Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[NH:11][N:10]=2)[C:5]([F:17])=[CH:4][N:3]=1.Cl.[F:19][C:20]1[CH:21]=[N:22][C:23]([C@@H:26]([NH2:28])[CH3:27])=[N:24][CH:25]=1.CCN(C(C)C)C(C)C>CCCCO>[CH3:15][N:14]([CH3:16])[C:12]1[NH:11][N:10]=[C:9]([NH:8][C:6]2[C:5]([F:17])=[CH:4][N:3]=[C:2]([NH:28][C@H:26]([C:23]3[N:24]=[CH:25][C:20]([F:19])=[CH:21][N:22]=3)[CH3:27])[N:7]=2)[CH:13]=1
Reactant: CN(C)c1cc(Nc2nc(Cl)ncc2F)n[nH]1
Reactant: C[C@H](N)c1ncc(F)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncc(F)c(Nc2cc(N(C)C)[nH]n2)n1)c1ncc(F)cn1
Temperature: 160 °C
Yield: 67.8 %

Procedure:
A microwave reaction vessel was charged with N3-(2-chloro-5-fluoropyrimidin-4-yl)-N5,N5-dimethyl-1H-pyrazole-3,5-diamine (Method 35, 50 mg, 0.2 mmol), (S)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7, 50 mg, 0.23 mmol), and DIPEA (0.15 ml, 0.86 mmol) in n-BuOH (1 ml) was heated in a microwave reactor at 160° C. for 2 hours. Solvent was removed. The residue was purified by silica gel chromatography (by ISCO Combiflash with gradient 0-5% Methanol in methylene chloride with 1% NH4OH) to afford the title compound as a white solid (49 mg, 67%). 1H NMR (CD3OD, 400 MHz) δ 8.77 (s, 2H), 8.23 (s, 1H), 5.32 (br, 1H), 3.92 (q, 1H), 3.13 (s, 6H), 1.71 (d, 3H); m/z 362
Reaction SMILES: O(P(O[C:18]1[N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=1)(OC1C=CC=CC=1)=O)C1C=CC=CC=1.B([C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37]([OH:39])=[O:38])(O)O>>[C:27]([O:26][C:24]([N:19]1[C:18]([C:34]2[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=2)[C:37]([OH:39])=[O:38])=[CH:23][O:22][CH2:21][CH2:20]1)=[O:25])([CH3:28])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCOC=C1OP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: O=C(O)c1cccc(B(O)O)c1
Product: CC(C)(C)OC(=O)N1CCOC=C1c1cccc(C(=O)O)c1
Yield: 26 %

Procedure:
This compound was prepared from tert-butyl 5-((diphenoxyphosphoryl)oxy)-2H-1,4-oxazine-4(3H)-carboxylate and 3-boronobenzoic acid using a procedure similar to that described in Example 2 (Steps 1-3a) above. The product was isolated as an off-white solid (26% yield); 1H-NMR (d6-DMSO) 1.01 (9H, s), 3.71 (2H, t), 4.12 (2H, t), 6.50 (1H, s), 7.40-7.46 (2H, m), 7.74-7.77 (2H, m), 12.94 (1H, brs); 13C-NMR (d6-DMSO) 27.7, 41.5, 66.8, 126.8, 128.0, 128.2, 130.1, 133.0; MS ES(+) 249.9 (M+-tBu). IR λmax=1694 cm−1.
Reaction SMILES: [C:1](Cl)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:4]1([CH:3]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:1](=[O:10])[CH2:2]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Nc1ccccc1
Reactant: O=C(Cl)C=Cc1ccccc1
Product: O=C1CC(c2ccccc2)c2ccccc2N1

