Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:11]([CH3:12])=[CH:10][C:9]2[N:8]=[CH:7][N:6]=[C:5]([N:13]3[CH2:19][C:18]4[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:17]=4[O:16][CH2:15][CH2:14]3)[C:4]=2[CH2:3]1.[NH2:28][C:29]1[C:34]([S:35]([NH:38][CH2:39][CH:40]2[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]2)(=[O:37])=[O:36])=[CH:33][C:32](Br)=[CH:31][N:30]=1>>[NH2:28][C:29]1[C:34]([S:35]([NH:38][CH2:39][CH:40]2[CH2:41][CH2:42][N:43]([CH3:46])[CH2:44][CH2:45]2)(=[O:37])=[O:36])=[CH:33][C:32]([C:21]2[CH:22]=[CH:23][C:17]3[O:16][CH2:15][CH2:14][N:13]([C:5]4[C:4]5[CH2:3][C:2]([CH3:1])([CH3:27])[C:11]([CH3:12])=[CH:10][C:9]=5[N:8]=[CH:7][N:6]=4)[CH2:19][C:18]=3[CH:20]=2)=[CH:31][N:30]=1
Reactant: CC1=Cc2ncnc(N3CCOc4ccc(B(O)O)cc4C3)c2CC1(C)C
Reactant: CN1CCC(CNS(=O)(=O)c2cc(Br)cnc2N)CC1
Product: CC1=Cc2ncnc(N3CCOc4ccc(-c5cnc(N)c(S(=O)(=O)NCC6CCN(C)CC6)c5)cc4C3)c2CC1(C)C

Procedure:
Prepared according to the method of example 5 by using [4-(6,6,7-trimethyl-5,6-dihydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (reagent preparation 23) and 2-amino-5-bromo-N-((1-methylpiperidin-4-yl)methyl)pyridine-3-sulfonamide (reagent preparation 25) in step 1. 1H NMR (400 MHz, DMSO-d6) δ 8.50 (d, 1H), 8.37 (s, 1H), 8.03 (d, 1H), 7.84 (t, 1H), 7.55 (d, 1H), 7.45 (dd, 1H), 7.02 (d, 1H), 6.67 (br s, 2H), 6.13 (d, 1H), 4.62 (s, 2H), 4.37-4.29 (m, 2H), 3.88-3.78 (m, 2H), 2.72-2.60 (m, 6H), 2.07 (s, 3H), 1.88 (s, 3H), 1.74-1.62 (m, 2H), 1.61-1.50 (m, 2H), 1.34-1.16 (m, 1H), 1.09-0.95 (m, 2H), 0.91 (s, 6H); MS (EI) for C32H41N7O3S: 604 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.N1C=CC=CC=1.[C:32]([C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1)([CH3:35])([CH3:34])[CH3:33]>ClCCl>[C:32]([C:36]1[CH:37]=[CH:38][C:39]([C:40]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:16]=[C:15]4[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]4=[O:17])=[CH:10][CH:9]=3)=[N:6][CH:7]=2)=[O:41])=[CH:43][CH:44]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cn3)cc2C1=O
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(C)(C)C)cc4)cn3)cc2C1=O
Reaction time: 0.08 h

Procedure:
To a solution of compound of example 392 (100 mg, 0.295 mmol) in dichloromethane (3 mL), pyridine (70.53 mg, 0.885 mmol) was added and stirred for 5 min. To the reaction mixture, 4-tert-butylbenzoyl chloride (87.27 mg, 0.443 mmol) was added and stirred for about 16 h. After completion of the reaction, the solvent was evaporated and the crude material obtained was triturated with diethyl ether to obtain the title compound, which was filtered and dried.
Reaction SMILES: [C:1]([C:3]1[C:4]([OH:10])=[N:5][C:6]([OH:9])=[CH:7][CH:8]=1)#[N:2].[CH3:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](Cl)=[O:16]>>[C:1]([C:3]1[C:4]([OH:10])=[N:5][C:6]([O:9][C:15](=[O:16])[C:14]2[CH:18]=[CH:19][CH:20]=[C:12]([CH3:11])[CH:13]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(O)nc1O
Reactant: Cc1cccc(C(=O)Cl)c1
Product: Cc1cccc(C(=O)Oc2ccc(C#N)c(O)n2)c1
Yield: 57.9 %

