Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([CH3:13])[CH3:12])=[N:9][N:10]=2)[N:7]=1.[I-:14].[Na+].I>>[I:14][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([CH3:13])[CH3:12])=[N:9][N:10]=2)[N:7]=1
Reactant: [I-]
Reactant: CC(C)c1nnc2ccc(Cl)nn12
Agent: I
Agent: [Na+]
Product: CC(C)c1nnc2ccc(I)nn12
Temperature: 90 °C
Reaction time: 96 h
Yield: 157.6 %

Procedure:
Two reactions were set up side by side as follows. Each 250 mL round bottom flask was charged with 6-chloro-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine (7.5 g, 38.1 mmol, Preparation #G.1), sodium iodide (8.58 g, 57.2 mmol) and hydriodic acid (57 wt % in water, stabilized with <1.5% hypophosphorous acid; 52.1 mL, 381 mmol). The mixture was heated in an oil bath to about 90° C. with stirring for about 4 days. The combined reactions were filtered then the filtrate was basified with 25 wt % aqueous NaOH. The solids from the filtration were then added to the filtrate (still basic) and extracted with DCM (750 mL). The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was crystallized from DMF (90 mL, about 90° C.) to give the title compound (17.3 g, 78%): LC/MS (Table 1, Method a) Rt=1.67 min; MS m/z: 289.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][CH2:10][CH2:11][O:12][C:7]=2[C:6]([C:13]2[CH:14]=[C:15]([C:24]([O:26]CC)=[O:25])[C:16](=[CH:22][CH:23]=2)[C:17]([O:19]CC)=[O:18])=[CH:5][CH:4]=1.BrC1C=C(C(OCC)=O)C(=CC=1)C(OCC)=O.[OH-].[K+]>C(O)C>[CH3:1][O:2][C:3]1[C:8]2[O:9][CH2:10][CH2:11][O:12][C:7]=2[C:6]([C:13]2[CH:14]=[C:15]([C:24]([OH:26])=[O:25])[C:16](=[CH:22][CH:23]=2)[C:17]([OH:19])=[O:18])=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(OC)c3c2OCCO3)cc1C(=O)OCC
Agent: CCOC(=O)c1ccc(Br)cc1C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-c2ccc(C(=O)O)c(C(=O)O)c2)c2c1OCCO2
Yield: 92.5 %

Procedure:
To a mixture of diethyl 4-(8-methoxy-1,4-benzodioxan-5-yl)phthalate (0.69 g, 1.8 mmol) obtained by treating Compound A (0.70 g, 3.3 mmol) obtained in Reference Example 1 and known diethyl 4-bromophthalate (1.00 g, 3.3 mmol) by the same reaction as in Example 17 were added ethanol (7.0 mL) and a 6 mol/L aqueous solution of potassium hydroxide (1.4 mL), the mixture was stirred at room temperature for 2 hours, and then ethanol was evaporated in vacuo. Water was added to the resulting solution, the mixture was adjusted to pH 2 with 6 mol/L hydrochloric acid, and the precipitated solid was collected by filtration and dried in vacuo to give Compound B (0.55 g, 94%) as a white solid.
Reaction SMILES: [BH4-].[Li+].C[O:4][C:5]([C@H:7]1[CH2:11][C@H:10]([F:12])[CH2:9][N:8]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=O>C1COCC1>[C:16]([O:15][C:13]([N:8]1[CH2:9][C@@H:10]([F:12])[CH2:11][C@@H:7]1[CH2:5][OH:4])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: COC(=O)[C@H]1C[C@H](F)CN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@@H]1CO
Temperature: 25 °C
Yield: 101.1 %

