Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:6])[NH:4][NH2:5].[C:7](O)(=O)[C:8]1[CH:13]=[CH:12][CH:11]=[N:10][CH:9]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[OH-].[Na+].Cl.[Cl-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][N:2]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][N:4]=[C:3]1[SH:6]
Reactant: O=C(O)c1cccnc1
Reactant: CNC(=S)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1c(S)nnc1-c1cccnc1
Temperature: 25 °C

Procedure:
A solution of 4-methyl-3-thiosemicarbazide (902 mg, 8.58 mmol), nicotinic acid (960 mg, 7.80), EDCI (1.64 g, 8.58 mmol), HOBt (1.16 g, 8.58 mmol) in DMF (10 ml) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (100 ml), successively washed with hydrochloric acid (50 ml, 10% aqueous), water (50 ml), saturated sodium carbonate (50 ml, aqueous), water (50 ml) and brine (50 ml). The organic phase was dried (sodium sulfate), filtered and concentrated in-vacuo. The residue was stirred in sodium hydroxide (53.4 ml, 66.7 mmol, 5% aqueous) at 60° C. overnight. The reaction mixture was cooled to room temperature, then carefully brought to pH about 6 using hydrochloric acid (1 N water). The aqueous phase was saturated with solid sodium chloride, then extracted with ethyl acetate (4×50 ml). The combined organic phase was washed with brine (100 ml), dried (sodium sulfate), filtered and concentrated in-vacuo (180 mg, off-white solid). 1H NMR (CDCl3), δ (ppm): 11.6 (bs, 1H), 8.94 (s, 1H), 8.83 (dd, 1H), 7.98 (m, 1H), 7.51 (dd, 1H), 3.69 (s, 3H).
Reaction SMILES: [C:1]([OH:14])(=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1.[CH2:15](O)[CH2:16][CH3:17]>C1C=CC=CC=1>[C:1]([O:14][CH2:15][CH2:16][CH3:17])(=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1
Reactant: COc1cc(/C=C/C(=O)O)ccc1O
Reactant: CCCO
Solvent: c1ccccc1
Product: CCCOC(=O)/C=C/c1ccc(O)c(OC)c1
Temperature: 78 °C
Reaction time: 15 h
Yield: 64.3 %

Procedure:
In a three-necked flask, 19.4 g (0.1 mole) of ferulic acid, 6.01 g (0.1 mole) of n-propyl alcohol, and 1.0 g of paratoluenesulfonic acid were placed, and 200 ml of benzene was added. This reaction mixture was stirred at 78° C. for 15 hours. Thereafter, the same procedures were taken as in Example 1 to obtain 15.2 g (yield: 64%) of n-propyl ferulate.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[C:9]1([CH3:19])[CH:14]=[CH:13][CH:12]=[C:11]([S:15](Cl)(=[O:17])=[O:16])[CH:10]=1>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:15]([C:11]1[CH:10]=[C:9]([CH3:19])[CH:14]=[CH:13][CH:12]=1)(=[O:17])=[O:16]
Reactant: Cc1noc(N)c1Br
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Product: Cc1cccc(S(=O)(=O)Nc2onc(C)c2Br)c1
Yield: 63 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-3-toluenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 3-toluenesulfonyl chloride according to the procedures described in Example 30. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 138-140° C., yield 63%.
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:16]=[C:15]([N:17]3[CH2:22][C@H:21]([CH3:23])[NH:20][C@H:19]([CH3:24])[CH2:18]3)[CH:14]=[CH:13][C:12]=2[O:25][CH3:26])(=[O:9])=[O:8])=[CH:4][CH:3]=1.[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O.CC(C)([O-])C.[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:24][C@H:19]1[NH:20][C@@H:21]([CH3:23])[CH2:22][N:17]([C:15]2[CH:14]=[CH:13][C:12]([O:25][CH3:26])=[C:11]([NH:10][S:7]([C:5]3[S:6][C:2]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[F:27])=[CH:3][CH:4]=3)(=[O:9])=[O:8])[CH:16]=2)[CH2:18]1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)s1
Reactant: OB(O)c1ccccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2ccccc2F)s1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 5-bromo-N-[5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)phenyl]-2-thiophenesulfonamide (E122) (150 mg, 0.33 mmol) and (2-fluorophenyl)boronic acid (91 mg, 0.65 mmol) in DME (3 ml) was added potassium tert-butoxide (329 mg, 2.94 mmol) and tetrakis(triphenylphosphine)palladium(0) (37 mg, 0.033 mmol) in water (1 ml) and the resulting mixture stirred in a microwave (set at high absorbance) at 100° C. for 30 minutes. The resulting mixture was then reduced in vacuo, azeotroped with toluene (×3) and purified using SCX then mass directed autoprep HPLC to afford the title product (E124). MS (ES+) m/e 476 [M+H]+.
Reaction SMILES: Cl.[CH2:2]([O:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:29][CH2:28][NH:27][CH2:26]2)[CH2:19][CH2:18]1)[CH3:3].[CH3:36][S:37][C:38]1[CH:46]=[CH:45][C:44]([N:47]2[CH:51]=[N:50][N:49]=[N:48]2)=[CH:43][C:39]=1[C:40](O)=[O:41].O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.C(N=C=NCCCN(C)C)C>C(OCC)(=O)C.ClCCl>[CH3:36][S:37][C:38]1[CH:46]=[CH:45][C:44]([N:47]2[CH:51]=[N:50][N:49]=[N:48]2)=[CH:43][C:39]=1[C:40]([N:27]1[CH2:28][CH2:29][C:25]([CH2:24][CH2:23][N:20]2[CH2:21][CH2:22][CH:17]([NH:16][C:8]3[N:7]([CH2:6][CH2:5][O:4][CH2:2][CH3:3])[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[N:9]=3)[CH2:18][CH2:19]2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:26]1)=[O:41]
Reactant: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: CSc1ccc(-n2cnnn2)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(-n5cnnn5)ccc4SC)C3)CC2)nc2ccccc21
Reaction time: 18 h

