Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[N:5][N:6]=1.[CH2:7]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl>N1C=CC=CC=1>[CH2:7]([C:19]1[CH:20]=[CH:21][C:22]([S:25]([NH:1][C:2]2[S:3][CH:4]=[N:5][N:6]=2)(=[O:27])=[O:26])=[CH:23][CH:24]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: Nc1nncs1
Reactant: CCCCCCCCCCCCc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCc1ccc(S(=O)(=O)Nc2nncs2)cc1
Temperature: 95 °C
Reaction time: 1 h

Procedure:
2-Amino-1,3,4-thiadiazole (439 mg, 4.3 mmol) was suspended in pyridine (1.5 mL). p-Dodecylbenzenesulfonyl chloride (1.0 mg, 2.9 mmol) was added slowly at 0° C. The reaction mixture was then heated to 95° C. and was stirred at this temperature for 1 h. The reaction mixture was then added to aqueous 10% HCl (15 mL) and the resulting mixture extracted with ethyl acetate (3×30 mL). The organic extracts were washed with water (3×50 mL), brine (3×50 mL), dried over anhydrous Na2SO4, filtered, and volatiles evaporated to yield a solid mass. Chromatography on silica gel (70-230 mesh) eluted with 2% MeOH in CH2Cl2 gave the product (600 mg, 1.5 mmlo, 51%). Recrystallization from hexanes:ethyl acetate (3:7) gave an analytical sample, mp 126-127° C.; 1H NMR (500 MHz, CDCl3) δ 0.87 (3, t, J=6.5 Hz), 1.20-1.36 (18, m), 1.54-1.63 (2, m), 2.62 (2, t, J=7.5 Hz), 7.25 (2, d, J=8.0 Hz), 7.83 (2, d, J=8.0 Hz), 8.28 (1, s), 12.81 (1, br s); 13C NMR (125 MHz, CDCl3) δ 14.0, 22.6, 29.2, 29.3, 29.4, 29.5, 29.6, 31.0, 31.8, 35.8, 126.4, 128.9, 138.0, 142.8, 148.5, 167.5; MS (LCQ, ESI+) Calcd for C20H32N3O2S2 410.1936. found 410.10 (M+H)+; HRMS (ESI+, m/z) Calcd C20H32N3O2S2 410.1936. found 410.1932 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH:13][CH:14]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH2:15][OH:16])[S:11][CH:12]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:30](Cl)([O:32]C(=O)OC(Cl)(Cl)Cl)Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:13]3[CH:14]([CH2:17][C:18]([F:19])([F:21])[F:20])[CH2:15][O:16][C:30]3=[O:32])[S:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: OCC(CC(F)(F)F)Nc1nc(-c2ccc(Br)cc2)cs1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1OCC(CC(F)(F)F)N1c1nc(-c2ccc(Br)cc2)cs1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 83.2 %

Procedure:
2-{[4-(4-Bromophenyl)-1,3-thiazol-2-yl]amino}-4,4,4-trifluorobutan-1-ol (0.700 g, 1.83 mmol), prepared in the previous step, was dissolved in 20 mL of methylene chloride. Triethylamine (2.65 mL, 18.3 mmol) was added and the solution was cooled to 0° C. Triphosgene (1.36 g, 4.6 mmol) was added in two portions and the mixture was stirred at 0° C. for 45 min and then at 25° C. for 2 h. The mixture was diluted with methylene chloride and poured into 250 mL of saturated aqueous sodium bicarbonate and the layers were separated. The organics were washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. Flash chromatography (5% acetone/hexane) afforded the title compound (0.62 g, 83%) as a white solid. mp 163-165° C. HRMS: calcd for C14H10BrF3N2O2S+H+, 406.96712; found (ESI, [M+H]+), 406.9679. Analytical HPLC: retention time 10.8 min, 210-370 nm the Xterra® RP18 column, 3.5%, 150×4.6 mm 40° C. 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min, 1.2 mL/min 5 μL injection.
Reaction SMILES: CN(C=O)C.[C:6]([C:8]1[CH:9]=[C:10](/[CH:20]=[CH:21]/[C:22]([OH:24])=O)[CH:11]=[CH:12][C:13]=1[N:14]1[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]1)#[N:7].Cl.[C:26]1([C:32]2[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=2)[CH2:35][NH2:36])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1C=CC2N(O)N=NC=2C=1>C(Cl)CCl>[C:32]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:39]=[CH:38][CH:37]=[C:34]([CH2:35][NH:36][C:22](=[O:24])/[CH:21]=[CH:20]/[C:10]2[CH:11]=[CH:12][C:13]([N:14]3[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]3)=[C:8]([C:6]#[N:7])[CH:9]=2)[CH:33]=1
Reactant: Cc1cn(-c2ccc(/C=C/C(=O)O)cc2C#N)cn1
Reactant: NCc1cccc(-c2ccccc2)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1cn(-c2ccc(/C=C/C(=O)NCc3cccc(-c4ccccc4)c3)cc2C#N)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.2 %