Procedure:
4-Phenyl-3,4-dihydrocarbostyril (CAS# 4888-33-9) was prepared in two steps using the procedure described by Conley, R. T.; Knopka. W. N. J. Org. Chem. 1964, 29, 496-497. The starting materials for this preparation were cinnamoyl chloride (Aldrich) and aniline (Aldrich). The title compound was purified by flash chromatography eluting with CH2Cl2/EtOAc (4:1).
Reaction SMILES: [N:1]([C:4]([CH3:18])([CH3:17])[CH2:5][C:6]([N:8]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:10][CH2:11][CH3:12])=O)=[N+]=[N-].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:9]([N:8]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:6][CH2:5][C:4]([CH3:18])([NH2:1])[CH3:17])[CH2:10][CH2:11][CH3:12]
Reactant: CCCCN(CCCC)C(=O)CC(C)(C)N=[N+]=[N-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCN(CCCC)CCC(C)(C)N
Temperature: 70 °C
Reaction time: 17 h
Yield: 77 %

Procedure:
3-Azido-N,N-dibutyl-3-methylbutanamide (16.0 g, 61.8 mmol) was dissolved into anhdrous THF (100 mL, 0.2 M) and added dropwise to a suspension of LAH (4.60 g, 2.0 equiv, 0.124 mol) in anhydrous THF (150 mL) over 25 min. After complete addition, the flask was fitted with a condenser and the reaction heated in a 70° C. oil bath for 8 h. The reaction mixture was removed from the bath and stirred at room temperature for 17 h. The reaction mixture was cooled in an ice bath and water (4.6 mL) was added dropwise over 20 min. Then 15% NaOH solution (4.6 mL) was added dropwise over 10 min. The suspension was stirred for a further 10 min and water (9.0 mL) was added in one portion and the mixture stirred for 30 min to give a fine white suspension. The suspension was filtered through a pad of Celite® and the white cake was washed with isopropanol (3×150 mL) and the combined filtrate was concentrated on a rotovap and briefly dried under high vacuum give a pale yellow liquid (10.2 g, 76.9%). The crude product was used without further purification. LRMS (ESI+) for C13H30N2 (214.2); Found: 215 (MH+).
Reaction SMILES: ClC(OCC(C)C)=O.[C:9]([NH:19][CH2:20][C:21]([OH:23])=O)([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].CN1CCOCC1.[NH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][N:38]=[C:39]([NH:48][C:49](=[O:55])[O:50][C:51]([CH3:54])([CH3:53])[CH3:52])[NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44]>O1CCCC1>[CH3:53][C:51]([CH3:54])([O:50][C:49]([NH:48][C:39]([NH:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][NH:31][C:21](=[O:23])[CH2:20][NH:19][C:9]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10])=[N:40][C:41]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:47])=[O:55])[CH3:52]
Reactant: CC(C)(C)OC(=O)NC(=NCCCCCCN)NC(=O)OC(C)(C)C
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N=C(NCCCCCCNC(=O)CNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
A solution of 1.6 g (14×10-3 mol) of isobutyl chloroformate in 5 ml of tetrahydrofuran is added dropwise to a solution, cooled to -30° C., of 3 g (14×10-3 mol) of carbobenzyloxyglycine and 2.8 g (28×10-3 mol) of N-methylmorpholine in 50 ml of tetrahydrofuran. The reaction medium is stirred for 0.5 hour and a solution of 5.4 g (14×10-3 mol) of bis(1,1-dimethylethyl) [[(6-aminohexyl)imino]methylene]biscarbamate in 20 ml of tetrahydrofuran is added. Stirring is continued for 2 hours at -30° C. and then for 24 hours at room temperature. After filtration of the reaction medium and evaporation of the filtrate under reduced pressure, the residue obtained is purified by chromatography on silica using an ethyl acetate/methylcyclohexane mixture (1/1 v/v) as the eluent to give 7.16 g (yield: 91%) of the expected product in the form of an oil.
Reaction SMILES: [CH:1]1([NH:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Mg]Br.[F:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:19]=1[C:20]#[N:21]>C1(C)C=CC=CC=1.C(OCC)C>[CH:8]1([N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:20](=[NH:21])[C:19]2[C:18]([F:17])=[CH:25][CH:24]=[CH:23][C:22]=2[F:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: C1CCC(NC2CCCCC2)CC1
Reactant: N#Cc1c(F)cccc1F
Agent: C[Mg]Br
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: N=C(c1c(F)cccc1F)N(C1CCCCC1)C1CCCCC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
Dicyclohexylamine (9.06 g, 50.1 mmol) was dissolved in toluene (125 mL). The solution was warmed to 50° C. and a solution of methylmagnesiumbromide was added (16.7 mL, 3.0 M in diethylether, 50.1 mmol) and the reaction mixture was stirred for 2 hours at 50° C. The mixture was cooled to 0° C. and 2,6-difluorobenzonitrile (6.80 g, 48.9 mmol). After 45 hours, the reaction mixture was quenched with a solution of ammoniumchloride in water (3.0 g in 80 mL). The water and organic phases were separated and the water layer was extracted 3 times with diethylether (40 mL). The combined organic solutions were dried over sodium sulphate. The sodium sulphate was filtered off and the filtrate was evaporated to dryness yielding 14.2 g (89%) of the product. The product was characterized by 1H NMR (300 MHz) (CDCl3) δ (ppm): 7.2 (pent, 1H), 6.8 (dd, 2H), 5.9 (bs, 1H), 3.5-2.3 (bm, 3H), 1.9-0.6 (bm, 19H), by 13C NMR (75 MHz) (CDCl3) δ (ppm): 158.9 (dd, J=248 Hz, J=8 Hz) 156.4, 130.1, 130.0, 129.8, 118.8, 118.4, 118.1, 12.1, 111.7, 61.3 (bs), 56.9 (bs), 32.0 (bs), 30.1 (bs), 26.8 (bs), 25.8 and by 19F NMR (282 MHz) (CDCl3) δ (ppm): −114.3 (s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH:7](O)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[SH:19][C:20]1C=C[C:23]([B:26]([OH:28])[OH:27])=[CH:22][CH:21]=1>CC(O)=O>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH:7]([C:21]2[CH:22]=[C:23]([B:26]([OH:28])[OH:27])[S:19][CH:20]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(O)c2ccc(OC)cc2)cc1
Reactant: OB(O)c1ccc(S)cc1
Solvent: CC(=O)O
Product: COc1ccc(C(c2ccc(OC)cc2)c2csc(B(O)O)c2)cc1
Temperature: 60 °C