Procedure:
The general procedure of Example 81 was followed using 2.00 g of 3-cyano-2,6-dihydroxypyridine and 2.27 g of 3-methylbenzoyl chloride, thereby producing 2.16 g of the title compound in a yield of 58%.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][C:22]([CH2:38][CH2:39][CH2:40][CH3:41])=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:27][CH:26]=3)[CH:24]=2)=[O:18])([F:14])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:42]>C(Cl)Cl.O1CCOCC1>[ClH:42].[ClH:42].[F:14][C:11]1([CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][C:22]([CH2:38][CH2:39][CH2:40][CH3:41])=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:27][CH:26]=3)[CH:24]=2)=[O:18])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CCCCc1nnc(C(=O)NCC2(F)CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCCCc1nnc(C(=O)NCC2(F)CCNCC2)cc1-c1ccc(OC2CCCCC2)cc1
Reaction time: 1 h

Procedure:
To a solution of 4-({[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carbonyl]-amino}-methyl)-4-fluoro-piperidine-1-carboxylic acid tert-butyl ester (70 mg) in DCM (2 mL) was added 4 N HCl in dioxane (1.0 mL), and the reaction was stirred for 1 h. The volatiles were removed under reduced pressure, and the residue was triturated with anhydrous ethyl ether and dried under high vacuum to provide 6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carboxylic acid (4-fluoro-piperidin-4-ylmethyl)-amide dihydrochloride.
Reaction SMILES: [NH:1]([C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH3:12])=[C:5]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[N:4]=1)[NH2:2].[CH3:24][C:25](=O)[CH2:26][C:27](=O)[CH3:28]>>[CH3:24][C:25]1[CH:26]=[C:27]([CH3:28])[N:1]([C:3]2[N:11]=[C:10]3[C:6]([N:7]=[CH:8][N:9]3[CH3:12])=[C:5]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=3)[N:4]=2)[N:2]=1
Reactant: CC(=O)CC(C)=O
Reactant: Cn1cnc2c(Nc3ccc(C(F)(F)F)cc3)nc(NN)nc21
Product: Cc1cc(C)n(-c2nc(Nc3ccc(C(F)(F)F)cc3)c3ncn(C)c3n2)n1

Procedure:
Was prepared according to Example 9 from (2-hydrazino-9-methyl-9H-purin-6-yl)-(4-trifluoromethyl-phenyl)-amine and 2,4-pentanedione.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[C@H:5]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[NH:6][C:7](=[O:21])[C@H:8]([CH3:20])[NH:9]C(OCC1C=CC=CC=1)=O)[CH3:2].C(OCC)C.[BrH:35]>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:29])[C@H:5]([CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[NH:6][C:7](=[O:21])[C@H:8]([CH3:20])[NH2:9])[CH3:2].[BrH:35]
Reactant: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)OCc1ccccc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)N
Reaction time: 1 h

