Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]2[CH:18]=[CH:17][N:16]([CH2:19][C:20]([OH:22])=O)[C:15](=[O:23])[CH:14]=2)=[CH:4][N:3]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.Cl.[CH2:46]([NH:48][CH2:49][CH3:50])[CH3:47].C(N(CC)CC)C>CN(C)C=O.O>[CH2:46]([N:48]([CH2:49][CH3:50])[C:20](=[O:22])[CH2:19][N:16]1[CH:17]=[CH:18][C:13]([C:5]2[C:6]([C:8]3[O:9][CH:10]=[CH:11][CH:12]=3)=[N:7][C:2]([NH2:1])=[N:3][CH:4]=2)=[CH:14][C:15]1=[O:23])[CH3:47]
Reactant: Nc1ncc(-c2ccn(CC(=O)O)c(=O)c2)c(-c2ccco2)n1
Reactant: CCNCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCN(CC)C(=O)Cn1ccc(-c2cnc(N)nc2-c2ccco2)cc1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 6.2 %

Procedure:
A suspension of {4-[2-amino-4-(2-furyl)-5-pyrimidinyl]-2-oxo-1,2-dihydro-1-pyridinyl}acetic acid (10 mg, 32 μmol), 1-hydroxybenzotriazole (15 mg, 98 μmol), 3-(3′-dimethylaminopropyl)-1-ethylcarbodiimide (15 mg, 96 μmol), diethylamine hydrochloride (18 mg, 164 μmol) and triethylamine (22 μl, 160 μmol) in N,N-dimethylformamide (1.0 ml) was stirred at room temperature for 17 hours. The reaction mixture was diluted with water and then extracted with ethyl acetate. The organic layer was concentrated and then purified by HPLC, to give the title compound (0.73 mg, 6%).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=C(C#N)[CH:16]=[C:15]([CH3:21])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].C([N:24]([CH2:27][CH3:28])CC)C.Cl.[NH2:30][OH:31]>C(O)C>[Cl:1][C:2]1[CH:18]=[C:28]([C:27](=[NH:24])[NH:30][OH:31])[CH:16]=[C:15]([CH3:21])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: NO
Reactant: Cc1cc(C#N)cc(Cl)c1OCCCC(=O)OC(C)(C)C
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CCO
Product: Cc1cc(C(=N)NO)cc(Cl)c1OCCCC(=O)OC(C)(C)C
Yield: 20.4 %

Procedure:
A solution of tert-butyl 4-(2-chloro-4-cyano-6-methylphenoxy)butanoate (640 mg, 2.07 mmol), triethylamine (418 mg, 4.13 mmol) and hydroxylamine hydrochloride (215 mg, 3.10 mmol) in ethanol (5 mL) is stirred at 65° C. for 72 h. The mixture is concentrated and the crude product is purified by prep. HPLC to give tert-butyl 4-(2-chloro-4-(N-hydroxycarbamimidoyl)-6-methylphenoxy)butanoate (145 mg) as a pale grey solid; LC-MS: tR=0.65 min, [M+H]+=343.20.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:28]([O-])=O)=[C:6]([CH:27]=1)[CH2:7][N:8]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH:9]([CH2:14][OH:15])[C:10]([O:12][CH3:13])=[O:11].O.O.[Sn](Cl)(Cl)(Cl)Cl.[C:38]([O-])(O)=O.[Na+].C(O[CH2:47][CH3:48])(=O)C>C(O)C>[NH2:28][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:27][C:6]=1[CH2:7][N:8]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:38]#[C:47][CH3:48])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH:9]([CH2:14][OH:15])[C:10]([O:12][CH3:13])=[O:11]
Reactant: CCOC(C)=O
Reactant: COC(=O)C(CO)N(Cc1cc(F)ccc1[N+](=O)[O-])S(=O)(=O)c1ccc(OC)cc1
Reactant: O=C([O-])O
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC#CCOc1ccc(S(=O)(=O)N(Cc2cc(F)ccc2N)C(CO)C(=O)OC)cc1
Temperature: 70 °C
Yield: 58 %