Procedure:
4,4′-Dimethoxybenzhydrol (2.7 g, 11 mmol) and 4-mercaptophenylboronic acid (1.54 g, 10 mmol) were dissolved in AcOH (20 mL) and heated at 60° C. for 1 h. Solvent was evaporated and the residue was dried under high vacuum. This material was used without further purification.
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][C@H:13]2[O:18][C@@:17]3([C:26]4[C:21](=[CH:22][C:23]([Cl:36])=[C:24]([CH2:27][C:28]5[CH:33]=[CH:32][C:31]([CH2:34][CH3:35])=[CH:30][CH:29]=5)[CH:25]=4)[CH2:20][O:19]3)[C@H:16]([OH:37])[C@@H:15]([OH:38])[C@@H:14]2[OH:39])(=O)=O)=CC=1.[CH3:40][O-].[Na+]>>[Cl:36][C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][C:24]=1[CH2:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][CH3:33])=[CH:30][CH:29]=1)[C@:17]1([C@H:16]([OH:37])[C@@H:15]([OH:38])[C@H:14]([OH:39])[C@@H:13]([CH2:12][O:11][CH3:40])[O:18]1)[O:19][CH2:20]2
Reactant: C[O-]
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)CO[C@]32O[C@H](COS(=O)(=O)c3ccc(C)cc3)[C@@H](O)[C@H](O)[C@H]2O)cc1
Agent: [Na+]
Product: CCc1ccc(Cc2cc3c(cc2Cl)CO[C@]32O[C@H](COC)[C@@H](O)[C@H](O)[C@H]2O)cc1
Reaction time: 8 h