Procedure:
Synthesis of p-hydroxybenzoyl-L-alanyl-L-phenylalanine: 0.1 g (0.1 mol) of triethylamine was added to a suspension of 23.0 g (0.1 mol) of L-phenylalanine ethyl ester·HCl in 500 ml of dichloromethane, and to this mixture in an ice bath was added 22.3 g (0.1 mol) of carbobenzoxy-L-alanine, and then 19.2 g (0.1 mol) of 1-ethyl-3(3-dimethyaminopropyl) carbodiimide·HCl was added to the mixture. This mixture was stirred for three hours. This reaction mixture was washed with a 0.1% aqueous solution of Na2CO3 three times and with a 0.1 N HCl solution three times, and then with distilled water three times. Thereafter, the mixture was dried over anhydrous sodium sulfate, and dichloromethane was removed from the mixture under reduced pressure to obtain carbobenzoxy-L-alanyl-L-phenylalanine ethyl ester. This ester was dissolved in 260 ml of 25% HBr in glacial acetic acid, and this solution was stirred for one hour. To this solution was added 5 l of absolute ethyl ether to produce a precipitate. The precipitate was filtered and washed with ethyl ether to obtain L-alanyl-L-phenylalanine ethyl ester·HBr.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[CH2:9]([O:8][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][N:5]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=c1cc(Br)cc[nH]1
Reactant: BrCc1ccccc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: c1ccccc1
Product: Brc1ccnc(OCc2ccccc2)c1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A mixture of 4-Bromo-1H-pyridin-2-one (0.613 g), silver carbonate (0.63 g) and benzyl bromide (0.50 mL) in benzene (10 mL) was heated at 50° C. for 24 hours, protected from light. Reaction mixture stirred ambient temperature for 16 hours. Reaction mixture was filtered through a pad of CELITE, which was washed ethyl acetate. The filtrate was concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give 2-Benzyloxy-4-bromo-pyridine (0.6043 g): LCMS-ESI+: calc'd for C12H11BrNO: 265.12 (M+H+). Found: 263.8, 265.8 (M+H+).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)=O.[NH2:20][C:21]([NH2:23])=[S:22].CC([O-])=O.[Na+]>CCO>[NH2:23][C:21]1[S:22][CH:2]=[C:3]([C:5]2[CH:10]=[CH:9][C:8]([S:11]([NH:14][CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)(=[O:13])=[O:12])=[CH:7][CH:6]=2)[N:20]=1
Reactant: O=C(CBr)c1ccc(S(=O)(=O)NC2CCCC2)cc1
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Nc1nc(-c2ccc(S(=O)(=O)NC3CCCC3)cc2)cs1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-(2-Bromo-acetyl)-N-cyclopentyl-benzenesulfonamide (150 mg, 0.43 mmol) was combined with thiourea (33 mg, 0.43 mmol) in 7 ml of dry EtOH. To this solution was added NaOAc (53 mg, 0.65 mmol). Reaction mixture was stirred at room temperature for 4 hours. Reaction mixture was evaporated to dryness and used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[N:11]=[CH:10][C:9]([C:12](=O)[CH3:13])=[CH:8][C:7]=1[CH3:15].[CH3:19][C:20]([S@:23]([NH2:25])=[O:24])([CH3:22])[CH3:21]>>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[N:11]=[CH:10][C:9]([CH:12]([NH:25][S@@:23]([C:20]([CH3:22])([CH3:21])[CH3:19])=[O:24])[CH3:13])=[CH:8][C:7]=1[CH3:15]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cnc(Oc2cccc(F)c2)c(C)c1
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)cnc1Oc1cccc(F)c1
Yield: 79 %

Procedure:
The title compound is prepared in 79% yield (1.27 g, colorless amorphous) from 1-(6-(3-fluorophenoxy)-5-methylpyridin-3-yl)ethanone (1.13 g, 4.61 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide (838 mg, 6.91 mmol) in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.[N+:15]([O-])([OH:17])=[O:16]>C(O)(=O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16]
Reactant: CCOC(=O)C(C)c1cccc(O)c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CCOC(=O)C(C)c1ccc([N+](=O)[O-])c(O)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Ethyl 2-(3-hydroxyphenyl)propanoate (2.51 g, 12.9 mmol) in acetic acid (20 mL) was added nitric acid (60-62%, 1.45 g, 13.8 mmol) at room temperature. The mixture was stirred for 15 minutes at room temperature. The reaction mixture was poured into ice water (100 mL) and extracted with EtOAc. The organic layer was dried with MgSO4 and filtered. EtOAc was removed by evaporation. The residue was purified by column chromatography eluting with n-Hexane/EtOAc=6/1.
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1.[C:13](OCC)(=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH2:11][C:13](=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: COc1ccc(C(C)=O)cc1
Agent: [Na]
Product: CCOC(=O)C(=O)CC(=O)c1ccc(OC)cc1

