Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2)(=[O:12])=[O:11].[CH:23]1([NH:26][CH2:27][C@@H:28]2[CH2:32][CH2:31][CH2:30][N:29]2[C:33]([C:35]2[C:36]([CH3:43])=[C:37]([CH:41]=O)[NH:38][C:39]=2[CH3:40])=[O:34])[CH2:25][CH2:24]1>N1CCCCC1.C(O)C>[CH:23]1([NH:26][CH2:27][C@@H:28]2[CH2:32][CH2:31][CH2:30][N:29]2[C:33]([C:35]2[C:36]([CH3:43])=[C:37](/[CH:41]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])(=[O:12])=[O:11])=[CH:21][CH:20]=4)[NH:38][C:39]=2[CH3:40])=[O:34])[CH2:24][CH2:25]1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(F)cccc3F)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCC[C@H]1CNC1CC1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(F)cccc4F)cc32)c(C)c1C(=O)N1CCC[C@H]1CNC1CC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of 5-(2,6-difluoro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one (280 mg, 0.87 mmol), 4-((S)-2-cyclopropylaminomethyl-pyrrolidine-1-carbonyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (250 mg, 0.86 mmol) and piperidine (2 drops) in ethanol (2 mL) was stirred at rt for 4 days. The reaction was concentrated and purified on a silica gel column to give the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](SC)=[N:7][C:6]=2[CH:18]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[N:7][C:6]=2[CH:18]=1
Reactant: C1COCCN1
Reactant: CSC1=Nc2cc(Cl)ccc2Nc2ccccc21
Product: Clc1ccc2c(c1)N=C(N1CCOCC1)c1ccccc1N2
Yield: 16.1 %

Procedure:
Crude 8-chloro-11-methylsulfanyl-5H-dibenzo[b,e][1,4]diazepine (166JO50) (90 mg, purity 50%, 0.218 mmol) and morpholine (38 mg, 0.44 mmol) were reacted as described for Example 62 to give 11 mg of the title compound (166JO69B). MS (ESI) 314 (MH+). Purity for MH+ (UV/MS) 100/98.
Reaction SMILES: O=P(Cl)(Cl)Cl.[C:6]1([C:12]2[S:13][CH:14]=[CH:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CN([CH:26]=[O:27])C.[OH-].[Na+]>O>[CH:26]([C:14]1[S:13][C:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=1)=[O:27]
Reactant: c1ccc(-c2ccsc2-c2ccccc2)cc1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cc(-c2ccccc2)c(-c2ccccc2)s1
Temperature: 25 °C

Procedure:
POCl3 (80 mmol, 7.32 mL) was added at 0° C. to a solution of 2,3-diphenylthiophene (18 g, 76 mmol) in DMF (18 mL, 0.23 mol). At the end of the addition, the reaction mixture was allowed to warm to room temperature and refluxed for 3 h. Then it was cooled to room temperature and poured into a mixture of ice and a 10% solution of sodium hydroxide in water. The oily precipitate obtained was filtered and washed with cold methanol and hexane. The residue was crystallized. Yield 15 g (75%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9](Br)=[N:8][C:7]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:2].[C:31]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)#[N:32].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:36]2[CH:37]=[CH:38][C:33]([C:31]#[N:32])=[CH:34][CH:35]=2)=[N:8][C:7]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:2]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(Br)sc1C(=O)OCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(-c2ccc(C#N)cc2)sc1C(=O)OCC
Temperature: 25 °C
Yield: 35.8 %

Procedure:
A mixture of 2-bromo-4-{[(2,4-dimethoxy-benzyl)-ethoxycarbonylmethyl-amino]-methyl}-thiazole-5-carboxylic acid ethyl ester (1.19 g, 2.39 mmole), 4-cyanophenylboronic acid (702 mg, 4.77 mmole), cesium carbonate (2.33 g, 7.16 mmole) and tetrakis(triphenylphosphine)palladium (221 mg, 0.19 mmole) in dioxane (8 ml) was refluxed for 18 h before it was cooled to room temperature, quenched with water and filtered. The filtrate was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a yellow oil (448 mg). MS: (+) m/z 524.30 (M+H+)
Reaction SMILES: CCN(CC)CC.[N:8]1([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[Cl:21][C:22]1[S:26][C:25]([NH:27][C:28]([CH:30]([C:38]2[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=2)[CH2:31][CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:29])=[N:24][CH:23]=1>CC(N(C)C)=O>[Cl:21][C:22]1[S:26][C:25]([NH:27][C:28]([CH:30]([C:38]2[CH:39]=[CH:40][C:41]([S:44]([N:11]3[CH2:12][CH2:13][N:8]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9][CH2:10]3)(=[O:46])=[O:45])=[CH:42][CH:43]=2)[CH2:31][CH:32]2[CH2:33][CH2:34][O:35][CH2:36][CH2:37]2)=[O:29])=[N:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(Nc1ncc(Cl)s1)C(CC1CCOCC1)c1ccc(S(=O)(=O)Cl)cc1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(C(CC3CCOCC3)C(=O)Nc3ncc(Cl)s3)cc2)CC1
Reaction time: 16 h