Procedure:
Combine 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) (0.53 g, 1.0 mmol) (1.0 mmol) and dichloromethane (10 mL). Add 2-methylthio-5-(1H-tetrazol-1-yl)benzoic acid (0.24 g, 1.0 mmol), 1-hydroxybenzotriazole hydrate (0.16 g, 1.2 mmol), N,N-diisopropylethylamine (0.34 mL, 2.0 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.23 g, 1.2 mmol). After 18 hours, dilute the reaction mixture with ethyl acetate and extract with brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel to give the title compound.
Reaction SMILES: [CH2:1]([NH:4][C:5](=S)[NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[N:17])[N:8]=1)[CH2:2][CH3:3].[NH3:19]>>[CH2:1]([N:4]=[C:5]([NH2:19])[NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[N:17])[N:8]=1)[CH2:2][CH3:3]
Reactant: N
Reactant: CCCNC(=S)Nc1ccn(CCCCC#N)n1
Product: CCCN=C(N)Nc1ccn(CCCCC#N)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 5-(3-[3-propylthioureido]pyrazol-1-yl)valeronitrile (1.01 g.) in saturated methanolic ammonia (30 ml.) was treated with orange mercuric oxide (0.82 g.) and the suspension stirred at room temperature for 18 hours. The black suspension was filtered through diatomaceous earth and the filtrate evaporated to give 5-(3-[2-propylguanidino]pyrazol-1-yl)valeronitrile as a brown oil which was used without further purification.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[C:7](Br)[S:8][CH:9]=1)(=[O:3])[CH3:2].C([O-])(=O)C.[Na+].[H][H]>CO.[Pd]>[C:1]([NH:4][C:5]1[N:6]=[CH:7][S:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1csc(Br)n1
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)Nc1cscn1
Yield: 84.8 %

Procedure:
A solution of 4-acetamido-2-bromo-thiazole (22 g., 0.2 m) and sodium acetate (8.2 g, 0.1 m) in methanol (600 ml) was hydrogenated at room temperature and 1 atm. pressure oven 10% palladium on carbon (5 g) until the theoretical uptake of hydrogen had occurred (about 3 hours). The catalyst was removed by filtration and the filtrate evaporated to dryness under reduced pressure. The residue was extracted with carbon tetrachloride (200 ml) in a Soxlet apparatus. The extract was cooled and the crystals removed by filtration to yield 4-acetamidothiazole (12 g, 78%). m.p. 176° C. Found: C, 41.8; H, 4.3; N, 19.3. C5H6N2OS requires: C, 42.2; H, 4.3; N, 19.7%.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[CH3:12][C@H:13]1[O:18][C@@H:17]([CH3:19])[CH2:16][NH:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:19][C@H:17]1[O:18][C@@H:13]([CH3:12])[CH2:14][N:15]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=2)[CH2:16]1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H]1CN(c2ccc([N+](=O)[O-])c(N)c2)C[C@H](C)O1
Temperature: 110 °C
Reaction time: 48 h
Yield: 68.2 %