Procedure:
Methyl 2-{(5-fluoro-2-nitrobenzyl)[(4-methoxyphenyl)sulfonyl]amino}-3-hydroxypropanoate (1.0 g, 2.08 mmol) was dissolved in ethanol (18 mL). To this was added tin chloride dihydrate (2.35 g, 10.4 mmol) and the reaction was heated to 70° C. for 2 hours. The reaction was then cooled to room temperature and ice water followed by NaHCO3 was added to bring the solution to pH 8. Ethyl acetate was added and the suspension was filtered through celite. The organic layer was separated and washed with brine, dried over Na2SO4 concentrated in vacuo and chromatographed using 1:1 hexane:ethyl acetate as eluant to provide 0.55 g (58%) of the desired product as a yellow oil.
Reaction SMILES: B(O)O.Br[C:5]1[N:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8].[O:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH:15]=[C:14]1B(O)O>>[O:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH:15]=[C:14]1[C:5]1[N:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: O=Cc1cccnc1Br
Reactant: OB(O)c1cc2ccccc2o1
Agent: OBO
Product: O=Cc1cccnc1-c1cc2ccccc2o1

Procedure:
2-(benzofuran-2-yl)nicotinaldehyde was prepared using the general boronic acid coupling procedure for 2-bromonicotinaldehyde and benzofuran-2-ylboronic acid (72 mg, 120.1 mg theoretical, 60%). LC-MS m/z 224.2 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C:5]([CH3:9])([CH3:8])[S:4][C:3]1=[N:10][OH:11].[CH3:12][N:13]([S:17][S:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:14](F)=[O:15].C(N(CC)CC)C>O1CCOCC1>[CH3:12][N:13]([S:17][S:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:14]([O:11][N:10]=[C:3]1[N:2]([CH3:1])[C:6](=[O:7])[C:5]([CH3:9])([CH3:8])[S:4]1)=[O:15]
Reactant: CN(SSc1ccccc1)C(=O)F
Reactant: CN1C(=O)C(C)(C)SC1=NO
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CN(SSc1ccccc1)C(=O)ON=C1SC(C)(C)C(=O)N1C

Procedure:
2-[[O-[N-Methyl-N-(phenylthiosulfenyl)carbamoyl]oximino]]-3,5,5-trimethylthiazolidin-4-one was prepared according to the procedure described in Example I, by reacting 5.0 g (0.0287 m) of 3,5,5-trimethyl-2-oximinothiazolidin-4-one, 6.24 g (0.0287 m) of N-methyl-N-(phenylthiosulfenyl)carbamoyl fluoride and 2.9 g (0.0287 m) of triethylamine in 100 ml of dioxane. 2-[[O-[N-Methyl-N-(phenylthiosulfenyl)carbamoyl]oximino]]-3,5,5-trimethylthiazolidin-4-one was crystallized from isopropyl ether to yield 7.0 g of a white solid. m.p. 73°-74° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([C:10]([NH:12][CH:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[CH2:14][O:15][CH2:16][CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[O:11])[S:7][C:6]=2[CH:30]=1.[CH3:31][C:32]([CH3:34])=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([C:10]([NH:12][CH:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[CH2:14][O:15][CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([CH:32]([CH3:34])[CH3:31])[CH2:19][CH2:18]3)=[O:11])[S:7][C:6]=2[CH:30]=1
Reactant: O=C(NC(COCC1CCNCC1)c1ccccc1Cl)c1cc2ccc(Cl)cc2s1
Reactant: CC(C)=O
Product: CC(C)N1CCC(COCC(NC(=O)c2cc3ccc(Cl)cc3s2)c2ccccc2Cl)CC1

Procedure:
Using alkylation method A, 6-chloro-N-[1-(2-chloro-phenyl)-2-(piperidin-4-ylmethoxy)ethyl]benzo[b]thiophene-2-carboxamide (255 mg, 0.55 mmol) and acetone (2.0 mL, 27 mmol) afforded, after purification (SiO2: 4:4:1 hexane EtOAc:isopropylamine), 150 mg (54%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]2[C:15]([C:16](O)=[O:17])=[C:14]([CH3:19])[NH:13][C:12]([CH3:20])=[C:11]2[C:21]([O:23][CH3:24])=[O:22])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C1(N=C=NC2CCCCC2)CCCCC1.[C:40]1([CH:50]=[CH:51][CH2:52][CH2:53][OH:54])[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=[CH:42][CH:41]=1>CN(C)C1C=CN=CC=1.ClC(Cl)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]2[C:15]([C:16]([O:54][CH2:53][CH2:52][CH:51]=[CH:50][C:40]3[C:49]4[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=4)[CH:43]=[CH:42][CH:41]=3)=[O:17])=[C:14]([CH3:19])[NH:13][C:12]([CH3:20])=[C:11]2[C:21]([O:23][CH3:24])=[O:22])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Reactant: OCCC=Cc1cccc2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CC(Cl)Cl
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCC=Cc2cccc3ccccc23)C1c1cccc([N+](=O)[O-])c1
Yield: 99 %