Procedure:
NEt3 (278 μL, 2.0 mmol) and tert-butyl piperazine-1-carboxylate (373 mg, 2.0 mmol) were added to a stirred solution of 4-[1-(5-chlorothiazol-2-ylcarbamoyl)-2-(tetrahydropyran-4-yl)ethyl]benzenesulfonyl chloride (Preparation 60, 449 mg, 1.0 mmol) in anhydrous DMAc (4 mL). The mixture was stirred for 16 h, then the solvents were removed in vacuo. The residue was dissolved in EtOAc (50 mL) to give a solution that was washed with H2O (15 mL), saturated aqueous Na2CO3 (15 mL), and brine (15 mL), before being dried (MgSO4). Filtration, solvent evaporation, and column chromatography (IH-EtOAc, 7:3 to 1:1) gave tert-butyl 4-{4-[1-(5-chlorothiazol-2-ylcarbamoyl)-2-(tetrahydropyran-4-yl)ethyl]benzenesulfonyl}piperazine-1-carboxylate: m/z (ES+)=599.5 [M+H]+. A solution of this compound (189 mg, 316 μmol) in CH2Cl2-TFA (1:1, 7 mL) was stirred for 1 h. The solvents were evaporated off under reduced pressure, then the residue was triturated with Et2O. The product was collected, washed with Et2O, and air-dried to furnish the trifluoroacetate salt of the title compound: RTA=2.64 min; m/z (ES+)=499.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH2:11][OH:12])=[N:10][C:5]2=[N:4][CH:3]=1.N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>ClCCl>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH2:11][O:12][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])=[N:10][C:5]2=[N:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1ccn2c(Br)cnc2n1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1ccn2c(Br)cnc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
3-Bromoimidazo[1,2-a]pyrimidin-7-ylmethanol (912 mg, 4.00 mmol) was dissolved in dichloromethane (10 ml) and treated with imidazole (0.70 g, 10.3 mmol) and tert-butyldimethylsilyl chloride (0.77 g, 5.1 mmol) and the mixture left to stir at ambient temperature for 1 h. The reaction was diluted with dichloromethane (75 ml) and washed with 0.01N hydrochloric acid (2×50 ml). The organic phase was washed with saturated sodium hydrogencarbonate solution (50 ml), water (50 ml) and brine (50 ml), dried over anhydrous magnesium sulfate, filtered and evaporated to give crude 3-bromo-7-(tert-butyldimethylsilanyloxymethyl)imidazo[1,2-a]pyrimidine (1.37 g, 100%) as a yellow solid.
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24](O)=[O:25])[CH:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[CH3:27][N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH2:30][CH2:29]1.CC(C)N=C=NC(C)C.C1C=C2N=NN(O)C2=CC=1.O>C(Cl)Cl>[CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24]([N:38]3[CH2:37][CH2:36][N:35]([CH2:34][CH:31]4[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]4)[CH2:40][CH2:39]3)=[O:25])[CH:20]=2)[S:5]([C:8]2[C:9]([CH3:17])=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=2[CH3:14])(=[O:6])=[O:7])[CH2:2][CH2:3]1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)O)co2)C2CC2)c(C)c1
Reactant: CN1CCC(CN2CCNCC2)CC1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)N3CCN(CC4CCN(C)CC4)CC3)co2)C2CC2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AM using 5-({cyclopropyl[(4-methoxy-2,6 dimethylphenyl)sulfonyl]amino}methyl)furan-3-carboxylic acid (126 mg, 0.33 mmol), 1-[(1-methylpiperidin-4-yl)methyl]piperazine (59 mg, 0.30 mmol), DIC (79 μL, 0.5 mmol) and HOBt monohydrate (76 mg, 0.5 mmol) in DCM (2.5 mL). The crude product was purified by FCC eluting with 95:5 DCM:7N NH3 in MeOH.
Reaction SMILES: [OH:1][CH:2](CO)[CH2:3][CH2:4][CH2:5][C:6]1([CH2:35][CH2:36][CH2:37][CH:38]([OH:41])CO)[CH2:11][C:10](=[O:12])[C:9]2[CH:13]=[CH:14][C:15]([O:20][CH2:21][CH2:22][CH2:23][O:24][C:25]3[C:34]4[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=4[CH:28]=[CH:27][CH:26]=3)=[C:16]([CH2:17][CH2:18][CH3:19])[C:8]=2[O:7]1.I([O-])(=O)(=O)=O.[Na+]>C(O)(C)(C)C.O>[O:12]=[C:10]1[C:9]2[CH:13]=[CH:14][C:15]([O:20][CH2:21][CH2:22][CH2:23][O:24][C:25]3[C:34]4[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=4[CH:28]=[CH:27][CH:26]=3)=[C:16]([CH2:17][CH2:18][CH3:19])[C:8]=2[O:7][C:6]([CH2:35][CH2:36][CH2:37][CH:38]=[O:41])([CH2:5][CH2:4][CH2:3][CH:2]=[O:1])[CH2:11]1
Reactant: CCCc1c(OCCCOc2cccc3c2CCCC3)ccc2c1OC(CCCC(O)CO)(CCCC(O)CO)CC2=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(C)(C)O
Solvent: O
Product: CCCc1c(OCCCOc2cccc3c2CCCC3)ccc2c1OC(CCCC=O)(CCCC=O)CC2=O
Reaction time: 2 h
Yield: 60.9 %