Procedure:
A mixture of 5-chloro-2-nitrophenylamine (1.3 g, 7.0 mmol), cis-2,6-dimethylmorpholine (2.5 g, 20 mmol), and K2CO3 (3.0 g, 22 mmol) in DMF (20 mL) was stirred at 110° C. for 48 h. The reaction mixture was cooled to room temperature, poured into water (300 mL). The resulting crude yellow solid was collected by vacuum filtration, air dried, and purified by flash chromatography (silica gel, 4×7.5 cm, eluted with 95/5 CHCl3/ether) to yield the product as a yellow solid (1.2 g, 68%).
Reaction SMILES: [CH2:1]([OH:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].[C:13]([O-:16])(=[O:15])[CH3:14].[Na+].BrN1C(=O)CCC1=O.C(OC(=O)C)(=O)C>O.C1COCC1>[C:13]([O:16][CH:5]1[CH:4]=[CH:3][C:1](=[O:7])[CH2:2][O:6]1)(=[O:15])[CH3:14]
Reactant: OCc1ccco1
Reactant: CC(=O)[O-]
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OC1C=CC(=O)CO1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 42.6 %

Procedure:
500 g (5.10 mol) of furfuryl alcohol (Compound 1) was dissolved in 1.65 L of water and 6.6 L of THF in a nitrogen gas stream and cooled to 0° C. or lower. To this, a mixture of 855 g (10.2 mol) of sodium hydrogen carbonate, 418 g (5.10 mol) of sodium acetate and 953 g (5.35 mol) of N-bromosuccinimide was added by spending 40 minutes. Thereafter, the resultant was agitated for an hour, and 2,083 g (20.4 mol) of acetic anhydride was added at 0° C. or lower. Then, the resultant was heated to room temperature and agitated overnight. At the end of the reaction, 20.5 L of a saturated aqueous sodium hydrogen carbonate solution was added, followed by extraction with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate and subjected to vacuum concentration to obtain 776 g of a crude product (crude yield: 42.6%). The obtained crude product was subjected to column purification (n-Hex:AcOEt=3:1) to obtain 339 g of Compound (±) 4 as a yellow-brown oily product.
Reaction SMILES: [C:1]([C:3]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH3:19])(=[O:17])=[O:16])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2].[CH3:20][C:21](C)([O-])[CH3:22].[K+].C(Br)C#C>>[C:1]([C:3]1[N:7]([CH2:22][C:21]#[CH:20])[C:6]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:15]([CH2:18][CH3:19])(=[O:17])=[O:16])=[CH:12][CH:13]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(C)(C)[O-]
Reactant: CCS(=O)(=O)Nc1ccc(-c2ccc(C#N)[nH]2)cc1
Agent: C#CCBr
Agent: [K+]
Product: C#CCn1c(C#N)ccc1-c1ccc(NS(=O)(=O)CC)cc1
Yield: 6.3 %

Procedure:
N-[4-(5-cyano-1H-pyrrol-2-yl)phenyl]ethanesulfonamide (0.150 g, 0.54 mmol) was alkylated according to the procedure of Example 40 using potassium tert-butoxide (1.08 mL of a 1M solution, 1.08 mmol) and propargyl bromide (80% in toluene, 0.055 mL, 0.50 mmol) to afford the title compound (0.10 g, 6.3%).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].C[O-].[Na+].CO.O=[C:11]1[CH2:16][CH2:15][N:14]([C@H:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])[CH2:13][C@@H:12]1[C:25](OCC)=[O:26]>C1COCC1.O.CCOC(C)=O>[C:19]1([C@@H:17]([N:14]2[CH2:15][CH2:16][C:11]3[N:1]=[C:2]([OH:3])[N:4]=[C:25]([OH:26])[C:12]=3[CH2:13]2)[CH3:18])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)[C@H]1CN([C@@H](C)c2ccccc2)CCC1=O
Reactant: NC(N)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](c1ccccc1)N1CCc2nc(O)nc(O)c2C1
Temperature: 25 °C

