([OH:22])[CH:28]=1
Reactant: Cc1cccc(C2CC2)c1[O-]
Reactant: Oc1cc(Cl)nnc1Cl
Agent: Cc1cccc(C2CC2)c1O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCCCC(CC)CO
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
To a mixture of 25.5 g (150 mmol) of sodium 2-cyclopropyl-6-methylphenoxide and 12.5 g of 2-ethyl-1-hexanol was added 2.5 g (purity: 99%; 15.0 mmol) of 4-hydroxy-3,6-dichloropyridazine at room temperature. Then, the resultant mixture was heated from room temperature to 140° C. to effect a reaction for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and 100 g of pure water and 120 g of toluene were added to the cooled mixture, and stirred for 30 minutes, and an organic phase containing 2-cyclopropyl-6-methylphenol added in an excess amount was separated. Then, the resultant aqueous phase containing a sodium salt of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol was quantitatively determined by an HPLC internal standard analysis method, which showed that 2.85 g of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 69.0%) and 9.0 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.2%) were obtained.
Reaction SMILES: Cl.[C:2]([N:6]1[CH:14]=[C:13]2[C:8]([C:9](=[O:20])[NH:10][C:11]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:12]2)=[N:7]1)([CH3:5])([CH3:4])[CH3:3].[Cl:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][C:26]([C:32](O)=[O:33])=[CH:27][CH:28]=2)[N:23]=1.FC(F)(F)CNC1C=CC2C(=CC(C(O)=O)=CC=2)N=1>>[C:2]([N:6]1[CH:14]=[C:13]2[C:8]([C:9](=[O:20])[NH:10][C:11]3([CH2:19][CH2:18][N:17]([C:32]([C:26]4[CH:25]=[C:24]5[C:29]([CH:30]=[CH:31][C:22]([Cl:21])=[N:23]5)=[CH:28][CH:27]=4)=[O:33])[CH2:16][CH2:15]3)[CH2:12]2)=[N:7]1)([CH3:5])([CH3:3])[CH3:4]
Reactant: O=C(O)c1ccc2ccc(Cl)nc2c1
Reactant: CC(C)(C)n1cc2c(n1)C(=O)NC1(CCNCC1)C2
Agent: Cl
Agent: O=C(O)c1ccc2ccc(NCC(F)(F)F)nc2c1
Product: CC(C)(C)n1cc2c(n1)C(=O)NC1(CCN(C(=O)c3ccc4ccc(Cl)nc4c3)CC1)C2

Procedure:
The title compound was prepared by a method analogous to that described for Example 3 using 2′-tert-butyl-4′,6′-dihydrospiro[piperidine-4,5′-pyrazolo[3,4-c]pyridin]-7′(2′H)-one hydrochloride salt (Intermediate 4) and 2-chloroquinoline-7-carboxylic acid (Intermediate 44). +ESI (M+H) 452.3; 1H NMR (400 MHz, CDCl3, δ): 8.12 (d, J=8.2 Hz, 1H), 7.98 (br. s., 1H), 7.88 (dd, J=8.4 Hz, 1H), 7.61 (dd, J=8.4, 1.6 Hz, 1H), 7.44 (d, J=8.6 Hz, 1H), 7.39 (s, 1H), 5.91 (br. s., 1H), 4.06-4.22 (m, 1H), 3.38-3.64 (m, 3H), 2.85 (br. s., 2H), 1.67-1.97 (m, 4H), 1.61 (s, 9H).
Reaction SMILES: [CH3:1][CH2:2][C:3]1([CH2:12][CH3:13])[C:9](=[O:10])[N:8]=[C:7]([O-:11])[NH:6][C:4]1=[O:5].[Na+].[N-]=[N+]=[N-].[Na+].Cl>>[CH3:1][CH2:2][C:3]1([CH2:12][CH3:13])[C:4](=[O:5])[NH:6][C:7](=[O:11])[NH:8][C:9]1=[O:10]
Reactant: CCC1(CC)C(=O)N=C([O-])NC1=O
Agent: Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Product: CCC1(CC)C(=O)NC(=O)NC1=O

Procedure:
Sodium Barbitone was made up to a final concentration of 0.07M together with 0.1% (w/v) sodium azide. The pH of this solution was adjusted to 8.4 with concentrated hydrochloric acid before making up to the final volume.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[CH2:19][N:18]([CH:23]2[CH2:25][CH2:24]2)[CH2:17][C:16]3([CH3:27])[CH3:26])=[CH:7][CH:6]=1.CO.O.[OH-].[Li+]>O>[CH:23]1([N:18]2[CH2:17][C:16]([CH3:26])([CH3:27])[C:15]3[C:20](=[CH:21][CH:22]=[C:13]([C:12]#[C:11][C:8]4[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:28])=[O:2])=[CH:10][CH:9]=4)[CH:14]=3)[CH2:19]2)[CH2:24][CH2:25]1
Reactant: COC(=O)Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CN(C2CC2)C3)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)CN(C2CC2)Cc2ccc(C#Cc3ccc(CC(=O)O)cc3)cc21

Procedure:
Following general procedure J and using [4-(2-cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinolin-6ylethynyl)-phenyl]-acetic acid methyl ester (Compound 23, 0.01 g, 0.027 mmol), methanol (1 mL), tetrahydrofiuran (1 mL), water (0.5 mL) and lithium hydroxide monohydrate (0.042 g, 1 mmol) the title compound was obtained as a pale yellow solid foam (0.0065 g, 68%).