Procedure:
To ((1S,3′R,4′S,5′S,6′R)-5-chloro-6-(4-ethylbenzyl)-3′,4′,5′-trihydroxy-3′,4′,5′,6′-tetrahydro-3H-spiro[isobenzofuran-1,2′-pyran]-6′-yl)methyl 4-methylbenzenesulfonate (14 mg, 0.0243 mmol) was added 1 mL of freshly prepared sodium methoxide solution (3 M). After stirring overnight, the reaction was quenched with 2 mL of water. The organic solvent was distilled off and the water layer was extracted with ethyl acetate. The combined organic layers were washed with brine prior to drying over Na2SO4. Concentration under reduced pressure provided the crude product, which was purified by preparative TLC to give 7 mg of title compound. 1H NMR (CD3OD, 400 MHz) δ 7.36 (s, 1H), 7.23 (s, 1H), 7.10 (s, 4H), 5.13 (d, J=13.0 Hz, 1H), 5.07 (d, J=13.0 Hz, 1H), 4.09 (s, 2H), 3.91-3.86 (m, 1H), 3.76-3.67 (m, 2H), 3.62-3.55 (m, 2H), 3.43 (dd, J=10.4, 8.4 Hz, 1H), 3.31 (m, 3H), 2.60 (q, J=7.6 Hz, 2H), 1.20 (t, J=7.6 Hz, 3H); MS ESI (m/z) 435 (M+1)+, calc. 434.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[O:7][CH2:8][C:9](OCC)=[O:10])([O-:3])=[O:2].Cl.CN.[CH:20]([N:23](C(C)C)CC)(C)C>CO.O>[CH3:20][NH:23][C:9](=[O:10])[CH2:8][O:7][C:6]1[CH:14]=[CH:15][CH:16]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)COc1cccc([N+](=O)[O-])c1
Agent: CN
Agent: Cl
Solvent: O
Solvent: CO
Product: CNC(=O)COc1cccc([N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 6 h
Yield: 95 %

Procedure:
A mixture of ethyl 3-nitrophenoxyacetate (9.12 g, 40 mmol), methylamine hydrochloride (26.8 g, 400 mmol) and diisopropylethylamine (35.5 mL, 200 mL) in MeOH (100 mL) was stirred in a pressure vial at 90° C. for 6 h. The reaction was cooled to room temperature, diluted with water (1 liter), the solid formed was filtered, washed with water and dried to get the desired N-methyl 3-nitrophenoxyacetamide (8 g, 95%). 1H NMR CDCl3): δ 7.91 (dd, 1H, J=1.8 and 8.1 Hz), 7.78 (t, 1H, J=2.4 Hz), 7.50 (t, 1H, J=8.7 Hz), 7.29 (dd, 1H, J=1.8 and 8.4 Hz), 6.50 (bs, 2H), 4.57 (s, 2H), 2.95 and 2.93 (2s, 3H); LCMS: ret. time: 17.54 min.; purity: 100%; MS (m/e): 211 (MH+).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:10]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][NH:23][CH3:24])[CH2:17][CH2:16]2)=[N:11][CH:12]=[CH:13][N:14]=1.Cl.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([S:32](Cl)(=[O:34])=[O:33])[CH:27]=1>ClCCl.C(=O)(O)[O-].[Na+]>[Cl:8][C:9]1[C:10]([N:15]2[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][N:23]([CH3:24])[S:32]([C:28]3[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=3)(=[O:34])=[O:33])[CH2:19][CH2:20]2)=[N:11][CH:12]=[CH:13][N:14]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CNCCN1CCN(c2nccnc2Cl)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CCN1CCN(c2nccnc2Cl)CC1)S(=O)(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91 %

