Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12](=[O:41])[C:13](=O)[CH:14](Br)[CH:15]([CH3:38])[CH:16]2[CH:19]([CH:20]([O:22][Si](C(C)(C)C)(C)C)[CH3:21])[C:18](=[O:30])[N:17]2[Si](C(C)(C)C)(C)C)=[CH:6][CH:5]=1)([O-:3])=[O:2].[SH:42][CH:43]1[CH2:47][O:46][CH:45]([CH2:48][OH:49])[CH2:44]1.O1CCCC1>C(N(CC)CC)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][O:11][C:12]([C:13]2[N:17]3[CH:16]([CH:15]([CH3:38])[C:14]=2[S:42][CH:43]2[CH2:44][CH:45]([CH2:48][OH:49])[O:46][CH2:47]2)[CH:19]([CH:20]([OH:22])[CH3:21])[C:18]3=[O:30])=[O:41])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: OCC1CC(S)CO1
Reactant: CC(O[Si](C)(C)C(C)(C)C)C1C(=O)N([Si](C)(C)C(C)(C)C)C1C(C)C(Br)C(=O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(O)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3COC(CO)C3)C(C)C12

Procedure:
The title compound is prepared by the procedure of Example 104 using 0.166 g of product from Example 103, 0.0396 g of product from Example 77, 2.3 ml of dry tetrahydrofuran and 0.0413 ml of triethylamine to obtain the crude β-lactam. The subsequent cyclization uses the above product, 1.48 ml of 1M solution in methylene chloride of titanium tetrachloride and 1.6 ml of dry tetrahydrofuran to give 0.053 g of the desired product as a white solid.
Reaction SMILES: [C:1]([CH2:3][C:4]1[S:8][CH:7]=[C:6]([C:9](O)=[O:10])[CH:5]=1)#[N:2].CSC.B.O>C1COCC1>[OH:10][CH2:9][C:6]1[CH:5]=[C:4]([CH2:3][C:1]#[N:2])[S:8][CH:7]=1
Reactant: N#CCc1cc(C(=O)O)cs1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Solvent: O
Product: N#CCc1cc(CO)cs1
Yield: 68.9 %

Procedure:
A solution of 5-cyanomethyl-thiophene-3-carboxylic acid (2.7 g, 16.1 mmol) in THF (95 mL) is treated with borane dimethylsulfide (1.78 mL, 10.0 M, 17.8 mmol) in a dropwise maner. After the addition is complete, the solution is warmed to reflux for 1 h. After cooling, water is added and the mixture is extracted with dichloromethane (3×). The combined extracts are dried over Na2SO4, filtered and concentrated in vacuo. The residue is purified by flash chromatography (silica gel, 30-50% ethyl acetate in heptane) to give (4-hydroxymethyl-thiophen-2-yl)-acetonitrile (1.7 g, 69%) as a white solid: mp 45-47° C.; 1H NMR (CDCl3, 300 MHz) δ 7.16 (s, 1 H), 7.02 (s, 1 H), 4.60 (s, 2 H), 3.84 (s, 2 H), 1.79 (s, 1 H).
Reaction SMILES: CON(C)[C:4]([C@@H:6]1[CH2:10][C@H:9]([CH3:11])[CH2:8][N:7]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH:4]([C@@H:6]1[CH2:10][C@H:9]([CH3:11])[CH2:8][N:7]1[C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])=[O:5]
Reactant: CON(C)C(=O)[C@@H]1C[C@H](C)CN1C(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H]1C[C@@H](C=O)N(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
(2S,4S)-tert-butyl 2-(methoxy(methyl)carbamoyl)-4-methylpyrrolidine-1-carboxylate (5.30 g, 19.5 mmol) was dissolved in 120 mL THF, cooled to −78° C. and treated with lithium aluminium hydride (1M in THF, 19.5 mL, 19.5 mmol) dropwise via addition funnel. After 1 hour, the mixture was brought to 0° C. and kept at that temperature for 2 hours. It was quenched by dropwise addition of a 50 mL solution of 3.0 g KHSO4 in water, removed from the ice bath, and stirred 15 minutes at room temperature. The product was extracted with three 75 mL portions of ethyl acetate and washed with brine. The organic phase was dried over sodium sulphate, filtered, and concentrated to give crude (2S,4S)-tert-butyl 2-formyl-4-methylpyrrolidine-1-carboxylate. (4.89 g)
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:21]2[C:20]([CH3:22])=[CH:19][N:18]=[C:17]([NH2:23])[C:16]=2[N:15]=[C:14]1[CH2:24][O:25][CH2:26][CH3:27]>>[NH2:23][C:17]1[C:16]2[N:15]=[C:14]([CH2:24][O:25][CH2:26][CH3:27])[N:13]([CH2:12][CH2:11][CH2:10][CH2:9][NH:8][S:3]([N:2]([CH3:7])[CH3:1])(=[O:5])=[O:4])[C:21]=2[C:20]([CH3:22])=[CH:19][N:18]=1
Reactant: CCOCc1nc2c(N)ncc(C)c2n1CCCCN
Reactant: CN(C)S(=O)(=O)Cl
Product: CCOCc1nc2c(N)ncc(C)c2n1CCCCNS(=O)(=O)N(C)C