Procedure:
Add lithium borohydride (0.43 g, 19.6 mmol) to an ice cold solution of 4-(S)-fluoropyrrolidine-N1,2-(R)-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (3.9 g, 13.08 mmol) in THF (50 mL). Warm to room temperature over 18 h. Cool in ice bath. Slowly add acetic acid (3 mL) and water and extract with ethyl acetate. Wash extract with water, saturated aqueous sodium bicarbonate solution, saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with hexanes and ethyl acetate) to give the title compound as a thick oil (2.90 g, 100%).
Reaction SMILES: [CH2:1]([C:4]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([Br:11])[C:5]=1[OH:12])[CH:2]=[CH2:3].ClC1C=C(C=CC=1)C(OO)=[O:18].C(=O)([O-])[O-].[K+].[K+]>>[Br:11][C:6]1[C:5]2[O:12][CH:2]([CH2:3][OH:18])[CH2:1][C:4]=2[C:9]([F:10])=[CH:8][CH:7]=1
Reactant: C=CCc1c(F)ccc(Br)c1O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: OCC1Cc2c(F)ccc(Br)c2O1
Yield: 69.6 %

Procedure:
Treatment of 2-allyl-6-bromo-3-fluorophenol (9.01 g, 0.039 mol) with 3-chloroperoxybenzoic acid (77%, 13.46 g, 0.06 mol) followed by potassium carbonate (13.82 g, 0.10 mol) generally according to the reaction procedure described for Intermediate 9 gave 6.71 g (70%) of (±)-(7-bromo-4-fluoro-2,3-dihydro-1-benzofuran-2-yl)methanol as a white solid. Rf=0.20 (silica, ethyl acetate:hexanes 1:4); mp 40-43° C.; Anal. calcd. for C9H8BrFO2.0.2H2O: C, 43.13; H, 3.38. Found: C, 42.94; H, 3.15.
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C@@H:16]1([NH2:26])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1>>[CH:1]1([O:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH2:11][NH:26][C@@H:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][CH2:17]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: O=Cc1cccc(OC2CCCCC2)c1
Product: c1cc(CN[C@H]2CCCc3ccccc32)cc(OC2CCCCC2)c1

Procedure:
The product from Example 54A and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][C:11](OC)([O:13]C)[CH2:10][CH2:9][CH2:8][C:7]=2[CH:17]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CC(C)=O>O.ClCCl.C(=O)([O-])O.[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][C:11](=[O:13])[CH2:10][CH2:9][CH2:8][C:7]=2[CH:17]=1
Reactant: COc1ccc2c(c1)CCCC(OC)(OC)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc2c(c1)CCCC(=O)C2
Yield: 80.2 %

Procedure:
A solution of 2,6,6-trimethoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene (387 mg) and p-toluenesulfonic acid monohydrate (31 mg) was stirred in 5 mL of 1:1 water:acetone. The mixture was diluted with 50 mL of dichloromethane and 50 mL of saturated sodium hydrogen carbonate. The aqueous layer was re-extracted with 50 mL more dichloromethane and the combined organics were dried over sodium sulfate. Evaporation of the solvent gave 250 mg of 2-methoxy-5,7,8,9-tetrahydro-benzocyclohepten-6-one, which was converted to 2-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ylamine by using Procedure X.
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[C:11]([Cl:26])=[CH:12][C:13]([F:25])=[C:14]([C:16]2[C:20]([CH3:21])=[C:19]([C:22]#[N:23])[N:18]([CH3:24])[N:17]=2)[CH:15]=1.[I:27]CI>>[Cl:26][C:11]1[C:10]([I:27])=[CH:15][C:14]([C:16]2[C:20]([CH3:21])=[C:19]([C:22]#[N:23])[N:18]([CH3:24])[N:17]=2)=[C:13]([F:25])[CH:12]=1
Reactant: ICI
Reactant: Cc1c(-c2cc(N)c(Cl)cc2F)nn(C)c1C#N
Agent: CC(C)CCON=O
Product: Cc1c(-c2cc(I)c(Cl)cc2F)nn(C)c1C#N
Temperature: 22 °C
Reaction time: 14 h