Procedure:
Add triethylamine (0.426 mL, 3.058 mmol) to a stirring solution of [2-(3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)-ethyl]-methyl-amine (0.200 g, 0.612 mmol) in dichloromethane (5 mL). Add pyridine-3-sulfonyl chloride hydrochloride salt (0.157 g, 0.734 mmol) at room temperature. Stir at room temperature for 20 min. Dilute with dichloromethane and saturated aqueous sodium bicarbonate. Separate and extract the aqueous fraction with dichloromethane. Combine the organic fractions, dry over sodium sulfate, filter, and concentrate. Purify the resulting material by silica gel chromatography eluting with hexanes:acetone 4:1 to afford the title preparation (0.220 g, 91% yield). MS ES: m/z=397 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[CH:8][C:9]=1[NH2:10])([O-:3])=[O:2].C(=O)([O-])[O-].[Ca+2].Cl[C:18]([O:20][CH2:21][CH2:22][CH2:23][Cl:24])=[O:19]>C(COC)OC>[N+:1]([C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[CH:8][C:9]=1[NH:10][C:18](=[O:19])[O:20][CH2:21][CH2:22][CH2:23][Cl:24])([O-:3])=[O:2]
Reactant: O=C(Cl)OCCCCl
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: COCCOC
Product: O=C(Nc1ccc(O)cc1[N+](=O)[O-])OCCCCl
Reaction time: 1 h

Procedure:
77 g (0.5 mole) of 3-nitro-4-aminophenol are dissolved in 200 ml of dimethoxy ethane, 27 g of calcium carbonate are added, and 80 g (0.51 mole) of γ-chloropropyl chloroformate are added dropwise at 70° C. After 1 hour, the reaction mixture is filtered hot and the filtrate is stirred into 700 ml of ice-water, after which 128 g (93%) of the desired compound precipitate. The melting point is 103°-105° C., and after recrystallisation from toluene is 106° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15](=[N:24][NH2:25])[NH:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[Cl:23])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1.C1N=CN([C:32](N2C=NC=C2)=[O:33])C=1>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]4[N:16]([C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=5[Cl:23])[C:32](=[O:33])[NH:25][N:24]=4)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NN=C(Nc1ccccc1Cl)c1cc2c(s1)-c1ccc(Br)cc1OCC2
Solvent: O
Solvent: C1CCOC1
Product: O=c1[nH]nc(-c2cc3c(s2)-c2ccc(Br)cc2OCC3)n1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
A solution of 8-bromo-N-(2-chlorophenyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carbohydrazonamide (200 mg, 0.45 mmol) in anhydrous THF (8 mL) was treated with CDI (145 mg, 0.89 mmol) and stirred at room temperature overnight, diluted with water. The solid was washed with water and dried in vacuum to give 3-(8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)-4-(2-chlorophenyl)-1H-1,2,4-triazol-5(4H)-one (195 mg, yield: 92%). ESI-MS: 473.96
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:14]([CH3:16])=O)[C:12]=2[OH:13])=[CH:4][CH:3]=1.[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][NH:23][C:24]([C:26]1[S:27][C:28]([C:31]([NH:33][NH2:34])=[O:32])=[CH:29][CH:30]=1)=[O:25]>CC(O)C>[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][NH:23][C:24]([C:26]1[S:27][C:28]([C:31]([NH:33][N:34]=[C:14]([C:11]2[C:12]([OH:13])=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)[S:9][CH:10]=2)[CH3:16])=[O:32])=[CH:29][CH:30]=1)=[O:25]
Reactant: CC(=O)c1csc(-c2ccc(Br)cc2)c1O
Reactant: NNC(=O)c1ccc(C(=O)NCc2ccco2)s1
Solvent: CC(C)O
Product: CC(=NNC(=O)c1ccc(C(=O)NCc2ccco2)s1)c1csc(-c2ccc(Br)cc2)c1O
Temperature: 25 °C
Yield: 72 %