Procedure:
Using the method of Examples 115-135, dimethylsulfamoyl chloride was reacted with 1-(4-aminobutyl)-2-(ethoxymethyl)-7-methyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired product. The observed accurate mass was 385.2029.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([CH2:9][C:10]([OH:12])=[O:11])=[O:8].[NH2:13][CH:14]1[C:32](=[O:33])[N:16]2[C:17]([C:29]([OH:31])=[O:30])=[C:18]([CH2:21][S:22][C:23]3[S:27][C:26]([CH3:28])=[N:25][N:24]=3)[CH2:19][S:20][C@H:15]12>>[CH3:9][C:10]([O:12][CH2:21][C:18]1[CH2:19][S:20][C@@H:15]2[C@H:14]([NH2:13])[C:32](=[O:33])[N:16]2[C:17]=1[C:29]([OH:31])=[O:30])=[O:11].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([CH2:9][C:10]([NH:13][CH:14]1[C:32](=[O:33])[N:16]2[C:17]([C:29]([OH:31])=[O:30])=[C:18]([CH2:21][S:22][C:23]3[S:27][C:26]([CH3:28])=[N:25][N:24]=3)[CH2:19][S:20][C@H:15]12)=[O:12])=[O:8]
Reactant: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Reactant: O=C(O)CS(=O)c1ccccn1
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)CS(=O)c4ccccn4)[C@H]3SC2)s1

Procedure:
Procedures of Example 10 were repeated by using 2-pyridylsulfinylacetic acid and 7-amino-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid instead of the 4-pyridylsulfinylacetic acid and the 7-aminocephalosporanic acid respectively to obtain 7-(2-pyridylsulfinylacetamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid of the R form.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[S:10][CH:11]=[C:12]([CH:14]=O)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:16]1[CH2:22][C:20](=[O:21])[N:19]([CH2:23][C:24]([OH:26])=[O:25])[C:17]1=[S:18].[Cl-].[NH4+]>C(O)C>[NH3:8].[CH2:1]([NH:8][C:9]1[S:10][CH:11]=[C:12]([CH:14]=[C:22]2[S:16][C:17](=[S:18])[N:19]([CH2:23][C:24]([OH:26])=[O:25])[C:20]2=[O:21])[N:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CN1C(=O)CSC1=S
Reactant: O=Cc1csc(NCc2ccccc2)n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: N
Product: O=C(O)CN1C(=O)C(=Cc2csc(NCc3ccccc3)n2)SC1=S