Procedure:
A combination of urea (0.37 g, 15.6 mmol), sodium methoxide (1.47 g, 27.2 mmol) and MeOH (50 mL) was cooled to 0° C. and then a solution of (S)-ethyl 4-oxo-1-((S)-1-phenylethyl)piperidine-3-carboxylate (9.0 g, 7.8 mmol) in THF was added. The reaction mixture was allowed to warm to rt and then warmed to 60° C. and heated for 3 h. The mixture was diluted with water and EtOAc and the organic layer was then separated, dried (Na2SO4), filtered and concentrated. The residue was purified by FCC (8-10% MeOH/CH2Cl2) to give (S)-6-(1-phenylethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diol.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:15]1[O:16][C:17]([Sn](CCCC)(CCCC)CCCC)=[CH:18][CH:19]=1)CCC>O1CCOCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([C:17]2[O:16][C:15]([C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=3)=[CH:19][CH:18]=2)=[N:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc([Sn](CCCC)(CCCC)CCCC)o1
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2ccc(-c3ccc(C#N)cn3)o2)nc1
Yield: 85 %

Procedure:
Referring now to Scheme 4, a mixture of 6-chloronicotinonitrile (1.38 g, 10 mmol), 2,5-bis(tri-n-butylstannyl)furan (3.2 g, 5 mmol) and tetrakis(triphenyl-phosphine)palladium(0) (125 mg) in dry 1,4-dioxane (40 mL) was heated under nitrogen at reflux (100–110° C.) for 24 h. The solvent was evaporated under reduced pressure and the residue was dissolved in methylene chloride and the solution was passed through CELITE® matrix (available from Word Minerals Corporation of Santa Barbara, Calif., United States of America) to remove Pd. The solution was evaporated, filtered and the precipitate was washed with hexanes to afford 21 in 85% yield, mp 311–312° C. (DMF). 1H nmr (DMSO-d6); δ 7.55 (s, 2H), 8.20 (d, J=8.4 Hz, 2H), 8.44 (dd, J=8.4, 2.1 Hz, 2H). 9.06 (d, J=2.1 Hz, 2H). 13C nmr; δ 153.5, 152.8, 150.0, 141.0, 118.8, 117.1, 114.8, 107.3. Calcd. for C16H8N4O: C, 70.58; H, 2.96; N, 20.57. Found. C, 70.35; H, 3.04; N, 20.35.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]([N:15]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[CH2:19][N:18]4[CH:26]=[CH:27][CH:28]=[C:17]4[CH2:16]3)=[O:14])=[CH:9][C:8]=2[S:29]([NH2:32])(=[O:31])=[O:30])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:33][C:34]([Cl:39])([Cl:38])[C:35](Cl)=[O:36].O>O1CCOCC1>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]([N:15]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[CH2:19][N:18]4[C:26]([C:35](=[O:36])[C:34]([Cl:39])([Cl:38])[Cl:33])=[CH:27][CH:28]=[C:17]4[CH2:16]3)=[O:14])=[CH:9][C:8]=2[S:29]([NH2:32])(=[O:30])=[O:31])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: NS(=O)(=O)c1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1N1CCOCC1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: C1COCCO1
Solvent: O
Product: NS(=O)(=O)c1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1N1CCOCC1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
A solution containing 0.77 g (0.0017 mol) of 2-morpholin-4-yl-5-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)benzenesulfonamide of Step B and 0.62 g (0.0034 mol) of trichloroacetyl chloride in 50 mL of 1,4-dioxane was heated under reflux for 3 hrours. The solution was allowed to cool to room temperature and then poured into 750 mL of water with stirring. The solid was collected, washed and dries to provide the title compound (0.88 g), m.p. 165-167° C. dec.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1([C:15]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[S:30]([CH3:33])(=[O:32])=[O:31])[CH2:20][CH:19]2[OH:34])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7].C(N(CC)CC)C>CS(C)=O.C(OCC)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1([C:15]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[S:30]([CH3:33])(=[O:32])=[O:31])[CH2:20][C:19]2=[O:34])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7]
Reactant: CS(=O)(=O)c1ccccc1N1CCC(NC(=O)C2(NC(=O)c3ccco3)CCCCC2)C(O)C1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccccc1N1CCC(NC(=O)C2(NC(=O)c3ccco3)CCCCC2)C(=O)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 41.3 %