Procedure:
2-(4-Bromophenyl)-3-hydroxy-4-methylcarbonylthiophene (50.1 mg, 0.17 mmol) and 5-hydrazinocarbonylthiophene-2-carboxylic acid (furan-2-ylmethyl)amide (45.0 mg, 0.17 mmol) prepared in Reference Synthetic Example 13 in 2-propanol (4.0 mL) were heated with p-tosylic acid monohydrate (6 mg) at 100° C. for 7.5 hours and cooled to room temperature. The precipitated solid was recovered by filtration, washed with 2-propanol (1 mL) and dried to give the desired product (yield 72%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:39][CH3:40])=[C:6]([C:8]([CH3:38])([CH3:37])[CH2:9][C:10]([OH:36])([C:32]([F:35])([F:34])[F:33])[CH2:11][NH:12][C:13]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]3[C:14]=2[CH:15]=[N:16][N:17]3[C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26](O)=[O:27])[CH:7]=1.[NH:41]1[CH2:48][CH2:47][CH2:46][C@H:42]1[C:43]([NH2:45])=[O:44]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:39][CH3:40])=[C:6]([C:8]([CH3:37])([CH3:38])[CH2:9][C:10]([OH:36])([C:32]([F:34])([F:35])[F:33])[CH2:11][NH:12][C:13]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]3[C:14]=2[CH:15]=[N:16][N:17]3[C:23]2[CH:24]=[C:25]([C:26]([N:41]3[CH2:48][CH2:47][CH2:46][C@H:42]3[C:43]([NH2:45])=[O:44])=[O:27])[CH:29]=[CH:30][CH:31]=2)[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)O)c1)C(F)(F)F
Reactant: NC(=O)[C@@H]1CCCN1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)N2CCC[C@H]2C(N)=O)c1)C(F)(F)F

Procedure:
Prepared similarly to Example 1 from 3-(4-{[4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazol-1-yl)benzoic acid and L-prolinamide with System A used for purification by mass directed autopreparation
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH:12][C:13]([N:15]2[CH2:20][CH2:19][N:18](CC3C=CC=CC=3)[CH2:17][CH2:16]2)=[O:14])[C:6]([O:10][CH3:11])=[N:7][C:8]=1[CH3:9])[CH3:2].C(O)C>[Pd].C(O)(=O)C>[CH2:1]([C:3]1[CH:4]=[C:5]([NH:12][C:13]([N:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)=[O:14])[C:6]([O:10][CH3:11])=[N:7][C:8]=1[CH3:9])[CH3:2]
Reactant: CCc1cc(NC(=O)N2CCN(Cc3ccccc3)CC2)c(OC)nc1C
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CCc1cc(NC(=O)N2CCNCC2)c(OC)nc1C
Reaction time: 4 h
Yield: 93.5 %

Procedure:
After 1-[(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4-benzyl piperazine (1.71 g, 4.61 mmol) was added the solution of 30 ml of ethanol and 10 ml of glacial acetic acid in the presence of 5% Pd/C, the reaction mixture were stirred under hydrogen gas(40 psi) for 4 hours and extracted with dichloromethane. The mixture was dried with anhydrous magnesium sulfate, filtrated, concentrated and chromatographed to obtain 1.2 g of white solid of the titled compound.
Reaction SMILES: [NH:1]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:2]([C:15](O)=[O:16])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH:13]=[O:14])[CH:5]=1.Cl.[NH2:26][C@H:27]([C:35]([N:37]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH3:38])=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[NH:1]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[C@@H:2]([C:15]([NH:26][C@H:27]([C:35]([N:37]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH3:38])=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:16])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH:13]=[O:14])[CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1cn(C=O)c2ccccc12)C(=O)O
Reactant: CN(Cc1ccccc1)C(=O)[C@@H](N)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CN(Cc1ccccc1)C(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](Cc1cn(C=O)c2ccccc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 86.8 %

Procedure:
Boc-D-Trp(CHO)-OH (3.26 g), HCl.H-Phe-NMeBzl (2.99 g) and HOBT (1.32 g) were dissolved in DMF (40 ml). To this solution was added WSC under ice cooling. The reaction mixture was stirred for an hour at this temperature and for additional an hour at room temperature. After evaporation and extraction with ethyl acetate, the organic layer was washed successively with diluted sodium hydrogencarbonate solution, water, 0.5N hydrochloric acid, and sodium chloride solution and dried over magnesium sulfate. The evaporated residue was crystallized from a mixed solvent of ethyl acetate and diisopropyl ether (3:4) (35 ml) with seeding. The crystals were collected by filtration after addition of diisopropyl ether (55 ml) and dried to give Boc-D-Trp(CHO)-Phe-NMeBzl (4.96 g).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[C:6]([CH:7]=O)[C:5]=1[OH:15])([O-:3])=[O:2].[CH3:16][O:17][C:18]1[CH:31]=[CH:30][C:21]([CH2:22][S:23]([CH2:26][C:27](O)=[O:28])(=[O:25])=[O:24])=[CH:20][CH:19]=1>C(O)(=O)C>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][S:23]([C:26]2[C:27](=[O:28])[O:15][C:5]3[C:6]([CH:7]=2)=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:4]=3[N+:1]([O-:3])=[O:2])(=[O:24])=[O:25])=[CH:30][CH:31]=1
Reactant: O=Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1O
Reactant: COc1ccc(CS(=O)(=O)CC(=O)O)cc1
Solvent: CC(=O)O
Product: COc1ccc(CS(=O)(=O)c2cc3cc([N+](=O)[O-])cc([N+](=O)[O-])c3oc2=O)cc1