Procedure:
The reaction described in Example 1 was repeated, but using 0.58 g of 2-benzylaminothiazol-4-carbaldehyde, 0.5 g of rhodanine-3-acetic acid 0.3 g of ammonium chloride. 0.3 ml of 28% v/v aqueous ammonia and 40 ml of ethanol, giving the title compound as yellow needles.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[N:16]=[CH:15][C:14]([C:17]4[O:18][C:19]([CH3:30])=[C:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[N:21]=4)=[C:13]([NH:31][CH:32]([CH3:34])[CH3:33])[CH:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[H-].[Na+].[CH3:37][C:38](OC(C)=O)=[O:39]>O1CCCC1>[C:38]([N:22]([C:20]1[N:21]=[C:17]([C:14]2[CH:15]=[N:16][C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]4[N:3]=[CH:2][S:1][C:5]=4[CH:6]=3)=[CH:12][C:13]=2[NH:31][CH:32]([CH3:34])[CH3:33])[O:18][C:19]=1[CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])(=[O:39])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1oc(-c2cnc(Nc3ccc4ncsc4c3)cc2NC(C)C)nc1NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N(C(=O)OC(C)(C)C)c1nc(-c2cnc(Nc3ccc4ncsc4c3)cc2NC(C)C)oc1C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of tert-butyl 2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-methyloxazol-4-ylcarbamate (Example 106) (20 mg, 0.042 mmol) in Tetrahydrofuran (5 mL) was cooled to 0° C. and treated with NaH (0.042 mmol). Stirred the reaction mixture at 0° C. for 10 min. Added Ac2O (0.042 mmol) to the reaction mixture and stirred at 0° C. for 0.5 h. The reaction mixture was quenched with ice pieces and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4, filtered and concentrated to afford tert-butyl acetyl(2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-methyloxazol-4-yl)carbamate. LC/MS: Acquity BEH C18 2.1×50 mm, 1.8 micron; Solvent A=0.1% TFA in water; Solvent B=0.1% TFA in ACN; gradient 0-100% B over 2 min; retention time: 0.90 min; LCMS (ES-API), m/z 523.6 (M+H).
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[C:18]([S:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:17][C:16]([Br:26])=[CH:15][N:14]=1)=[S:11])(=O)C1C=CC=CC=1.CO.[OH-].[Na+]>O>[Br:26][C:16]1[CH:17]=[C:18]([S:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:13]([NH:12][C:10]([NH2:9])=[S:11])=[N:14][CH:15]=1
Reactant: O=C(NC(=S)Nc1ncc(Br)cc1Sc1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: NC(=S)Nc1ncc(Br)cc1Sc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
To 1-Benzoyl-3-(5-bromo-3-(phenylthio)pyridin-2-yl)thiourea (25.7 g, 57.8 mmol) and MeOH (250 mL) was added sodium hydroxide (38.6 mL, 116 mmol) and stirred at ambient temperature for 8 hours. Diluted with water (250 mL) and filtered and washed with water. The precipitate was dried in vacuum oven to afford the title compound (19.0 g, 96.5% yield).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.Br[CH2:14][CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[C:17]1[CH2:25][C:26]([O:28][CH3:29])=[O:27].C(NC(C)C)(C)C.[Li]>O1CCCC1.O>[CH:25]1([C:26]([O:28][CH3:29])=[O:27])[CH2:14][CH2:15][N:16]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[C:17]12
Reactant: COC(=O)Cc1c(C(=O)OC)ccn1CCBr
Agent: [Li]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: O
Product: COC(=O)c1ccn2c1C(C(=O)OC)CC2
Temperature: 10 °C
Reaction time: 2 h

Procedure:
Under nitrogen, n-butyllithium (1.3M in hexane, 75 mL, 98 mmol) was added slowly at -5°-0° C., with stirring, to a solution of di(isopropyl)amine (13.8 mL, 10.0 g, 98 mmol) in tetrahydrofuran (dry, 50 mL). The resulting solution was transferred to an addition funnel and added, under nitrogen at 0°-5° C., to a stirred slurry of methyl N-(2-bromoethyl)-3-methoxycarbonyl-2-pyrroleacetate (20.0 g, 66 mmol) in tetrahydrofuran (dry, 100 mL). There was a slight temperature rise, and complete dissolution occurred after addition of about two-thirds of the lithium di(isopropyl)amine solution. The resulting solution was stirred for 2 hours while warming to 10° C., then diluted with water (100 mL) with slight heat evolution. The solvents were stripped by atmospheric distillation: 240 mL collected, with a pot temperature of 80° C., to afford a solution of dimethyl 2,3-dihydro-1H-pyrrolo-[1,2-a]pyrrole-1,7-dicarboxylate. The diester may be isolated at this point by quenching with water, extraction into an organic solvent such as ethyl acetate, and evaporation of the solvent; and purified by conventional methods. However, it is also convenient to saponify the diester to the dicarboxylic acid without isolation from the solution.
Reaction SMILES: Cl.[C:2]1([CH:8]2[CH:13]=[CH:12][NH:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O.CCO.[Pd]>[C:2]1([CH:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1=CC(c2ccccc2)CCN1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: c1ccc(C2CCNCC2)cc1
Reaction time: 2 h
Yield: 59.1 %