Procedure:
To a DMF (0.2 mL) solution of (E)-3-[3-cyano-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (15 mg) and 3-phenylbenzylamine monohydrochloride (16 mg), TEA (0.007 mL), HOBT (10 mg) and EDC (14 mg) were added one by one, and the reaction mixture was agitated at room temperature overnight. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (Carrier: Chromatorex®NH, elution solvent: hexane-ethyl acetate system), and 5 mg of the title compound was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[C@@H:11]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][O:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[C:45]#[N:46])=[CH:30][CH:29]=2)[C@H:10]([O:47][CH2:48][C@H:49]([OH:62])[CH2:50]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([O:47][CH2:48][C@H:49]2[CH2:50][O:62]2)[C@H:11]([C:28]2[CH:29]=[CH:30][C:31]([O:34][CH2:35][CH2:36][CH2:37][O:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[C:45]#[N:46])=[CH:32][CH:33]=2)[C@@H:12]([O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cc(CO[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H](OC[C@H](O)COS(=O)(=O)c3ccc(C)cc3)[C@@H]2c2ccc(OCCCOc3ccccc3C#N)cc2)cc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1cc(CO[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H](OC[C@H]3CO3)[C@@H]2c2ccc(OCCCOc3ccccc3C#N)cc2)cc2ccccc12

Procedure:
In analogy to the procedure described in example 1) (j) the (3S,4R,5R)-4-[4-[3-(2-cyano-phenoxy)-propoxy]-phenyl]-3-[(2S)-2-hydroxy-3-(toluene-4-sulfonyloxy)-propoxy]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester was treated with sodium hydroxide solution in dimethylsulfoxide to yield the (3R,4R,5S)-4-[4-[3-(2-cyano-phenoxy)-propoxy]-phenyl]-3-(4-methoxy-naphthalen-2-ylmethoxy)-5-[(2R)-oxiranylmethoxy]-piperidine-1-carboxylic acid tert-butyl ester as colorless oil; MS: 695 (M+H)+.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:9][C:10]1[CH:15]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:13]=[CH:12][C:11]=1[C:25]1[S:26][C:27]2[C:32]([N:33]=1)=[CH:31][CH:30]=[C:29]([C:34]1([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:36][CH2:35]1)[N:28]=2.FC(F)(F)S(O[C:49]1[CH2:53][N:52]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[C@H:51]([C:61]([O:63][CH3:64])=[O:62])[CH:50]=1)(=O)=O>CN(C=O)C>[F:9][C:10]1[CH:15]=[C:14]([C:49]2[CH2:53][N:52]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[C@H:51]([C:61]([O:63][CH3:64])=[O:62])[CH:50]=2)[CH:13]=[CH:12][C:11]=1[C:25]1[S:26][C:27]2[C:32]([N:33]=1)=[CH:31][CH:30]=[C:29]([C:34]1([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:35][CH2:36]1)[N:28]=2
Reactant: COC(=O)[C@@H]1C=C(OS(=O)(=O)C(F)(F)F)CN1C(=O)OC(C)(C)C
Reactant: CC1(C)OB(c2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)OC1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C=C(c2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)CN1C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A slurry of potassium phosphate (2.50 g, 11.8 mmol), (Amphos)2PdCl2 (0.125 g, 0.177 mmol), 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine (2.78 g, 5.89 mmol) and (S)-1-tert-butyl 2-methyl 4-(trifluoromethylsulfonyloxy)-1H-pyrrole-1,2(2H,5H)-dicarboxylate (2.21 g, 5.89 mmol, synthesized according to literature reference: Bioorganic and Medicinal Chemistry Letters, 2007, 2715) in 15 mL DMF was flushed with argon, sealed, and heated to 80° C. After 6 h, the reaction was judged complete, cooled, and filtered through celite, rinsing with 200 mL EtOAc. The filtrate was washed with water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gel chromatography, EA/hexanes gradient, gave (2S)-1-tert-butyl 2-methyl 4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)-2H-pyrrole-1,2(5H)-dicarboxylate as a light yellow solid. MS (ESI) m/z: Calculated: 571.2; Observed: 572.1 (M++1).
Reaction SMILES: Br[CH2:2][C:3]1[CH:15]=[CH:14][C:6]2[S:7][C:8]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:9][C:5]=2[CH:4]=1.[C:16]([O-:19])(=[O:18])[CH3:17].[Na+]>C(N(CC)CC)C.C(O)(=O)C>[C:16]([O:19][CH2:2][C:3]1[CH:15]=[CH:14][C:6]2[S:7][C:8]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:9][C:5]=2[CH:4]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)[O-]
Reactant: NS(=O)(=O)c1cc2cc(CBr)ccc2s1
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CC(=O)OCc1ccc2sc(S(N)(=O)=O)cc2c1
Yield: 87.6 %