Procedure:
5.86 g of isoamyl nitrite are added dropwise at a temperature of below 15° C. to a solution of 2.64 g of 3-(5-amino-4-chloro-2-fluoro-phenyl)-4-methyl-5-cyano-1-methyl-[1H]-pyrazole in 54 g (16 ml) of diiodomethane. The reaction mixture is stirred for 14 hours at 22° C., and excess diiodomethane is evaporated in vacuo. All the diiodomethane is subsequently distilled off at 70-75° C./14 torr, and the crude product is purified over a silica gel column (eluent: ethyl acetate/hexane 1/5). The desired product is obtained in a yield of 1.88 g (50.2% of theory).
Reaction SMILES: CN(CCN(C)C)C.[Li]C(CC)C.[F:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[C:17]([O:24][CH3:25])[CH:16]=1.[CH3:26][S:27]SC>C1COCC1>[F:14][C:15]1[CH:23]=[C:22]([S:27][CH3:26])[C:18]([C:19]([OH:21])=[O:20])=[C:17]([O:24][CH3:25])[CH:16]=1
Reactant: COc1cc(F)ccc1C(=O)O
Reactant: CSSC
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: COc1cc(F)cc(SC)c1C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of TMEDA (1.95 mL, 12.9 mmol) in anhydrous THF (8 mL) was slowly added a solution of sec-BuLi (1.4 M solution in cyclohexane, 18.5 mL, 25.8 mmol) at −78° C., followed by a solution of 4-fluoro-2-methoxy-benzoic acid (44, 1.0 g, 5.88 mmol) in anhydrous THF (2 mL) at −78° C. under an atmosphere of N2. The mixture stirred at −78° C. for 2 h before a solution of dimethyl disulfide (2.1 mL, 23.5 mmol) in anhydrous THF (2 mL) was added slowly. The mixture was stirred at same temperature for 1 h before it was warmed up to room temperature and quenched with H2O. The crude mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL). Aqueous layer was collected and acidified with 2 M HCl, followed by extraction by EtOAc (2×20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (Isco CombiFlash Companion unit, 40 g Redisep column, 20% to 50% EtOAc/hexane) to give 4-fluoro-2-methoxy-6-(methylthio) benzoic acid as a white solid (46, 0.22 g, 17%): 1H NMR (300 MHz, CDCl3) δ 8.07 (dd, J=15.3, 4.5 Hz, 1H), 7.03 (t, J=8.7 Hz, 1H), 4.11 (s, 3H), 2.49 (s, 1H); MS (ESI+) m/z 217 (M+H).
Reaction SMILES: N1C=CC(C2C(C3C=CC(OCC4C=NC5C(=CC=CC=5)N=4)=CC=3)=NN(CC(F)(F)F)C=2)=CC=1.[CH3:35][N:36]1[CH:40]=[C:39]([C:41]2[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=2)[C:38]([C:47]2[CH:52]=[CH:51][C:50]([OH:53])=[CH:49][CH:48]=2)=[N:37]1.[CH3:54][O:55][C:56]1[CH:57]=[CH:58][CH:59]=[C:60]2[C:65]=1[N:64]=[C:63]([CH2:66]O)[CH:62]=[CH:61]2>>[CH3:54][O:55][C:56]1[CH:57]=[CH:58][CH:59]=[C:60]2[C:65]=1[N:64]=[C:63]([CH2:66][O:53][C:50]1[CH:51]=[CH:52][C:47]([C:38]3[C:39]([C:41]4[CH:42]=[CH:43][N:44]=[CH:45][CH:46]=4)=[CH:40][N:36]([CH3:35])[N:37]=3)=[CH:48][CH:49]=1)[CH:62]=[CH:61]2
Reactant: COc1cccc2ccc(CO)nc12
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(O)cc2)n1
Agent: FC(F)(F)Cn1cc(-c2ccncc2)c(-c2ccc(OCc3cnc4ccccc4n3)cc2)n1
Product: COc1cccc2ccc(COc3ccc(-c4nn(C)cc4-c4ccncc4)cc3)nc12