Procedure:
A mixture of 20.5 g (104.9 mmol) of 4-phenyltetrahydropyridine hydrochloride (Aldrich) and 0.5 g of 10% Pd/C in 40 mL of H2O and 160 mL of EtOH was stirred under hydrogen at 45 psi for 2 h. The reaction mixture was then filtered though a thin pad of celite eluting with EtOH and H2O. The filtrate was concentrated and the residue was stirred in 75 mL of ether. To it at 0° C. was added 5 g of solid NaOH. The layers were separated and the aqueous layer was extracted with ether. The combined organic fractions were washed with sat'd NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated. The residue was crystalized from cold heptane to give 10 g of the title compound. 1H NMR (CDCl3) δ7.33 (t, 2H, J=7.7 Hz), 7.25-7.28 (m, 3H), 6.90 (bs, 1H), 3.65 (d, 2H, J=12.6 Hz), 3.04 (d of d,2H, J=13.0, 2.5 hz), 2.78 (t of d, 1H, J=12.1, 3.2 Hz), 2.21-2.30 (m,2H), 2.05 (d, 2H, J=14.0 Hz).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([F:14])[F:13])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([OH:27])=O)[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[NH2:28][C@@H:29]1[CH2:33][C@@H:32]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C@H:31]([F:42])[CH2:30]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([F:14])[F:13])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:28][C@H:29]4[CH2:33][C@H:32]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:38])([CH3:40])[CH3:39])[C@@H:31]([F:42])[CH2:30]4)=[O:27])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:2][CH2:3]1
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@@H](N)C[C@H]1F
Product: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1C[C@H](NC(=O)OC(C)(C)C)[C@@H](F)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.g1) and tert-butyl [(1R*,2R*,4R*)-4-amino-2-fluorocyclopentyl]carbamate (example C44) the title compound is obtained as pale yellow foam.
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8](=[N:31][O:32][CH2:33][C:34](=[O:56])[NH:35][NH:36][C:37](=[O:55])[NH:38][C:39](=[O:54])[C:40]2[CH:45]=[CH:44][C:43]([O:46]C(=O)C)=[C:42]([O:50]C(=O)C)[CH:41]=2)[C:9]([NH:11][CH:12]2[C:29](=[O:30])[N:14]3[C:15]([C:26]([OH:28])=[O:27])=[C:16]([CH2:19][S:20][C:21]4[S:22][CH:23]=[N:24][N:25]=4)[CH2:17][S:18][C@H:13]23)=[O:10])[N:7]=1.N.C(OC1C=C(C=CC=1OC(=O)C)C([N:67]=C=O)=O)(=O)C.CCOCC>CO>[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8](=[N:31][O:32][CH2:33][C:34](=[O:56])[NH:35][NH:36][C:37](=[O:55])[NH:38][C:39](=[O:54])[C:40]2[CH:45]=[CH:44][C:43]([OH:46])=[C:42]([OH:50])[CH:41]=2)[C:9]([NH:11][CH:12]2[C:29](=[O:30])[N:14]3[C:15]([C:26]([O-:28])=[O:27])=[C:16]([CH2:19][S:20][C:21]4[S:22][CH:23]=[N:24][N:25]=4)[CH2:17][S:18][C@H:13]23)=[O:10])[N:7]=1.[NH4+:67]
Reactant: CC(=O)Oc1ccc(C(=O)NC(=O)NNC(=O)CON=C(C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nncs4)CS[C@H]23)c2csc(N)n2)cc1OC(C)=O
Reactant: CC(=O)Oc1ccc(C(=O)N=C=O)cc1OC(C)=O
Agent: Cl
Agent: N
Solvent: CCOCC
Solvent: CO
Product: Nc1nc(C(=NOCC(=O)NNC(=O)NC(=O)c2ccc(O)c(O)c2)C(=O)NC2C(=O)N3C(C(=O)[O-])=C(CSc4nncs4)CS[C@H]23)cs1
Product: [NH4+]
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
In 10 ml of methanol was dissolved 0.41 g (0.47 mmole) of 7-{2-[2-amino-1,3-thiazol-4-yl]-2-[3-((3,4-diacetoxybenzoyl)carbamoyl)carbazoyl]methoxyiminoacetamido}-3-[(1,3,4-thiadiazol-2-yl)thiomethyl]-3-cephem-4-carboxylic acid hydrochloride obtained in Example 49, and 0.3 ml of 25% aqueous ammonia was added thereto and the mixture was stirred at room temperature for one hour. To the resulting solution was added 0.22 g (0.84 mmole) of 3,4-diacetoxybenzoylisocyanate and the mixture was stirred at room temperature for 8 hours. To the resulting mixture was added 20 ml of ether and resulting precipitates were collected by filtration, washed with ether and then dried to obtain 0.26 g of the title compound. (Yield: 70.3%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([NH2:14])[CH:11]=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Br:15]N1C(=O)CCC1=O>CS(C)=O.O>[Br:15][C:9]1[N:10]=[CH:11][C:12]([NH2:14])=[N:13][C:8]=1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: Nc1cncc(-c2cccc(F)c2)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CS(C)=O
Product: Nc1cnc(Br)c(-c2cccc(F)c2)n1
Temperature: 0 °C
Reaction time: 5 h
Yield: 84.8 %