Procedure:
To a mixture of 5-bromomethyl-2-sulfamoylbenzo[b]thiophene (3.06,0.01 mol), anhydrous sodium acetate (0.98 g, 0.01 mol) and glacial acetic acid (15 ml) was added three drops of triethylamine. The mixture was heated and the resulting solution was stirred at reflux for 6 hours and was left at room temperature over night. The acetic acid was removed in vacuo and the residual gum was diluted with 25 ml of ice water. The product was extracted into 3×50 ml of ether. The combined extracts were washed with water, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give 2.5 g of yellow solid (88% yield). Recrystallization from chloroform gave material with a m.p. of 113°-115° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][NH2:23])[N:17]=3)=[N:13][C:12]=2[CH3:24])=[O:10])[CH:2]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][NH:23][S:32]([C:29]4[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=4)(=[O:34])=[O:33])[N:17]=3)=[N:13][C:12]=2[CH3:24])=[O:10])[CH:2]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: Cc1nc(-c2ccn(CCN)n2)sc1C(=O)NCc1cccnc1
Product: Cc1nc(-c2ccn(CCNS(=O)(=O)c3ccc(F)cc3)n2)sc1C(=O)NCc1cccnc1

Procedure:
The title compound was prepared from 2-[1-(2-amino-ethyl)-1H-pyrazol-3-yl]-4-methyl-thiazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide) and 4-fluoro-benzenesulfonyl chloride as describe in Example 81 and isolated as a white solid (0.052 g, 37% yield). 1H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 8.56 (d, J=4 Hz, 1H), 7.83-7.87 (m, 2H), 7.73 (d, J=8 Hz, 1H), 7.42 (d, J=2 Hz, 1H), 7.27-7.33 (m, 1H), 7.16 (t, J=8 Hz, 2H), 6.79 (d, J=2 Hz, 1H), 6.09-6.14 (bm, 1H), 5.36 (bs, 1H), 4.64 (d, J=8 Hz, 2H), 4.25-4.29 (m, 2H), 3.47 (bs, 2H), 2.74 (s, 3H); MS (M+H)+=500.8; Rt=1.08 min; HRMS (M+H)+=501.12.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][CH3:11])[C:3]=1[C:4]#[N:5].[Br:12]Br>C(Cl)(Cl)(Cl)Cl.ClCCl.[Fe].II>[Br:12][C:9]1[C:2]([Cl:1])=[C:3]([C:6]([S:10][CH3:11])=[CH:7][CH:8]=1)[C:4]#[N:5]
Reactant: BrBr
Reactant: CSc1cccc(Cl)c1C#N
Agent: [Fe]
Agent: II
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CSc1ccc(Br)c(Cl)c1C#N
Temperature: 30 °C
Yield: 45.5 %