Procedure:
To a solution of 200 mg (0.350 mmol) of the title product of Example 71 in 9.8 ml of t-butanol was added with stirring a solution of 300 mg (1.40 mmol) of sodium periodate in 2.2 ml of water. After two hours, the mixture was partitioned between diethyl ether and water. The organic layer was washed with brine, dried over sodium sulfate, filtered, and the solvent removed under reduced pressure. The residue was chromatographed on a silica gel column, using ethyl acetate/hexane as eluent. Crystallization from diethyl ether/hexane gave 114 mg of the title compound, m.p. 72°-73° C.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[N:19]([CH3:20])[NH:18][C:17](=[O:21])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCCC1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[N:19]([CH3:20])[NH:18][C:17](=[O:21])[CH:16]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C2CC(=O)NN2C)cc1OC1CCCC1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(=O)[nH]n2C)cc1OC1CCCC1
Yield: 32.7 %

Procedure:
To a magnetically-stirred solution of 5-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-methyl-3-pyrazolidinone (68.88 mmol, 20.0 g) in dry tetrahydrofuran (300 mL) at 0° C. is added, via cannula, a suspension of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 68.88 mmol, 15.64 g) in 200 mL dry tetrahydrofuran. The resulting heterogeneous mixture is allowed to warm slowly from O° C. to room temperature overnight. The solvent is removed in vacuo and the reddish-brown residue is triturated with methylene chloride. The undissolved yellow solid is removed via suction and discarded. The filtrate is concentrated in vacuo to produce a brownish foam which is purified by flash chromatography (SiO2 : gradient ranging from 15% ethyl acetate/methylene chloride to 30% ethyl acetate/methylene chloride). Concentration in vacuo affords a light tan solid which is dried overnight in vacuo at 50° C. to give the title compound (22.54 mmol, 6.50 g., 32.7%). 1H NMR (DMSO-d6,400 MHz) δ 9.58 (s, 1H); 6.98 (m, 3H); 5.53 (s, 1H); 4.83 (m, 1H); 3.77 (s, 3H); 3.60 (s, 3H); 1.90 (m, 2H); 1.70 (m, 4H); 1.55 (m, 2H). IR (KBr, cm-1) 3440, 2950, 2830, 1950, 1600, 1517, 1483, 1310, 1252, 1235, 1165, 1135, 1020, 770.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:5][CH:4]([CH:6]([NH:16][C:17]2[CH:18]=[N:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[C:22]([F:27])[CH:21]=3)[C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)[CH2:3]1.Cl.[CH2:30]([O:32][C:33](=[O:37])[CH2:34][CH2:35][NH2:36])[CH3:31].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][C:2]1([CH3:28])[CH2:3][CH:4]([CH:6]([NH:16][C:17]2[CH:18]=[N:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[C:22]([F:27])[CH:21]=3)[C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH:36][CH2:35][CH2:34][C:33]([O:32][CH2:30][CH3:31])=[O:37])=[O:12])=[CH:9][CH:8]=2)[CH2:5]1
Reactant: CCOC(=O)CCN
Reactant: CC1(C)CC(C(Nc2cnc3cc(F)ccc3c2)c2ccc(C(=O)O)cc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCNC(=O)c1ccc(C(Nc2cnc3cc(F)ccc3c2)C2CC(C)(C)C2)cc1
Reaction time: 2 h
Yield: 44.8 %