Procedure:
To a 0° C. cooled stirred solution of 6-(3-fluorophenyl)pyrazin-2-ylamine (0.5 g, 2.64 mmol) in a mixture of DMSO (10 mL) and water (0.25 mL), was added N-bromosuccinimide (0.518 g, 2.90 mmol) in portions. After stirring for 5 h, the mixture was poured into water, the precipitate collected by filtration, washed with water and dried to give the title compound as a yellow solid (0.60 g, 85%).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:20]([F:23])([F:22])[F:21])[C:12]2=[O:24])[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[CH3:31][O:32][C:33]([CH3:42])([CH3:41])[CH2:34][N:35]1[CH:39]=[CH:38][C:37]([NH2:40])=[N:36]1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:20]([F:21])([F:23])[F:22])[C:12]2=[O:24])[C:8]([NH:40][C:37]2[CH:38]=[CH:39][N:35]([CH2:34][C:33]([O:32][CH3:31])([CH3:41])[CH3:42])[N:36]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)[C@H](CC1CCCC1)N1Cc2c(cccc2C(F)(F)F)C1=O
Reactant: COC(C)(C)Cn1ccc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(C)(C)Cn1ccc(NC(=O)[C@H](CC2CCCC2)N2Cc3c(cccc3C(F)(F)F)C2=O)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 69 %

Procedure:
A solution of (S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionic acid (50 mg, 0.15 mmol, prepared as in Example 1) in methylene chloride (5 mL) and N,N-dimethylformamide (1 drop) cooled to 0° C. was treated with a solution of oxalyl chloride in methylene chloride (2.0 M, 88 μL, 0.18 mmol) and stirred at 0° C. for 10 min. After this time, the reaction mixture was warmed to room temperature and then stirred for another 25 min. After this time, the reaction mixture was then concentrated in vacuo and the residue taken up in methylene chloride (2 mL) and added dropwise to a separate reaction flask containing a mixture of 1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-ylamine (prepared as in US 20080021032, Example 94, 37 mg, 0.22 mmol) and 2,6-lutidine (32 μL, 0.29 mmol) in methylene chloride (5 mL) cooled to 0° C. The resulting reaction mixture was then allowed to warm to room temperature and stirred for 16 h. After such time, the reaction mixture was quenched with a saturated aqueous sodium bicarbonate solution (10 mL) and then extracted with methylene chloride (3×15 mL). The organic layers were then washed with a 1N aqueous hydrochloric acid solution (10 mL), dried over magnesium sulfate, filtered to remove the drying agent, and the filtrate concentrated in vacuo. The crude material was purified via automated flash chromatography (4 g silica gel column, 50% ethyl acetate/hexanes) to afford (S)-3-cyclopentyl-N-[1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide (51 mg, 71%) as a white foam: [α]32D=−41.1°, (c=0.09, methylene chloride); HR-ES(+) m/e calcd for C25H31N4O3F3 [M+H]+ 493.2421, observed 493.2419; 1H NMR (300 MHz, DMSO-d6) δ ppm 10.95 (s, 1H), 8.01 (t, J=8.60 Hz, 2H), 7.68-7.81 (m, 1H), 7.49 (d, J=1.81 Hz, 1H), 6.44 (d, J=2.11 Hz, 1H), 4.97-5.17 (m, 2H), 4.71 (d, J=18.41 Hz, 1H), 3.92-4.08 (m, 2H), 3.06-3.22 (m, 3H), 0.93-2.16 (m, 17H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:28])(=[O:27])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)=[CH:8][CH:7]=1.[NH2:30][CH2:31][C@@H:32]([C:34]1[CH:35]=[CH:36][C:37]([OH:45])=[C:38]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])[CH:39]=1)[OH:33]>>[CH3:1][O:2][C:3](=[O:29])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:21][CH2:22][CH:23]([NH:30][CH2:31][C@H:32]([OH:33])[C:34]4[CH:35]=[CH:36][C:37]([OH:45])=[C:38]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])[CH:39]=4)[CH2:24][CH2:25]3)=[CH:18][CH:19]=2)(=[O:28])=[O:27])=[CH:8][CH:7]=1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: COC(=O)COc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Product: COC(=O)COc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NC[C@H](O)c4ccc(O)c(NS(C)(=O)=O)c4)CC3)cc2)cc1