Procedure:
A solution of 3,5-dinitrosalicylaldehyde (1 mmol) and 2-(4-methoxybenzylsulfonyl)acetic acid (1 mmol) in acetic acid (10 mL) was subjected to the General Procedure 2, Method A to yield the title compound.
Reaction SMILES: Cl.C([O:4][C:5](=O)[CH2:6][NH:7][CH3:8])C.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([O:20][CH3:21])=[C:15]([N:17]=[C:18]=[S:19])[CH:16]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([O:20][CH3:21])=[C:15]([N:17]2[C:5](=[O:4])[CH2:6][N:7]([CH3:8])[C:18]2=[S:19])[CH:16]=1
Reactant: COc1ccc(Cl)cc1N=C=S
Reactant: CCOC(=O)CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(Cl)cc1N1C(=O)CN(C)C1=S
Temperature: 25 °C
Yield: 87.2 %

Procedure:
A mixture of sarcosine ethyl ester hydrochloride (7.68 g), 5-chloro-2-methoxyphenyl-isothiocyanate (10.0 g), triethylamine (10.0 g) and chloroform (150 mL) was heated at reflux for 4.5 hours. The mixture was cooled to ambient temperature. The precipitated solid was collected, washed with chloroform and air dried to give the title compound (11.8 g) as an off-white solid, m.p. 245°-247° C. Anal. Calcd. for C11H11Cl N2O S: C, 48.80; H, 4.10; N,10.35. Found: C, 48.42; H, 3.96; N, 10.33. Mass spectrum (El, M.+) m/z 270.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:13]2[C:14]([NH:18]C(C)(CC(C)(C)C)C)=[N:15][CH:16]=[CH:17][C:12]=2[N:11]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH:10]=1>ClCCl>[NH2:18][C:14]1[C:13]2[C:9]([Cl:8])=[CH:10][N:11]([C:27]([O:29][CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[O:28])[C:12]=2[CH:17]=[CH:16][N:15]=1
Reactant: CC(C)(C)CC(C)(C)Nc1nccc2c1c(Cl)cn2C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nccc2c1c(Cl)cn2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.8 %

Procedure:
Trifluoroacetic acid (1.5 mL) was added drop wise to an ice-cooled suspension of benzyl 3-chloro-4-[(2,4,4-trimethylpentan-2-yl)amino]-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (610 mg) in dichloromethane (10 mL). The reaction mixture was stirred at room temperature for about 4 hours. Upon completion, the reaction mixture was concentrated under vacuum and the residue was stirred in excess aqueous ammonia solution. The precipitated solid was filtered under suction, washed with water and dried to afford benzyl 4-amino-3-chloro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (354.8 mg, 95%) as an off-white solid.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].[CH3:25][C:26]1[S:30][CH:29]=[N:28][CH:27]=1>>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([C:29]3[S:30][C:26]([CH3:25])=[CH:27][N:28]=3)=[O:5])[N:7]=[CH:8]2)[CH:12]=1
Reactant: Cc1cncs1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3Cl)c2)cn1
Product: Cc1cnc(C(=O)c2cn(-c3cccc(-c4ccccc4Cl)c3)cn2)s1

Procedure:
This compound is prepared by method C using compound 12e and 5-methylthiazole