Procedure:
332 mg (1 mM) of 4-(3-nitrophenyl)-2,6-dimethyl-3-methoxycarbonyl-1,4-dihydropyridine-5-carboxylic acid, 226 mg (1.1 mM) of dicyclohexylcarbodiimide, 122 mg (1 mM) of 4-dimethylaminopyridine and 238 mg (1.2 mM) of 4-(1-naphthyl)-3-buten-1-ol were dissolved in 10 ml of dichloroethane, and refluxed for 2 hours. After the reaction mixture was chilled, insoluble matters were filtered off. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography to obtain 507 mg of methyl 4-(1-naphthyl)-3-butenyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (yield 99%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[C:10]1[CH:11]=[CH:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[N:14][CH:15]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([NH:33][CH3:34])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O.CCOC(C)=O>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:33]([C:30]2[CH:29]=[CH:28][C:27]([C:24]3[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=3)=[CH:32][CH:31]=2)[CH3:34])=[C:4]([C:10]2[CH:11]=[CH:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[N:14][CH:15]=2)[CH:5]=1
Reactant: COC(=O)c1ccc(-c2cc(Cl)ccc2CBr)cn1
Reactant: CNc1ccc(-c2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COC(=O)c1ccc(-c2cc(Cl)ccc2CN(C)c2ccc(-c3ccc(Cl)cc3)cc2)cn1
Temperature: 50 °C

Procedure:
Methyl 5-(2-(bromomethyl)-5-chlorophenyl)picolinate (200 mg, 0.59 mmol), 4′-chloro-N-methyl-[1,1′-biphenyl]-4-amine (141 mg, 0.65 mmol), and K2CO3 (122 mg, 0.88 mmol) were diluted with acetone (3 mL) and heated to 50° C. After 18 h the resulting mixture was diluted with EtOAc, washed with water and brine, dried (Na2SO4), and dry packed onto silica gel. Column chromatography yielded the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([F:10])([F:9])[F:8])=[C:4]([C:11]([OH:13])=O)[CH:3]=1.[CH:14]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[N:23]=[N:24][C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:26][CH:27]=2)=[O:21])[CH2:16][CH2:15]1>>[CH:14]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[N:23]=[N:24][C:25]([N:28]3[CH2:33][CH2:32][N:31]([C:11]([C:4]4[CH:3]=[C:2]([CH3:1])[O:6][C:5]=4[C:7]([F:8])([F:9])[F:10])=[O:13])[CH2:30][CH2:29]3)=[CH:26][CH:27]=2)=[O:21])[CH2:16][CH2:15]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: Cc1cc(C(=O)O)c(C(F)(F)F)o1
Product: Cc1cc(C(=O)N2CCN(c3ccc(C(=O)NCCC4CC4)nn3)CC2)c(C(F)(F)F)o1

Procedure:
Following the procedure of Example 9, making variations only as required to use 5-methyl-2-trifluoromethylfuran-3-carboxylic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (53% yield). m.p. 128-130° C. 1H NMR (500 MHz, CDCl3) δ 8.08, 7.99, 7.01, 6.15, 3.89-3.94), 3.77-3.82, 3.52-3.60, 2.39, 1.52, 0.71-0.80, 0.45-0.49, 0.08-0.13. MS (ES+) m/z 452 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([CH2:43][CH2:44][CH2:45][S:46]([CH3:49])(=[O:48])=[O:47])=[CH:38][C:37]=1[CH3:50].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:42][C:41]1[CH:40]=[C:39]([CH2:43][CH2:44][CH2:45][S:46]([CH3:49])(=[O:47])=[O:48])[CH:38]=[C:37]([CH3:50])[C:36]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C@H:9]2[O:11][C:12]1[CH:25]=[CH:24][C:15]2[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: Cc1cc(CCCS(C)(=O)=O)cc(C)c1Br
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(CCCS(C)(=O)=O)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate and 2-bromo-1,3-dimethyl-5-(3-(methylsulfonyl)propyl)benzene following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 8): tR=0.66 min; Mass spectrum (ESI+): m/z=567 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:5]2.[Cl-].C[Al+]C.Cl[C:23](=[O:32])[CH2:24][C@@H:25]([CH3:31])[CH2:26][C:27]([O:29][CH3:30])=[O:28].[Cl-].[NH4+]>C(Cl)Cl.C(OCC)(=O)C>[CH3:30][O:29][C:27](=[O:28])[CH2:26][C@H:25]([CH3:31])[CH2:24][C:23]([C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)[N:7]([CH3:11])[C:6]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:32]
Reactant: CCCCCCc1cc2cc(Cl)ccc2n1C
Reactant: COC(=O)C[C@H](C)CC(=O)Cl
Agent: C[Al+]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCCCc1c(C(=O)C[C@@H](C)CC(=O)OC)c2cc(Cl)ccc2n1C
Reaction time: 0.5 h