Procedure:
To a vial containing 4-((3,3-dimethylcyclobutyl)(7-fluoroquinolin-3-ylamino)methyl)benzoic acid (11.0 mg, 0.0290 mmol) was added 3-aminopropionic acid ethyl ester hydrochloride (4.90 mg, 0.0320 mmol), 1-Hydroxy-7-azabenzotriazole (4.80 mg, 0.0350 mmol) and 1-ethyl-3-(3-dimethylamino propyl)carbodiimide hydrochloride (6.70 mg, 0.0350 mmol). Anhydrous methylene chloride (0.290 mL) was added followed by triethylamine (0.005 mL, 0.0380 mmol). After 2 h, the reaction was diluted with methylene chloride and quenched with a saturated solution of ammonium chloride. The aqueous layer was extracted three times with methylene chloride. The combined organic layers were dried with sodium sulfate, filtered, and concentrated to give 16.0 mg of crude material. Purification by silica gel flash chromatography (0-70% ethyl acetate in heptane) provided ethyl 3-(4-((3,3-dimethylcyclobutyl)(7-fluoroquinolin-3-ylamino)methyl)benzamido)propanoate (6.20 mg, 45% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3, δ): 8.50 (d, J=2.3 Hz, 1H), 7.75-7.68 (m, 2H), 7.54 (dd, J=9.9, 2.5 Hz, 1H), 7.45-7.41 (m, 2H), 7.38 (dd, J=9.1, 6.0 Hz, 1H), 7.14 (td, J=8.7, 2.7 Hz, 1H), 6.80 (t, J=5.9 Hz, 1H), 6.70 (d, J=2.7 Hz, 1H), 4.40 (s, 1H), 4.23 (dd, J=9.4, 4.1 Hz, 1H), 4.20-4.08 (m, 2H), 3.70 (q, J=6.2 Hz, 2H), 2.62 (t, J=6.0 Hz, 2H), 2.52 (sxt, J=8.8 Hz, 1H), 2.09-1.97 (m, 1H), 1.71 (dd, J=19.7, 0.4 Hz, 2H), 1.63 (dd, J=8.0, 4.1 Hz, 1H), 1.31-1.21 (m, 3H), 1.13 (s, 3H), 1.09 (s, 3H). (M+1): 478.3.
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[C:8]([Cl:12])[N:9]=[C:10](Cl)[C:5]=2[S:4][CH:3]=1.[C:13]1([C@H:19]([NH2:21])[CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Br:1][C:2]1[C:6]2[N:7]=[C:8]([Cl:12])[N:9]=[C:10]([NH:21][C@@H:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH3:20])[C:5]=2[S:4][CH:3]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: Clc1nc(Cl)c2scc(Br)c2n1
Product: C[C@@H](Nc1nc(Cl)nc2c(Br)csc12)c1ccccc1
Yield: 82.8 %

Procedure:
The target compound (540 mg, 83% yield) was prepared in the same manner as Step 1 of Example 44 using 7-bromo-2,4-dichlorothieno[3,2-d]pyrimidine (500 mg, 1.77 mmol) and (R)-1-phenylethanamine (0.68 mL, 5.31 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:12]=1[C:13]([NH:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:14].[O:28]1CCOC[CH2:29]1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[C:11]2[C:12](=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[C:13](=[O:14])[N:15]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:29]1=[O:28]
Reactant: C1COCCO1
Reactant: CCOC(=O)CNC(=O)c1cc(OC)ccc1NCc1ccc(Cl)cc1Cl
Product: CCOC(=O)Cn1c(=O)c2cc(OC)ccc2n(Cc2ccc(Cl)cc2Cl)c1=O
Temperature: 140 °C