Procedure:
Following the procedure for the preparation of 2-{4-[4-Pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoxaline but substituting 4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenol and (8-Methoxy-quinolin-2-yl)-methanol provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J=6.2 Hz, 2H), 8.15 (d, J=8.7 Hz, 1H), 7.73 (d, J=8.3 Hz, 1H), 7.55 (s, 1H), 7.44 (m, 1H), 7.37 (m, 3H), 7.15 (d, J=5.8, Hz, 2H), 7.07 (d, J=7.5 Hz, 1H), 6.99 (d, J=8.7 Hz, 2H), 5.46 (s, 2H), 4.08 (s, 3H), 3.94 (s, 3H); MS: (M+H m/z=423.1).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[N:4]1.[H][H].[Cl:10][C:11]1[C:16]([C:17]([N:19]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH2:23][N:22]3[CH:30]=[CH:31][CH:32]=[C:21]3[CH2:20]2)=[O:18])=[CH:15][CH:14]=[C:13](Cl)[N:12]=1>CN(C)C=O.[Cl-].[Na+].O>[Cl:10][C:11]1[C:16]([C:17]([N:19]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH2:23][N:22]3[CH:30]=[CH:31][CH:32]=[C:21]3[CH2:20]2)=[O:18])=[CH:15][CH:14]=[C:13]([N:3]2[CH:7]=[CH:6][CH:5]=[N:4]2)[N:12]=1
Reactant: c1cn[nH]c1
Reactant: [H][H]
Reactant: O=C(c1ccc(Cl)nc1Cl)N1Cc2cccn2Cc2ccccc21
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc(-n2cccn2)nc1Cl)N1Cc2cccn2Cc2ccccc21
Temperature: 110 °C
Yield: 24.7 %

Procedure:
To a suspension of 60% sodium hydride in oil (0.1 g) in dimethylformamide (25 ml) was added dropwise pyrazole (0.15 g). After hydrogen gas evolution ceased, (2,6-dichloropyridin-3-yl)(5H,11H-pyrrolo[2, 1-c][1,4]benzodiazepin-10-yl)-methanone (0.67 g) was added and the reaction mixture was heated in a sand bath at 110° C. for 18 hours. The mixture was poured onto ice, diluted with brine, and extracted with dichloromethane. The combined extracts were dried over anhydrous sodium sulfate and filtered through a short column of anhydrous sodium magnesium silicate. The solution was concentrated in vacuo and triturated with diethyl ether to give 0.18 g of the title compound as a colorless solid, m.p. 133-135° C. MS m/z: 390.8 (M+H)+, 779.1 (2M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[C:7]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].[NH2:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:26]1[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1.Cl[C:34](Cl)([O:36]C(=O)OC(Cl)(Cl)Cl)Cl>C(N(CC)CC)C>[Cl:1][C:2]1[C:8]([Cl:9])=[C:7]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:34]([NH:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:26]1[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1)=[O:36]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(-c2ccncc2)c(Cl)c1Cl
Solvent: CCN(CC)CC
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)Nc4ccc(-c5ccncc5)c(Cl)c4Cl)cc23)CC1

Procedure:
The title compound was prepared in a similar manner to Example 1 from 2,3-dichloro-4-(pyridin-4-yl)aniline (D9, 0.20 g, 0.85 mmole), 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole (D2, 0.15 g, 0.66 mmole), triphosgene (0.10 g, 0.34 mmole) and triethylamine (0.30 ml). This was obtained as a pink white solid (0.18 g).
Reaction SMILES: [C:1]([C@@H:4]([O:6][CH:7]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])=[CH:15][CH:14]=2)[CH2:11][CH2:10][N:9]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:8]1)[CH3:5])([OH:3])=O.[NH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[CH2:47][CH2:48][NH:49][C:50](=[O:52])[CH3:51]>>[C:50]([NH:49][CH2:48][CH2:47][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=1[NH:40][C:1]([C@@H:4]([O:6][CH:7]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])=[CH:15][CH:14]=2)[CH2:11][CH2:10][N:9]([C:33]([O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34])[CH2:8]1)[CH3:5])=[O:3])(=[O:52])[CH3:51]
Reactant: CC(=O)NCCc1ccccc1N
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O[C@@H](C)C(=O)O)cc1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O[C@@H](C)C(=O)Nc2ccccc2CCNC(C)=O)cc1