Procedure:
The title compound was prepared in the same manner as intermediate 29 using sodium metal (0.168 g, 7.32 mmol), 1-[4-(methyloxy)phenyl]ethanone (1 g, 6.66 mmol), and diethyl ethanedioate (0.903 mL, 6.66 mmol). The crude product was purified using column chromatography (0 to 100% EtOAc/hexanes) to give 0.95 g of product (57%). LCMS E-S (M+H)=250.9. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.43 (m, 3 H), 3.91 (s, 3 H), 4.41 (q, J=6.65 Hz, 2 H), 6.94-7.12 (m, 3 H), 8.01 (d, J=8.59 Hz, 2 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=3)=[CH:11][C:10]([CH3:21])=[C:9]2[CH3:22])=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9]([CH3:22])=[C:10]([CH3:21])[CH:11]=[C:12]2[C:13]2[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2cc(C)c(C)n2-c2ccc(Br)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(-c2ccc(O)cc2)n(-c2ccc(Br)cc2)c1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
To a solution of 1-(4-bromophenyl)-5-(4-methoxyphenyl)-2,3-dimethyl-1H-pyrrole (610 mg, 1.71 mmol) in methylene chloride (30 ml) was added boron tribromide (0.647 ml, 6.84 mmol) at 0° C. The obtained solution was stirred at 0° C. for 1 hour, poured into ice water and extracted with ethyl acetate. The extracts were collected and washed with saturated aqueous sodium bicarbonate and dried over magnesium sulfate anhydride, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=6:1) to isolate the object compound as an oily substance. 358 mg (yield: 61.2%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([C:28]([C:30]2[CH:31]=[C:32]3[C:36](=[C:37]([CH3:39])[CH:38]=2)[N:35]([CH3:40])[CH2:34][C:33]3([CH3:42])[CH3:41])=[O:29])[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:23]=[C:24]([C:28]([C:30]5[CH:31]=[C:32]6[C:36](=[C:37]([CH3:39])[CH:38]=5)[N:35]([CH3:40])[CH2:34][C:33]6([CH3:42])[CH3:41])=[O:29])[N:25]=[CH:26][N:27]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2c1N(C)CC2(C)C
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5c(c4)C(C)(C)CN5C)ncn3)CC1)C(=O)N2
Temperature: 40 °C
Reaction time: 8 h

Procedure:
48 mg (0.17 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 55 mg (0.17 mmol) (6-chloro-pyrimidin-4-yl)-(1,3,3,7-tetramethyl-2,3-dihydro-1H-indol-5-yl)-methanone and 0.050 mL (0.29 mmol) DIPEA were combined in 2 mL DMF and stirred overnight at 40° C. Then the reaction mixture was purified by preparative HPLC-MS. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Br:15][C:16]1[CH:17]=[C:18]([C:23](=[O:25])[CH3:24])[CH:19]=[CH:20][C:21]=1[CH3:22].C(N(CC)CC)C>CCCCCCC>[Br:15][C:16]1[CH:17]=[C:18]([C:23](=[O:25])[CH2:24][C:9]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)([OH:14])[C:10]([F:11])([F:12])[F:13])[CH:19]=[CH:20][C:21]=1[CH3:22]
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: CC(=O)c1ccc(C)c(Br)c1
Solvent: CCN(CC)CC
Solvent: CCCCCCC
Product: Cc1ccc(C(=O)CC(O)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1Br
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 3.42 g of 3′,5′-dichloro-2,2,2-trifluoroacetophenone and 3.00 g of 3′-bromo-4′-methylacetophenone in 5 mL of heptane, 0.71 g of triethylamine was added and the resultant reaction mixture was stirred at 60° C. for 8 hours. After the completion of the reaction, the reaction mixture was left to be cooled down to room temperature. A deposited solid was separated off and was washed with 3 mL of hexane to obtain 6.16 g of the objective substance as a white crystal.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:7][CH:6]([CH2:8][CH2:9][C:10]([O:12]CC(C)C)=O)[NH:5][CH2:4]1.C(=O)([O-])O.[Na+]>O>[O:2]=[C:3]1[CH2:4][N:5]2[C:10](=[O:12])[CH2:9][CH2:8][CH:6]2[NH:7]1
Reactant: CC(C)COC(=O)CCC1NCC(=O)N1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C1CN2C(=O)CCC2N1
Temperature: 100 °C
Yield: 37.2 %