Procedure:
Into 10 ml of dioxane were dissolved 5.2 g of ethyl (2-((2,4-dichlorophenyl)methyl)amino-5-methoxybenzoyl)aminoacetate and 6.2 g of N,N'-carbonyldiimidazole, and the solution was heated to 140° to 150° C. After distilled off dioxane, the mixture was further heated for 15 minutes at 140° C. After cooling, ethanol was added and the crystalline substances were collected by filtration. They were recrystallized from ethanol to obtain 2,8 g of title compound. m.p. 167°-168° C.
Reaction SMILES: [C:1]([C:3]1[C:7]([S:8]([C:10]([F:13])([F:12])[F:11])=[O:9])=[C:6]([N:14]=[CH:15]OCC)[N:5]([C:19]2[C:24]([Cl:25])=[CH:23][C:22]([C:26]([F:29])([F:28])[F:27])=[CH:21][C:20]=2[Cl:30])[N:4]=1)#[N:2].[BH4-].[Na+].C(O)(=[O:35])C>C(O)C>[C:1]([C:3]1[C:7]([S:8]([C:10]([F:12])([F:13])[F:11])(=[O:35])=[O:9])=[C:6]([NH:14][CH3:15])[N:5]([C:19]2[C:24]([Cl:25])=[CH:23][C:22]([C:26]([F:29])([F:28])[F:27])=[CH:21][C:20]=2[Cl:30])[N:4]=1)#[N:2]
Reactant: CC(=O)O
Reactant: CCOC=Nc1c(S(=O)C(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CNc1c(S(=O)(=O)C(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 10 °C
Reaction time: 6.75 h
Yield: 22.5 %

Procedure:
A 50 L reactor was charged with 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-ethoxymethylideneamino-4-trifluoromethylsulfinylpyrazole (1.645 g, 3.335 moles) and absolute ethanol (16 L) under nitrogen. The solution was cooled to 10° C., and sodium borohydride (266 g, 7.03 moles) was added slowly such that the temperature remained generally below 35° C. After 6.75 h, some additional sodium borohydride (25 g, 0.66 mole) was added and stirring was continued overnight. Acetic acid (1.3 L, 22.7 moles) was added to quench, followed by 16 L of water. The resulting precipitate was collected by filtration, washed with water, and air-dried. Recrystallization from methanol afforded 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-methylamino-4-trifluoromethylsulfonylpyrazole (350 g) as an off-white solid (m.p. about 227° C.).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]([OH:19])=O)=[CH:16][C:9]=23)[C:5]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[N:4]1)[CH3:2].[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][NH2:38])[CH2:32][CH2:31]1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]([NH:38][CH2:37][CH2:36][N:33]4[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]4)=[O:19])=[CH:16][C:9]=23)[C:5]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[N:4]1)[CH3:2]
Reactant: CCn1cc(-c2ccnc3[nH]c(C(=O)O)cc23)c(-c2ccc([N+](=O)[O-])cc2)n1
Reactant: CN1CCN(CCN)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CCn1cc(-c2ccnc3[nH]c(C(=O)NCCN4CCN(C)CC4)cc23)c(-c2ccc([N+](=O)[O-])cc2)n1
Yield: 20 %

Procedure:
A solution of 4-[1-ethyl-3-(4-nitrophenyl)-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (0.331 mmol), 2-(4-methyl-piperazin-1-yl)-ethylamine (0.993 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.397 mmol) in N,N-dimethylformamide (1 mL) under nitrogen was stirred for 17 h at room temperature. The reaction was concentrated in vacuo and purification by Gilson reverse phase HPLC afforded the title compound as a solid (20%). ESMS [M+H]+: 503.4
Reaction SMILES: [CH2:1]([C:3]([C:21]1[S:25][C:24]([C:26]([OH:28])=O)=[C:23]([CH3:29])[CH:22]=1)([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([OH:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[C:8]([CH3:20])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].CCN(CC)CC.[NH2:37][CH2:38][CH2:39][S:40]([CH3:43])(=[O:42])=[O:41].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[CH3:43][S:40]([CH2:39][CH2:38][NH:37][C:26]([C:24]1[S:25][C:21]([C:3]([CH2:1][CH3:2])([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([OH:19])[C:15]([CH3:17])([CH3:16])[CH3:18])=[C:8]([CH3:20])[CH:7]=2)[CH2:4][CH3:5])=[CH:22][C:23]=1[CH3:29])=[O:28])(=[O:42])=[O:41]
Reactant: CS(=O)(=O)CCN
Reactant: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc(C)c(C(=O)O)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc(C)c(C(=O)NCCS(C)(=O)=O)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.7 %