Procedure:
Analogously to Example 3a, 0.175 g of tert-butyl 3-(1(S)-carboxyethoxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.065 g of N-[2-(2-aminophenyl)ethyl]acetamide (Example 34c) are reacted. The title compound is obtained as a brown oil. Rf=0.35 (95:5 dichloromethane-methanol); Rt=5.32.
Reaction SMILES: C[O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13]C)=[C:5]([CH3:15])[C:4]=1/[CH:16]=[C:17](\[CH2:21][CH2:22][CH2:23][CH3:24])/[C:18]([OH:20])=[O:19].C1(=O)C2C(=CC=CC=2)C(=O)C=C1/C=C(\C)/C(O)=O>CCOCC>[CH3:15][C:5]1[C:6](=[O:13])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3](=[O:2])[C:4]=1/[CH:16]=[C:17](\[CH2:21][CH2:22][CH2:23][CH3:24])/[C:18]([OH:20])=[O:19]
Reactant: CCCC/C(=C\c1c(C)c(OC)c2ccccc2c1OC)C(=O)O
Agent: C/C(=C\C1=CC(=O)c2ccccc2C1=O)C(=O)O
Solvent: CCOCC
Product: CCCC/C(=C\C1=C(C)C(=O)c2ccccc2C1=O)C(=O)O

Procedure:
Compound 35b was prepared from 99b (0.148 g, 0.45 mmol) as described above for 30a to give 0.050 g (0.17 mmol, 37%) of the product as a yellow solid following flash chromatography (2:3 Et2O:hexanes 0.5% AcOH) and recrystallization from Et2O/hexanes.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]#[C:9][CH:10]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)O)[CH:5]=[CH:4][CH:3]=1.CC1C=CC=C(C#CC=C2CCNCC2)N=1.Cl[C:35]1[C:40]([C:41]#[N:42])=[N:39][CH:38]=[CH:37][N:36]=1>>[CH3:1][C:2]1[N:7]=[C:6]([C:8]#[C:9][CH:10]=[C:12]2[CH2:17][CH2:16][N:15]([C:35]3[C:40]([C:41]#[N:42])=[N:39][CH:38]=[CH:37][N:36]=3)[CH2:14][CH2:13]2)[CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1nccnc1Cl
Reactant: Cc1cccc(C#CC(O)C2CCNCC2)n1
Agent: Cc1cccc(C#CC=C2CCNCC2)n1
Product: Cc1cccc(C#CC=C2CCN(c3nccnc3C#N)CC2)n1
Yield: 81 %

Procedure:
The title compound was prepared as reported for the compound of Example 237 but starting from the compound of Example 3 instead of Compound 237a and using 2-chloro-3-cyanopyrazine instead of 2-bromo-3-nitropyridine After the work-up, the residue was purified by automated flash liquid chromatography (SP1™-Biotage) eluting with PE-EtOAc gradient from 7:3 affording the title product. Yellowish solid. Yield: 81%.
Reaction SMILES: C(OC(=O)C1C=CC([CH2:11][C:12]2[O:16][N:15]=[C:14]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[C:21]([OH:28])[C:20]=3[Cl:29])[N:13]=2)=CC=1)C.[CH2:31]([O:33][C:34](=[O:49])[C:35]1[CH:40]=[CH:39][CH:38]=[C:37](CC2ON=C(CO)N=2)[CH:36]=1)[CH3:32]>>[CH2:31]([O:33][C:34](=[O:49])[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH2:11][C:12]2[O:16][N:15]=[C:14]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[C:21]([OH:28])[C:20]=3[Cl:29])[N:13]=2)[CH:36]=1)[CH3:32]
Reactant: CCOC(=O)c1cccc(Cc2nc(CO)no2)c1
Reactant: CCOC(=O)c1ccc(Cc2nc(COc3ccc(C(C)=O)c(O)c3Cl)no2)cc1
Product: CCOC(=O)c1cccc(Cc2nc(COc3ccc(C(C)=O)c(O)c3Cl)no2)c1