Procedure:
To the cold solution of 5-Chloro-2-hexyl-1-methyl-1H-indole in methylene chloride was added dimethyl aluminum chloride solution and was stirred for 30 minutes. Then (S)-methyl 5-chloro-3-methyl-5-oxopentanoate in methylene chloride was added to the reaction mixture and was stirred for 3 hours. The reaction mixture was then treated with saturated ammonium chloride and ethyl acetate. The product was purified by column chromatography.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][C@H:3]([C:14]([OH:16])=[O:15])[NH:2]1.[OH-].[K+].C(O)C.[CH3:22]I.[C:24](=[S:26])=[S:25]>>[CH3:22][S:25][C:24]([N:2]1[C@@H:3]([C:14]([OH:16])=[O:15])[CH2:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:12][C:13]=2[CH2:1]1)=[S:26]
Reactant: CI
Reactant: S=C=S
Reactant: O=C(O)[C@H]1Cc2c([nH]c3ccccc23)CN1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CSC(=S)N1Cc2[nH]c3ccccc3c2C[C@@H]1C(=O)O
Reaction time: 1 h
Yield: 60 %

Procedure:
To a mixture of (3R)-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (6.49 g), KOH (3.5 g) and 50% ethanol (110 ml) is added dropwise carbon disulfide (1.82 ml) under ice-cooling. The mixture is stirred at room temprature for one hour, and thereto is added dropwise methyl iodide (2.5 ml). The mixture is further stirred at room temperature for 4 hours. The reaction mixture is distilled to remove the solvent. The residue is dissolved in water. The solution is acidified with 10% HCl and extracted with ethyl acetate. The extract is washed with water, dried and distilled to remove the solvent. The residue is purified by silica gel column chromatography (solvent, chloroform:methanol:acetic acid=97:2:1), and the product is crystallized from aqueous ethanol to give the title compound (5.5 g, 60%), m.p. 103°-106° C. (decomp.).
Reaction SMILES: [O:1]=[S:2]1(=[O:34])[C:8]2[CH:9]=[C:10]([O:15][CH2:16][C:17]([O:19]CC)=[O:18])[C:11]([S:13]C)=[CH:12][C:7]=2[N:6]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:5][C:4]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:28][CH3:29])[CH2:3]1.[CH2:35]1COC[CH2:36]1.[Li+].[OH-]>C(Cl)Cl.O.CC(O)=O>[O:1]=[S:2]1(=[O:34])[C:8]2[CH:9]=[C:10]([O:15][CH2:16][C:17]([OH:19])=[O:18])[C:11]([S:13][CH2:35][CH3:36])=[CH:12][C:7]=2[N:6]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:5][C:4]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:28][CH3:29])[CH2:3]1
Reactant: C1CCOC1
Reactant: CCCCC1(CC)CN(c2ccccc2)c2cc(SC)c(OCC(=O)OCC)cc2S(=O)(=O)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCCC1(CC)CN(c2ccccc2)c2cc(SCC)c(OCC(=O)O)cc2S(=O)(=O)C1
Reaction time: 1 h
Yield: 99 %