Procedure:
Iron powder (0.5 g) and iodine (0.05 g) were added to a solution of 2-chloro-6-(methylsulphenyl)benzonitrile (10.0 g) in a mixture of carbon tetrachloride and dichloromethane. The mixture was warmed to 30° C. and bromine (9.5 g) was added. The mixture was heated at 55° C. for 5 hours. It was cooled, washed with aqueous sodium bisulphite, water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was redissolved in a mixture of carbon tetrachloride and dichloromethane and treated with iron powder (0.5 g) and iodine (0.05 g). Bromine (6.5 g) was added and the mixture was heated at 55° C. for 5 hours. It was cooled and washed with sodium bisulphite, water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by column chromatography eluted with a mixture of ethyl acetate and n-hexane to give 3-bromo-2-chloro-6-(methylsulphenyl)benzonitrile (6.51 g) as an orange solid NMR (CDCl3) 2.5(s,3H) 7.0(d, 1H) 7.65(d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][C:15]1([CH3:24])[C:20]2[CH:21]=[CH:22][S:23][C:19]=2[CH2:18][CH2:17][NH:16]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[S:23][CH:22]=[CH:21][C:20]=4[C:15]3([CH3:24])[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1(C)NCCc2sccc21
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: CC1(C)c2ccsc2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 4,4-dimethyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine to provide the title compound in moderate yield.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=2)=[N:8][O:9][C:10]=1[CH3:11])=O)C.O.[OH-].[Na+]>C1COCC1>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:7]2[C:6]([CH2:4][OH:3])=[C:10]([CH3:11])[O:9][N:8]=2)=[N:13][CH:14]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cn2)noc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1onc(-c2ccc(F)cn2)c1CO
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.6 %

Procedure:
To a solution of 3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester (2.5 g, 10 mmol) in dry THF (34 mL), cooled to 0° C., was added lithiumaluminumhydride (209 mg, 2.3 mmol) portionwise. After allowing to warm up to room temperature over 1 h, the mixture was cooled to 0° C. and water (0.2 mL) was added carefully followed by aqueous sodium hydroxide (15%, 0.2 mL) and water (0.6 mL). The resulting suspension was stirred for 4 h at ambient temperature and filtered over Hyflo®. The filtrate was then concentrated and purification by chromatography (SiO2, heptane:ethyl acetate=50:50 to 0:100) afforded the title compound (1.47 g, 71%) as a light yellow solid. MS: m/e=209.1 [M+H]+.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[Cl:29])[CH:20]=[C:21]([F:22])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[F:22][C:21]1[C:15]2[O:14][CH:13]([CH2:12][NH:31][CH3:30])[CH2:17][C:16]=2[CH:18]=[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(-c4ccccc4Cl)cc(F)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cc(-c3ccccc3Cl)cc(F)c2O1