Procedure:
To the solution of 4-[N-[1-[N-(furan-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-(2-methanesulfonylphenyl)piperidin-3-ol (0.39 g, 0.77 mmol) obtained in Step 5 in 3 ml of dimethylsulfoxide (DMSO), was added 0.4 ml of triethylamine. The reaction mixture was cooled to 0° C. Pyridine-SO3 complex (0.4 g, 2.51 mmol) was added to the reaction mixture, which was then stirred for 2 hours. The reaction mixture was diluted with 20 ml of ethyl acetate, washed with brine. The resulting organic layer was dried and concentrated on sodium sulfate. The resulting residue was purified with column chromatography to give 155 mg of the titled compound as white solid.
Reaction SMILES: NC1C=CC=CC=1.[CH:8]([S:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=1[C:19]([F:22])([F:21])[F:20])([CH3:10])[CH3:9].C(N(CC)CC)C.[CH3:30][C:31]1([C:34](Cl)=[O:35])[CH2:33][CH2:32]1>O1CCCC1>[CH:8]([S:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:34]([C:31]2([CH3:30])[CH2:33][CH2:32]2)=[O:35])=[CH:14][C:13]=1[C:19]([F:22])([F:20])[F:21])([CH3:10])[CH3:9]
Reactant: CC(C)Sc1ccc(N)cc1C(F)(F)F
Reactant: CC1(C(=O)Cl)CC1
Solvent: Nc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)Sc1ccc(NC(=O)C2(C)CC2)cc1C(F)(F)F
Temperature: 0 °C
Yield: 79 %

Procedure:
To a stirred solution containing 23.5 g (0.1 mole) of the aniline prepared in (b) above and 10.1 g (0.1 mole) of triethylamine in 150 ml of tetrahydrofuran was added dropwise over 5 minutes 11.9 g (0.1 mole) of 1-methylcyclopropylcarboxylic chloride. This addition was exothermic to 55° C. The mixture was refluxed for 1 hour, poured into ice water and filtered. The filter cake was recrystallized from hexane to give 25 g (79%) of product as a colorless crystalline solid, m.p. 103°-105° C.
Reaction SMILES: C([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1([CH3:21])[C:17]([O:19][CH3:20])=[O:18])(OC(C)(C)C)=O.[ClH:22]>O1CCOCC1>[ClH:22].[CH3:21][C:9]1([C:17]([O:19][CH3:20])=[O:18])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:16][NH:8]1
Reactant: COC(=O)C1(C)c2ccccc2CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)C1(C)NCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a sample of N-BOC-1,3-dihydro-1-methyl-2H-isoindole-1-carboxylic acid, methyl ester (0.50 g, 1.7 mmol) was added HCl in dioxane (4 M, 5.0 mL). After stirring at rt for 1 hr, the reaction mixture was concentrated in vacuo, and the residue was triturated with Et2O and was concentrated to dryness to yield 1,3 -dihydro-1-methyl-2H-isoindole-1-carboxylic acid, methyl ester, hydrochloride (0.40 g, 100%) which was used in the subsequent reaction without purification.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=2[Cl:26])[CH:12]=[CH:11][C:10]=1[N+:27]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P([O-])(O)O.[Na+]>C(O)C.[Pd]>[CH2:1]([S:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:18][C:17]=2[Cl:26])[CH:12]=[CH:11][C:10]=1[NH2:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1SCc1ccccc1
Agent: [Pd]
Agent: [Na+]
Agent: [O-]P(O)O
Solvent: CCO
Product: Nc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1SCc1ccccc1