Procedure:
1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-ethoxycarbonylmethoxy-2,3,4,5 tetrahydro-1,5-benzothiazepine (Method 43; 478 mg, 0.95 mmol) was added THF (15 ml), water (3 ml) and LiOH (34 mg, 1.4 mmol). The reaction was then stirred for 1 hour. Then AcOH (0.2 ml) was added along with water (10 ml) and DCM (10 ml) The aqueous layer was then extracted three times with DCM. The combined organic phases were then dried and concentrated to give the title compound 450 mg (99%). NMR (400 MHz) 0.7-0.9 (m, 6H), 1.0-1.7 (m, 8H), 2.2 (s, 3H), 3.2 (q, 2H), 3.7 (m, 2H), 4.8 (s, 2H), 6.65 (s, 1H), 0-7.9 (m, 6H), 7.05 (d, 2H), 7.25 (t, 2H), 7.35 (s, 1H), 8.4 (brs, 1H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:7][C:8]([C:10]1[CH:11]=[N:12][N:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][CH2:22][CH2:21][C@@H:20]3[C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=3[F:31])=[N:15][C:14]=12)=[O:9])([CH3:6])[CH3:5].C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl.CCOC(C)=O>[F:31][C:25]1[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:24]=1[C@H:20]1[CH2:21][CH2:22][CH2:23][N:19]1[C:16]1[CH:17]=[CH:18][N:13]2[N:12]=[CH:11][C:10]([C:8]([NH:7][C:4]([CH3:6])([CH3:5])[CH2:3][NH:2][S:40]([CH3:39])(=[O:42])=[O:41])=[O:9])=[C:14]2[N:15]=1
Reactant: CC(C)(CN)NC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(CNS(C)(=O)=O)NC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.5 %

Procedure:
(R)—N-(1-amino-2-methylpropan-2-yl)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide hydrochloride (24.0 mg, 0.0532 mmol) was dissolved in DCM (0.53 mL) and triethylamine (15.2 μL, 0.109 mmol) followed by MeSO2Cl (4.34 μL, 0.0559 mmol) were added sequentially. The mixture was stirred at ambient temperature for 2 hours and was diluted with EtOAc. The mixture was washed with water and brine and was dried with MgSO4. The solution was filtered and concentrated to afford the title compound (8.0 mg, 30% yield) as a white solid. MS (apci) m/z=493.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.[OH-].[NH4+:14]>S(Cl)(Cl)=O.CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([NH2:14])=[O:12])=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: O=C(O)CCc1ccc(Br)cc1
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: NC(=O)CCc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
To a solution of 3-(4-bromophenyl)propanoic acid (15.0 g) in thionyl chloride (24.5 g) was added catalytic amount of N,N-dimethylformamide (one drop) and refluxed for 1.5 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was poured slowly into 28% aqueous ammonium hydroxide solution (150 ml) at 0° C. The mixture was extracted with ethyl acetate, washed with water and brine and dried over magnesium sulfate. Filtration followed by evaporation under reduced pressure gave 3-(4-bromophenyl)propanamide (13.7 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:21][CH2:20][C:13]3[N:14]=[CH:15][N:16]=[C:17](OC)[C:12]=3[CH2:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].CN(C)C1C=CC=CC=1.CN(C)C=O.P(Cl)(Cl)([Cl:38])=O.[OH-].[Na+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:21][CH2:20][C:13]3[N:14]=[CH:15][N:16]=[C:17]([Cl:38])[C:12]=3[CH2:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: COc1ncnc2c1CN(c1ccc(Cl)cc1C#N)CC2
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CN(C)c1ccccc1
Product: N#Cc1cc(Cl)ccc1N1CCc2ncnc(Cl)c2C1
Temperature: 110 °C