Procedure:
A solution of isobutyl 5-oxo-2-imidazolidinepropanoate hydrochloride (1.4 g, 5.76 mmol) in water (100 ml) was treated with sodium hydrogen carbonate (0.54 g, 6.4 mmol) and heated at 100° C. for 20 hours. The solution was evaporated and the residue was chromatographed over silica gel (ethyl acetate-acetonemethanol 6:3:1) to afford 300 mg (37%) of the title compound, m p. 155°-157° C.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:18]=[C:17]2[C:8]([NH:9][C:10]3[C:15]([S:16]2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:7]2[CH:19]=[CH:20][CH:21]=[CH:22][C:6]=12)(=[O:3])[CH3:2].[C:23](Br)(=[O:25])[CH3:24]>ClCCCl>[C:1]([O:4][C:5]1[CH:18]=[C:17]2[C:8]([N:9]([C:23](=[O:25])[CH3:24])[C:10]3[C:15]([S:16]2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:7]2[CH:19]=[CH:20][CH:21]=[CH:22][C:6]=12)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc2c(c3ccccc13)Nc1ccccc1S2
Reactant: CC(=O)Br
Solvent: ClCCCl
Product: CC(=O)Oc1cc2c(c3ccccc13)N(C(C)=O)c1ccccc1S2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 5-acetoxy-12H-benzo[a]phenothiazine (3.0 g) and powdered 4 Angstrom molecular sieves (7.5 g) in 1,2-dichloroethane (75 ml) there was added slowly acetyl bromide (1.05 ml). The mixture was stirred at room temperature for 1 hour, then filtered. The filtrate was evaporated down to an oil which was triturated with a mixture of ether and hexane to afford solid title product (3 g), m.p. 141°-142° C.
Reaction SMILES: [CH:1]([N:4]([C:16](=[O:35])/[CH:17]=[CH:18]/[C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:20]=1)[NH:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].BrC[CH2:44][O:45][CH3:46]>CC(C)=O>[CH:1]([N:4]([C:16](=[O:35])/[CH:17]=[CH:18]/[C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]([C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[CH:20]=1)[NH:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:44][O:45][CH3:46])=[CH:9][CH:8]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(C(=O)NN(C(=O)/C=C/c2cn(C(=O)OC(C)(C)C)c3ccccc23)C(C)C)cc1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCCOc1ccc(C(=O)NN(C(=O)/C=C/c2cn(C(=O)OC(C)(C)C)c3ccccc23)C(C)C)cc1
Temperature: 60 °C

Procedure:
To solution containing (E)-tert-butyl 3-(3-(1-isopropyl-2-(4-methoxybenzoyl)hydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate (100.0 mg, 0.22 mmol) and K2CO3 (35.8 mg, 0.26 mmol) dissolved in acetone (5.0 ml), 1-bromo-2-methoxyethane (0.024 ml, 0.26 mmol) was added drop-wise. The reaction mixture was refluxed at 60° C. for 48 hr. After concentration under reduced pressure, the solution was separated through silica gel chromatography (CHCl3: methanol=65:1) so that ivory solid form of (E)-tert-butyl 3-(3-(1-isopropyl-2-(4-(2-methoxyethoxy)benzoyl)hydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate was obtained (66.4 mg, 59%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]3[N:19]=[CH:20][C:21]([C:22]([OH:24])=O)=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:25][S:26]([C:29]1[CH:30]=[C:31]([NH2:35])[CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27].Cl>>[CH3:25][S:26]([C:29]1[CH:30]=[C:31]([NH:35][C:22]([C:21]2[CH:20]=[N:19][N:12]3[C:13]([C:15]([F:17])([F:18])[F:16])=[CH:14][C:9]([C:4]4[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=4)=[N:10][C:11]=23)=[O:24])[CH:32]=[CH:33][CH:34]=1)(=[O:27])=[O:28]
Reactant: CS(=O)(=O)c1cccc(N)c1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(F)c(F)c3)nc12
Agent: Cl
Product: CS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(F)c(F)c4)nc23)c1