Procedure:
The title compound was prepared (0.068 g, 47%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-fluoro-5-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.199 g, 0.46 mmol) and methylamine (0.28 g, 9.2 mmol). mp 217-222° C. (dec).
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][C:5]1[C:6]([CH3:27])=[N:7][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([OH:26])[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[C:9]=1[CH3:10].[OH-].[Na+].O.Cl>O1CCOCC1>[OH:26][CH:18]([C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:8]2[C:9]([CH3:10])=[C:5]([CH2:4][C:3]([OH:28])=[O:2])[C:6]([CH3:27])=[N:7]2)=[CH:13][CH:14]=1)[CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)Cc1c(C)nn(Cc2ccc(C(O)Cc3ccccc3)cc2)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nn(Cc2ccc(C(O)Cc3ccccc3)cc2)c(C)c1CC(=O)O
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
{1-[4-(1-Hydroxy-2-phenyl-ethyl)-benzyl]-3,5-dimethyl-1H-pyrazol-4-yl}-acetic acid methyl ester (intermediate 15.1.2, 110 mg, 0.29 mmol) was dissolved in 3 ml dioxane and aqueous NaOH solution (0.58 ml, 1 M) was added. After stirring for 2.5 h at 60° C. and dilution with water, aqueous HCl solution (0.61 ml, 1 M) was added. The mixture was extracted with ethyl acetate, and the organic layer was dried with MgSO4 and evaporated under reduced pressure. The residue was lyophilized.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([C:14]2[CH:15]=[C:16]([OH:25])[CH:17]=[C:18]([O:20][C:21]([F:24])([F:23])[F:22])[CH:19]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[C:26]1(O)C=CC=CC=1.IC>C1COCC1>[CH3:26][O:25][C:16]1[CH:15]=[C:14]([C:5]2[N:4]=[N:3][C:2]([NH2:1])=[N:7][C:6]=2[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:19]=[C:18]([O:20][C:21]([F:24])([F:22])[F:23])[CH:17]=1
Reactant: Oc1ccccc1
Reactant: Nc1nnc(-c2cc(O)cc(OC(F)(F)F)c2)c(-c2ccccc2)n1
Solvent: CI
Solvent: C1CCOC1
Product: COc1cc(OC(F)(F)F)cc(-c2nnc(N)nc2-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
6-(3-Methoxy-5-(trifluoromethoxy)phenyl)-5-phenyl-1,2,4-triazin-3-amine was prepared from 3-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-5-(trifluoromethoxy)phenol (100 mg, 0.287 mmol). The phenol was dissolved in THF (2 mL) and treated with iodomethane (17.87 μL, 0.287 mmol) at 0° C. After ˜15 minutes, the mixture was then allowed to warm to r.t. slowly.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][CH:4]=1.C1C(=O)N([Br:20])C(=O)C1>CN(C=O)C>[Br:20][C:4]1[CH:5]=[C:6]([N+:10]([O-:12])=[O:11])[C:7]([NH2:9])=[N:8][C:3]=1[O:2][CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc([N+](=O)[O-])c(N)n1
Solvent: CN(C)C=O
Product: COc1nc(N)c([N+](=O)[O-])cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a stirred solution of 6-methoxy-3-nitropyridin-2-amine (1.56 g, 9.2 mmol) in 15 mL of DMF at rt was added N-bromosuccimide (1.81 g, 10.1 mmol) in portions. The resulting mixture was stirred at rt for 1 h. TLC showed the reaction was complete. The reaction mixture was quenched with water and the reddish brown solid was collected by filtration, washed with water, and dried in a vacuum oven to give 5-bromo-6-methoxy-3-nitropyridin-2-amine (2.1 g, 92%). LCMS (ESI) m/z 248, 250 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C@@H:13]([NH2:39])[C@@H:14]([NH:16][CH2:17][C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=2[C:28]2[CH:33]=[C:32]([CH:34]([CH3:36])[CH3:35])[CH:31]=[CH:30][C:29]=2[O:37][CH3:38])[CH3:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N(CC)CC)C.C1C=CC(O[C:56](OC2C=CC=CC=2)=[N:57][C:58]#[N:59])=CC=1>ClC(Cl)C>[F:1][C:2]([F:40])([F:41])[C:3]1[CH:4]=[C:5]([C@@H:13]2[C@H:14]([CH3:15])[N:16]([CH2:17][C:18]3[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:20][C:19]=3[C:28]3[CH:33]=[C:32]([CH:34]([CH3:35])[CH3:36])[CH:31]=[CH:30][C:29]=3[O:37][CH3:38])[C:56](=[N:57][C:58]#[N:59])[NH:39]2)[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN[C@@H](C)[C@H](N)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=NC#N)N[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 60 °C