Procedure:
The title compound is prepared essentially as described for 4-[3-(4-acetyl-2-chloro-3-hydroxy-phenoxymethyl)-[1,2,4]oxadiazol-5-ylmethyl]-benzoic acid ethyl ester, employing 3-(3-hydroxymethyl-[1,2,4]oxadiazol-5-ylmethyl)-benzoic acid ethyl ester (71%). LC-MS (m/e): 429 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([NH:15][CH3:16])[N:7]=[C:6]2[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:18]=1.C(N(CC)CC)C.C(O)C.[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([NH:15][CH3:16])[N:7]=[C:6]2[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:18]=1
Reactant: CNc1nc(-c2cccc(C#Cc3ccccc3)c2)c2cc(OC)c(OC)cc2n1
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CNc1nc(-c2cccc(CCc3ccccc3)c2)c2cc(OC)c(OC)cc2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 63.6 %

Procedure:
70.0 mg of 6,7-dimethoxy-2-methylamino-4-[3-(2-phenyl ethynyl)phenyl]quinazoline obtained in Example 65, 50.0 mg Lindlar catalyst and 50.0 mg triethylamine were suspended in a mixed solvent of 5 ml ethanol and 5 ml tetrahydrofuran. After the atmosphere was replaced with hydrogen, the mixture was stirred for 6 hours at ordinary pressure at room temperature. The reaction solution was filtered, and the filtrate was evaporated. Then, the crude product was purified and separated by silica gel column chromatography (hexane:ethyl acetate=2:1). The product was recrystallized from hexane-isopropanol to give 45.0 mg of the title compound as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[C:12]([CH3:17])[S:13][C:14]=2[CH2:15][OH:16])[CH:5]=1.[O:19]1[CH:24]=[CH:23][CH2:22][CH2:21][CH2:20]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOC(C)=O>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[C:12]([CH3:17])[S:13][C:14]=2[CH2:15][O:16][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][O:19]2)[CH:5]=1
Reactant: C1=COCCC1
Reactant: COC(=O)c1cccc(-c2nc(C)sc2CO)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cccc(-c2nc(C)sc2COC2CCCCO2)c1