Procedure:
To a mixture of 5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butyoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carboxylic acid (0.6344 g, 1.52 mmol) and CH2Cl2 (10 mL) is added Et3N (0.85 mL, 6.07 mmol), followed by hydrochloride salt of 2-aminoethylmethylsulfone (0.2416 g, 1.52 mmol), EDCl (0.320 g, 1.67 mmol), and HOBT (0.226 g, 1.67 mmol). The resulting solution is stirred at RT overnight, diluted with CH2C2 (30 mL), washed with 1.0 M HCl (3×20 mL), brine (20 mL), dried over MgSO4, and concentrated. The resulting residue is purified by chromatography (50% EtOAc/Hex) to give the titled compound (0.4042 g, 0.77 mmol, 51%). 1H NMR (CDC3), δ 0.71 (t, J=7.3 Hz, 6H), 1.03 (s, 9H), 2.09 (q, J=7.3 Hz, 4H), 2.21 (s, 3H), 2.42 (d, J=3.0 Hz, 1H), 2.46 (s, 3H), 2.98 (s, 3H), 3.32 (t, J=6.4 Hz, 2H), 3.71 (dt, J=8.9, 2.9 Hz, 1H), 3.84-3.94 (m, 3H), 4.10 (dd, J=9.3, 2.5 Hz, 1H), 6.44 (t, J=5.8 Hz, 1H), 6.59 (s, 1H), 6.73 (d, J=8.4 Hz, 1H), 6.99 (d, J=1.7 Hz, 1H), 7.03 (dd, J=8.7, 2.5 Hz, 1H). LC/MS (m/z): calcd for C27H42NO5S2 (M+H)+:524.8; found: 524.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=3)[CH2:11][CH2:10][C@@H:9]2[C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.C(O)C>O=[Pt]=O.C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=3)[CH2:11][CH2:10][C@@H:9]2[C:22]2[CH:23]=[CH:24][C:25]([NH2:28])=[CH:26][CH:27]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc([C@H]2CC[C@H](c3ccc([N+](=O)[O-])cc3)N2c2ccc(F)cc2)cc1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1ccc([C@H]2CC[C@H](c3ccc(N)cc3)N2c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 36.9 %

Procedure:
To a solution of the product from Example 38B (2.34 g, 5.74 mmol) in 1:1 ethanol:THF (60 ml) in a 250 mL stainless steel pressure bottle was added PtO2 (0.47 g, 2.06 mmol) and the resulting mixture was placed under H2 pressure (30 psi) and stirred at rt. for 90 min. The mixture was filtered through a nylon membrane and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-65% ethyl acetate in hexanes to give the title compound as a solid (0.736 g, 37%).
Reaction SMILES: [NH:1]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[C@H:2]([C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH2:3][OH:4].[C:18](=O)([O:23]C1C2N=NNC=2C=CC=1)[O:19][CH2:20][CH:21]=[CH2:22]>>[NH:1]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[C@H:2]([C:5]([O:7][C:8]([CH3:11])([CH3:9])[CH3:10])=[O:6])[CH2:3][O:4][C:18]([O:19][CH2:20][CH:21]=[CH2:22])=[O:23]
Reactant: C=CCOC(=O)Oc1cccc2[nH]nnc12
Reactant: CC(C)(C)OC(=O)[C@H](CO)NN1CCOCC1
Product: C=CCOC(=O)OC[C@H](NN1CCOCC1)C(=O)OC(C)(C)C

Procedure:
Morpholino-Ser(OAloc) was prepared from SER(OtBu)-OtBu. Reaction of Ser(OtBu)-OtBu with 4-morpholineacarbonyl chloride in pyridine yielded morpholino-Ser(OtBu)-OtBu. Morpholino-Ser(OtBu)-OtBu was hydrolyzed with TFA to yield morpholino-Ser. Esterification of morpholino-Ser with isobutylene in the presence of a catalytic amount of H2SO4 afforded morpholino-Ser-OtBu. Reaction of morpholino-Ser-OtBu with allyl 1-benzotriazolyl carbonate yielded morpholino-Ser(OAloc)-OtBu. Morpholino-Ser(OAloc)-OtBu was hydrolyzed with TFA in CHCl3 (1:1) to yield morpholino-Ser(OAloc).