Procedure:
2 g of 1B was dissolved in 30 ml of ethanol and 0.5 g of 5% palladium on carbon catalyst and 10% aqueous sodium dihydrogen phosphite added in portions until vigorous effervescence ceased. The reaction mixture was filtered, extracted with 400 ml of a 1:1 v:v mixture of ethylene dichloride/water, and the organic layer separated and dried. Chromatographic purification yielded 2-benzylthio-4-(2-chloro-4-trifluoromethylphenoxy)aniline (1C) as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]2[O:26][C:13]3([CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[N:12]([CH3:27])[C:11](=[O:28])[C:10]=2[CH:29]=1.[ClH:31]>O1CCOCC1.C(Cl)Cl>[ClH:31].[CH3:1][O:2][C:3](=[O:30])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]2[O:26][C:13]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[N:12]([CH3:27])[C:11](=[O:28])[C:10]=2[CH:29]=1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)N(C)C1(CCN(C(=O)OC(C)(C)C)CC1)O2
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)N(C)C1(CCNCC1)O2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of (E)-3-{1′-tert-butoxycarbonyl-3,4-dihydro-3-methyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid methyl ester (3.00 g, 7.21 mmol) and 4 M HCl in dioxane (5 ml) in DCM (150 ml) was stirred at RT for 4 h. The precipitate was filtered off to give (E)-3-{3,4-dihydro-3-methyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid methyl ester hydrochloride (2.46 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C@H:9]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[NH:10][S@](C(C)(C)C)=O)=[N:5][CH:6]=[CH:7][CH:8]=1.Cl.O1CCOCC1.C([O-])(O)=O.[Na+]>CO.CCOC(C)=O.O>[CH3:1][O:2][C:3]1[C:4]([C@H:9]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=2)[NH2:10])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccnc1[C@@H](N[S@@](=O)C(C)(C)C)c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: COc1cccnc1[C@@H](N)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (S)—N—((S)-(3-methoxypyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-2-methylpropane-2-sulfinamide (0.576 g, 1.491 mmol) in MeOH (6 mL) was treated with hydrochloric acid, 4.0 M solution in 1,4-dioxane (0.75 mL, 3.00 mmol) and stirred at rt for 2 h. The reaction was concentrated on the rotary evaporator resulting in a gummy residue which was taken up in EtOAc (100 mL), saturated aqueous NaHCO3 (50 mL), and H2O (25 mL). The resulting mixture was transferred to a separatory funnel and after vigorous extraction, the organic layer was separated, dried over anhydrous sodium sulfate, and concentrated to yield the product (S)-(3-methoxypyridin-2-yl)(4-(trifluoromethyl)-phenyl)methanamine as a light-brown oil which was used without further purification in the next step.
Reaction SMILES: [C:1]1([N:7]2[C:14]([NH:15][OH:16])=[CH:13][C:11](=[O:12])[N:10]([CH3:17])[C:8]2=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:18]([O-])([O-])OCC>CN(C)C=O>[CH3:17][N:10]1[C:11](=[O:12])[C:13]2=[CH:18][O:16][N:15]=[C:14]2[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]1=[O:9]
Reactant: CCOC([O-])[O-]
Reactant: Cn1c(=O)cc(NO)n(-c2ccccc2)c1=O
Solvent: CN(C)C=O
Product: Cn1c(=O)c2conc2n(-c2ccccc2)c1=O

Procedure:
A mixture of 2 g of 1-phenyl-3-methyl-6-hydroxyaminouracil, 100 ml of dimethylformamide and 10 ml of ethyl orthoformate is reacted in the same manner as Example 11 to obtain 0.93 g of the captioned compound. melting point: 219°-221° C.
Reaction SMILES: C[O:2][C:3]1[CH:17]=[CH:16][C:6]2[NH:7][C:8](=[O:15])[C:9]3[CH:10]=[CH:11][CH:12]=[N:13][C:14]=3[C:5]=2[CH:4]=1.ClCCl.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:17]=[CH:16][C:6]2[NH:7][C:8](=[O:15])[C:9]3[CH:10]=[CH:11][CH:12]=[N:13][C:14]=3[C:5]=2[CH:4]=1
Reactant: COc1ccc2[nH]c(=O)c3cccnc3c2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=c1[nH]c2ccc(O)cc2c2ncccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
The compound (190 mg, 0.84 mmol) prepared in step 1 was dissolved in dichloromethane (2 ml), added with 1 M boron tribromide dichloromethane solution (4.2 ml). The mixture was stirred overnight at room temperature. The reaction mixture was poured into ice water and the precipitate was collected by filteration to obtain the title compound (125 mg, yield: 70%, yellow solid).