Procedure:
The title compound was prepared from 5-(3,4-difluoro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.21) and 3-methanesulfonyl-phenylamine [commercially available as hydrochloride] according to general procedure II. Yellow solid. MS (ISP) 497.1 [(M+H)+]; mp 256° C.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:18][N:6]2[CH2:7][CH2:8][CH2:9][CH:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:5]2[C:4]1=[O:19].[C:20]([O-:23])(=[S:22])[CH3:21].[K+]>CC(C)=O>[C:20]([S:22][CH2:2][CH:3]1[CH2:18][N:6]2[CH2:7][CH2:8][CH2:9][CH:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:5]2[C:4]1=[O:19])(=[O:23])[CH3:21]
Reactant: CC([O-])=S
Reactant: CC(C)(C)OC(=O)C1CCCN2CC(CBr)C(=O)N12
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)SCC1CN2CCCC(C(=O)OC(C)(C)C)N2C1=O
Yield: 76.5 %

Procedure:
1.42 g of tert.butyl 2-bromomethyl-hexahydro-3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate (diastereomer A) and 0.58 g of potassium thioacetate were stirred at room temperature in 20 ml of acetone for 17 hours. The solvent was removed by evaporation, the residue was diluted with 100 ml of ethyl acetate, the mixture was washed three times with sodium chloride solution, dried over magnesium sulfate and evaporated. After recrystallization of the residue from ethyl acetate/hexane, there were obtained 1.07 g of tert.-butyl 2-acetylthiomethyl-hexahydro-3-oxo-1H-pyrazolo[1,2-a]-pyridazine-5-carboxylate (diastereomer A) having a melting point of 92°-93° C. (from ethyl acetate/hexane).
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[NH2:7][CH2:8][CH2:9][SH:10].[C:11]([O:15][C:16](=[O:23])[NH:17][C@@H:18]([C:20](F)=[O:21])[CH3:19])([CH3:14])([CH3:13])[CH3:12]>O.C(Cl)Cl>[C:11]([O:15][C:16](=[O:23])[NH:17][C@H:18]([C:20](=[O:21])[NH:7][CH2:8][CH2:9][SH:10])[CH3:19])([CH3:12])([CH3:13])[CH3:14]
Reactant: NCCS
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCCS
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a 25 mL round-bottom flask charged with a solution of sodium bicarbonate (139.5 mg, 1.66 mmol) in 8.1 mL water was added 2-aminoethanethiol hydrochloride (101.2 mg, 0.89 mmol). To this stirring solution was added dropwise over 60 seconds a solution of 25b (155.1 mg, 0.81 mmol) in 8.1 mL CH2Cl2. The reaction was vigorously stirred for 25 minutes at room temperature, then extracted twice with fresh CH2Cl2. The combined CH2Cl2 extracts were washed once with 5% aqueous HCl, once with 10% aqueous sodium bicarbonate, then once with water. The organic fraction was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 72.6 mg (36% from 24b) of clean 26b as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[NH:4][N:3]=1.[CH2:11]([N:13]([CH2:17][CH3:18])[C:14](Cl)=[O:15])[CH3:12]>C(Cl)Cl>[CH2:11]([N:13]([CH2:17][CH3:18])[C:14]([NH:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[NH:4][N:3]=1)=[O:15])[CH3:12]
Reactant: CCN(CC)C(=O)Cl
Reactant: CC(C)(C)c1cc(N)n[nH]1
Solvent: ClCCl
Product: CCN(CC)C(=O)Nc1cc(C(C)(C)C)[nH]n1
Yield: 44.5 %

Procedure:
4.2 g of Compound [II] was dissolved in 50 ml of methylene chloride, and 4.1 g of N,N-diethylcarbamoyl chloride was added to the solution. The mixture was heated under refluxing for 5 hours and cooled, followed by washing with water. The organic layer was collected, and the solvent was distilled off. The residue was subjected to crystallization by the addition of hexane. The crystals obtained were collected by filtration and dried to obtain 3.2 g of N,N-diethyl N'-(5-t-butyl-3-pyrazolyl)urea.