Procedure:
To a solution of (1R,2S)-1-[3,5-bis(trifluoromethyl)phenyl]-N2-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}propane-1,2-diamine (25.1 mg, 0.0424 mmol) in dichloroethane (1.5 mL) was added triethylamine (15 μL, 0.105 mmol) and diphenyl cyanocarbonimidate (13 mg, 0.053 mmol). The reaction was heated at 60° C. overnight, cooled to room temperature, filtered, and loaded directly onto a silica gel column for purification by flash chromatography with 10 to 40% EtOAc/hexanes to afford ((4R,5S)-4-[3,5-bis(trifluoromethyl)phenyl]-1-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-methylimidazolidin-2-ylidene)cyanamide. Rf=0.20 (25% EtOAc/hexanes). LCMS=643.3 (M+1)+. 1H NMR (C6D6, 500 MHz; atropisomers present, doubling of some peaks) δ 6.53-8.83 (m, 10H), 3.61-4.91 (m, 3H), 3.28-2.70 (m, 5H), 1.14-1.25 (m, 6H), −0.39-0.26 (m, 3H).
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[C:22]([C:23](O)=[O:24])=[CH:21][N:20]=[CH:19][N:18]=1)[CH3:15].CCN=C=NCCCN(C)C.Cl.N1C=CC=CC=1>C1C=CC2N(O)N=NC=2C=1.O>[CH3:1][NH:2][C:3]1[C:8]([NH:9][C:23]([C:22]2[C:17]([S:16][CH2:14][CH3:15])=[N:18][CH:19]=[N:20][CH:21]=2)=[O:24])=[CH:7][C:6]([C:10]([F:13])([F:11])[F:12])=[CH:5][N:4]=1
Reactant: CCSc1ncncc1C(=O)O
Reactant: CNc1ncc(C(F)(F)F)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Solvent: O
Product: CCSc1ncncc1C(=O)Nc1cc(C(F)(F)F)cnc1NC
Temperature: 60 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
A mixture of 1.04 g of N2-methyl-5-trifluoromethylpyridine-2,3-diamine, 1.00 g of 4-ethylsulfanylpyrimidine-5-carboxylic acid, 1.57 g of EDCI hydrochloride, 73 mg of HOBt and 5 ml of pyridine was stirred at 60° C. for 4 hours. Water was poured to the cooled reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 1.94 g of 4-ethylsulfanylpyrimidine-5-carboxylic acid (2-methylamino-5-trifluoromethylpyridin-3-yl)-amide. 4-Ethylsulfanylpyrimidine-5-carboxylic acid (2-methylamino-5-trifluoromethylpyridin-3-yl)-amide
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4]/[CH:5]=[CH:6]/[C:7]1[N:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]2=[N:9][C:8]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].[H][H]>C(OCC)(=O)C.[C].[Pd]>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:11]2[CH2:12][CH2:13][CH2:14][CH2:15][C:10]2=[N:9][C:8]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)c1nc2ccccn2c1/C=C/CCOC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc2n(c1CCCCOC)CCCC2
Reaction time: 12 h
Yield: 79.7 %

Procedure:
Ethyl 3-[(1E)-4-methoxybut-1-en-1-yl]imidazo[1,2-a]pyridine-2-carboxylate (1.40 g) was dissolved in ethyl acetate (30 ml), 10% palladium carbon (50% in water) (510 mg) was added and the mixture was stirred in a hydrogen stream at ambient temperature and normal pressure for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-methanol (5:1) was concentrated under reduced pressure to give the object product (1.14 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][CH:10]([CH2:13][OH:14])[O:9][C:8]=2[CH:15]=1)([O-:3])=[O:2].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>N1C=CC=CC=1>[CH3:26][C:16]1[CH:21]=[CH:20][C:19]([S:22]([O:14][CH2:13][CH:10]2[O:9][C:8]3[CH:15]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=3[O:12][CH2:11]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=[N+]([O-])c1ccc2c(c1)OC(CO)CO2
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc([N+](=O)[O-])cc3O2)cc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
A 500 mL round bottomed flask equipped with a magnetic stir bar is charged with [7-nitro-2,3-dihydro-1,4-benzodioxin-2-yl]methanol (37.3 g, 177 mmol) and anhydrous pyridine (150 mL). The solution is cooled to 5° C. and p-toluenesulfonyl chloride (42.1 g, 221 mmol) is added in one portion. After 1 h, the cooling bath is removed, and the solution is stirred for another 3 h. The reaction mixture is poured into a rapidly stirred flack containing water (750 mL). The precipitate is collected by vacuum filtration, and the filter cake is rinsed with water and suction dried to give the title compound (63.8 g, 99%) as yellow granules. LCMS (Standard Method): 2.81 min, 388 (M+Na)+. 1H NMR (300 MHz, DMSO-d6) δ7.79-7.72 (m, 3H), 7.49-7.42 (m, 3H), 7.06 (d, J=8.8 Hz, 1H), 4.59-4.55 (m, 1H), 4.41 (dd, J=2.6, 11.6 Hz, 2H), 4.22 (dd, J=6.3, 11.5 Hz, 1H), 4.12 (dd, J=6.8, 11.7 Hz, 1H), 2.38 (s, 3H).