Procedure:
A mixture of 5-chloro-2-(4-methoxy-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzonitrile (4.15 g, 13.1 mmol), N,N-dimethylaniline (0.18 mL, 1.4 mmol), N,N-dimethylformamide (0.21 mL, 2.7 mmol) and acetonitrile (35 mL) was heated to dissolve at 105° C. Phosphoryl chloride (5.3 mL, 56 mmol) was added dropwise over 3 mins and the mixture was heated to reflux at 110° C. After another 20 hours refluxing, the reaction mixture was allowed to cool and poured over ice (200 g), and then 45% NaOH (75 mL) was added. The mixture was extracted with CH2Cl2 (3×200 mL). The combined organic layers were dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (0-100% EtOAc/hexane) to afford a yellow oil which became a solid in the freezer.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH:14]=[CH:15][CH2:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][C:22]=2[NH:23]C(OC(C)(C)C)=O)[C:10](=[O:31])[CH2:9]1)=O)(C)(C)C.[Cl:32][C:33]1[S:37][C:36]([CH:38]=[CH:39][S:40](Cl)(=[O:42])=[O:41])=[CH:35][CH:34]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl.CC#N>[NH2:23][C:22]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[CH2:16][CH:15]=[CH:14][N:11]1[CH2:12][CH2:13][N:8]([S:40]([CH:39]=[CH:38][C:36]2[S:37][C:33]([Cl:32])=[CH:34][CH:35]=2)(=[O:42])=[O:41])[CH2:9][C:10]1=[O:31]
Reactant: O=S(=O)(Cl)C=Cc1ccc(Cl)s1
Reactant: CC(C)(C)OC(=O)Nc1ccncc1CC=CN1CCN(C(=O)OC(C)(C)C)CC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: ClCCl
Product: Nc1ccncc1CC=CN1CCN(S(=O)(=O)C=Cc2ccc(Cl)s2)CC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-[3-(4-tert-Butoxycarbonylamino-pyridin-3-yl)-propenyl]-3-oxo-piperazine-1-carboxylic acid tert-butyl ester from EXAMPLE 96, Part B (45 mg, 0.10 mmol) is dissolved in 20% TFA/CH2Cl2 and stirred at r.t. for 2 hours. The solution is concentrated to residue. The residue is dissolved in MeCN (2.5 ml) and treated with 4-methylmorphorline (0.027 ml, 0.25 mmol). 2-(5-Chloro-thiophen-2-yl)-ethenesulfonyl chloride (24 mg, 0.10 mmol), EXAMPLE 3, in MeCN (1 mL) is then added dropwise. The reaction mixture is stirred at r.t. for 1 h, then subjected to reverse phase HPLC purification, to give the title compound as white solid (0.040 g, 0.037 mmol). MS m/z 439, 441 (M+H); 1H NMR (CD3OD, 300 MHz) δ8.20 (br, 1H), 8.10 (s, 1H), 8.08 (d, 1H), 7.60 (d, 1H), 7.53 (d. 1H), 7.35 (d, 1H), 7.21 (d, 1H), 7.07 (d, 1H), 6.82 (d, 1H), 5.27 (m, 1H), 3.88 (s, 2H), 3.60-3.50 (m, 4H), 3.30 (d, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:43])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][N:23]([CH2:41][CH3:42])[S:24]([C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:34]3[CH:35]=[C:36]([CH3:40])[CH:37]=[CH:38][CH:39]=3)=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH:6]=1.[H-].[Na+].I[CH3:47]>C1COCC1>[CH3:1][O:2][C:3](=[O:43])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:14][C:13]=2[CH2:22][N:23]([CH2:41][CH3:42])[S:24]([C:27]2[CH:32]=[CH:31][C:30]([N:33]([CH3:47])[C:34]3[CH:35]=[C:36]([CH3:40])[CH:37]=[CH:38][CH:39]=3)=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH:6]=1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)OC)c1)S(=O)(=O)c1ccc(Nc2cccc(C)c2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(Cc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)OC)c1)S(=O)(=O)c1ccc(N(C)c2cccc(C)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To [3-(2-{[ethyl-(4-m-tolylamino-benzenesulfonyl)-amino]-methyl}-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid methyl ester (0.080 g, 0.13 mmol) in THF (2 mL) under N2 was added sodium hydride (60% in mineral oil; 0.016 g, 0.39 mmol), and the mixture was stirred for 30 minutes at room temperature. Iodomethane (0.02 mL, 0.39 mmol) was added, and the reaction was stirred at room temperature for 4 hours. Analytical LCMS indicated that some starting material remained, so additional sodium hydride (60% in mineral oil; 0.008 g, 0.20 mmol)) and iodomethane (0.01 mL, 0.20=01) was added, and the reaction was stirred for 30 minutes and then taken directly to the hydrolysis step as a solution in THF.
Reaction SMILES: [CH:1]1([NH:4][CH3:5])[CH2:3][CH2:2]1.[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13](Cl)(=[O:15])=[O:14]>C(Cl)Cl>[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([N:4]([CH:1]1[CH2:3][CH2:2]1)[CH3:5])(=[O:15])=[O:14]
Reactant: O=S(=O)(Cl)c1ccccc1Br
Reactant: CNC1CC1
Solvent: ClCCl
Product: CN(C1CC1)S(=O)(=O)c1ccccc1Br
Temperature: 22 °C
Reaction time: 2 h

Procedure:
450 μl of N-cyclopropyl-N-methylamine are added dropwise with cooling to a solution of 640 mg of 2-bromobenzenesulfonyl chloride in 2.5 ml of DCM. The mixture is subsequently stirred at 22° C. for 2 h, extracted twice with 5 ml of 1N sodium hydroxide solution, the organic phase is dried over magnesium sulfate, filtered and evaporated in vacuo.