Procedure:
3-(5-Hydroxymethyl-2-methyl-thiazol-4-yl)-benzoic acid methyl ester (0.38 g), dihydropyrane (2.01 mL) and p-toluenesulfonic acid hydrate (0.21 g) in AcOEt (25 mL) was stirred at 20° C. for 1 h. The solution was diluted AcOEt, washed with 5% NaHCO3 solution and with brine, dried and evaporated. The residual oil was purified by chromatography on silica gel using AcOEt/hexane (1:3) as eluent to give 3-[2-methyl-5-(tetrahydro-pyran-2-yloxymethyl)-thiazol-4-yl]-benzoic acid methyl ester (3.8 g) as a pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8](O)[CH3:9])[CH:5]=[CH:4][N:3]=1.CCN(S(F)(F)[F:17])CC>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]([F:17])[CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(O)c1ccnc(Cl)c1
Solvent: ClCCl
Product: CC(F)c1ccnc(Cl)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
1-(2-Chloropyridin-4-yl)ethan-1-ol (115 g, 729 mmol, 1.00 equiv) and dichloromethane (3300 mL) were added to a 5000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen. DAST (144 g, 893 mmol, 1.25 equiv) was added dropwise with stirring at −78° C. in 30 min. The resulting solution was stirred overnight at room temperature. The reaction was then slowly quenched by the addition of water (1000 mL). The resulting solution was extracted with dichloromethane (3×1000 mL). The combined organic layer was washed with brine (3×1000 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography on silica gel column (1:10 ethyl acetate/petroleum ether) to afford 2-chloro-4-(1-fluoroethyl)pyridine as light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:46])=[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[C:25]([CH2:27][CH3:28])[CH:24]=[CH:23][C:22]=4[S:29](=[O:41])(=[O:40])[NH:30][C:31](=[O:39])[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[Cl:38])=[CH:17][CH:16]=3)[C:10]([CH2:42][CH2:43][CH2:44][CH3:45])=[N:9]2)[CH:7]=1.[C:47](Br)(=[O:50])[CH2:48][CH3:49]>CN(C1C=CN=CC=1)C>[CH2:42]([C:10]1[N:11]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[C:25]([CH2:27][CH3:28])[CH:24]=[CH:23][C:22]=3[S:29](=[O:40])(=[O:41])[NH:30][C:31](=[O:39])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:38])=[CH:19][CH:20]=2)[C:12](=[O:13])[N:8]([C:6]2[CH:7]=[C:2]([NH:1][C:47](=[O:50])[CH2:48][CH3:49])[CH:3]=[CH:4][C:5]=2[Cl:46])[N:9]=1)[CH2:43][CH2:44][CH3:45]
Reactant: CCC(=O)Br
Reactant: CCCCc1nn(-c2cc(N)ccc2Cl)c(=O)n1Cc1ccc(-c2cc(CC)ccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1
Agent: CN(C)c1ccncc1
Product: CCCCc1nn(-c2cc(NC(=O)CC)ccc2Cl)c(=O)n1Cc1ccc(-c2cc(CC)ccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1
Yield: 65 %

Procedure:
By the procedure of Example 69, 2-(5-amino-2-chlorophenyl)-5-n-butyl-4-[[2'-[N-(2-chlorobenzoyl)sulfamoyl]-5'-ethylbiphenyl-4-yl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step D) was reacted with propionyl bromide in the presence of DMAP. Purification of the crude product by flash chromatography on silica gel (gradient elution with 1-4% MeOH in CH2Cl2) afforded a 65% yield of the title compound as a cream-colored solid, mp 144°-146° C.; homogeneous by TLC in 9:1 CH2Cl2 --MeOH; m/e 734 (M+1)+.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[Cl:15][C:16]1[CH:17]=[C:18]([C:23](=[O:28])[C:24]([F:27])([F:26])[F:25])[CH:19]=[C:20]([Cl:22])[CH:21]=1.C(N(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[N:1]1([C:6]2[N:11]=[CH:10][C:9]([C:12](=[O:14])[CH2:13][C:23]([C:18]3[CH:19]=[C:20]([Cl:22])[CH:21]=[C:16]([Cl:15])[CH:17]=3)([OH:28])[C:24]([F:27])([F:26])[F:25])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: CC(=O)c1ccc(-n2cncn2)nc1
Solvent: Cc1ccccc1
Solvent: CCCCN(CCCC)CCCC
Product: O=C(CC(O)(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(-n2cncn2)nc1
Temperature: 60 °C
Reaction time: 7 h
Yield: 73.1 %

Procedure:
1.10 g (5.84 mmol) of 1-(6-(1H-1,2,4-triazol-1-yl)pyridin-3-yl)ethanone, 1.42 g (5.84 mmol) of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 2.84 g of toluene and 0.32 g (1.75 mmol) of tributylamine were fed and the mixture was stirred for 7 hours at 60° C. After leaving the reaction mixture for one night at room temperature, the solid was filtered under reduced pressure to obtain 1.84 g of 1-(6-(1H-1,2,4-triazol-1-yl)pyridin-3-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one as a white solid (yield 73.1%).