Procedure:
The title compound was prepared from {4-[4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-phenoxy}-acetic acid methyl ester (which was obtained in Example 232) and N-[5-((1 R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 278 as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.20–1.40 (m, 2 H), 1.75–1.90 (m, 2 H), 2.50–2.80 (m, 5 H), 2.92 (s, 3 H), 3.65–3.75 (m, 2 H), 3.67 (s, 3 H), 4.47 (dd, J=8.0, 4.1 Hz, 1 H), 4.87 (s, 2 H), 6.50–6.90) m, 8 H), 7.17 (d, J=1.8 Hz, 1 H), 7.59 (d, J=8.9 Hz, 2 H); MS (ES) m/z: 649.0 (MH+); HRMS Calcd. for C29H37N4O9S2 (MH+): 649.2004. Found: 649.2014.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:12]([C:28]3[CH:36]=[C:35]([O:37][CH3:38])[C:31]4[O:32][CH2:33][O:34][C:30]=4[CH:29]=3)[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=3[O:26][CH3:27])(=[O:18])=[O:17])=[O:14])=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.CN(C)[CH:41]=[O:42]>CCCCCC.O1CCCC1>[CH:41]([C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:12]([C:28]3[CH:36]=[C:35]([O:37][CH3:38])[C:31]4[O:32][CH2:33][O:34][C:30]=4[CH:29]=3)[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=3[O:26][CH3:27])(=[O:18])=[O:17])=[O:14])=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1)=[O:42]
Reactant: COc1cc(C)ccc1S(=O)(=O)NC(=O)C(c1cc(OC)c2c(c1)OCO2)c1cn(C)c2cc(Br)ccc12
Reactant: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc(C)ccc1S(=O)(=O)NC(=O)C(c1cc(OC)c2c(c1)OCO2)c1cn(C)c2cc(C=O)ccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Butylithium (0.8 ml of 2.5M solution in hexane) was added to a stirred solution of 6-bromo-3-{1-(7-methoxy-1,3-benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)sulfonamido]-2-oxoethyl}-1-methyl-1H-indole (from Example 92, 400 mg, 0.67 mmol) in anhydrous tetrahydrofuran at -75° C. under a nitrogen atmosphere. After 30 minutes dimethylformamide (0.15 ml) was added to the orange solution, and after a further 30 minutes the mixture was allowed to warm at 0° C. before quenching with excess 1N hydrochloric acid. Ethyl acetate was added and the organic layer was separated and washed with water. The organic layer was dried (magnesium sulphate), and the solvents removed in vacuo. The residue was flash chromatographed using 1% methanol in dichloromethane as eluant, and the product was crystallised from dichloromethane and diethyl ether mixture to give the title compound (187 mg).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].CO.[OH-].C([N+](C)(C)C)C1C=CC=CC=1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]1[C:28]([O:30][CH3:31])=[O:29]>O1CCOCC1>[C:1]([CH2:2][CH2:3][N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]1[C:28]([O:30][CH3:31])=[O:29])#[N:4]
Reactant: COC(=O)c1cc2ccccc2[nH]1
Reactant: C=CC#N
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)c1cc2ccccc2n1CCC#N
Temperature: 55 °C
Yield: 99.7 %

Procedure:
After 3.63 g (68.4 mmol) of acrylonitrile and 2.2 ml of 40% methanol solution of N-benzyltrimethyl-ammonium hydroxide was added to a solution of 10.0 g (57.1 mmol) of methyl 2-indolecarboxylate in 150 ml of 1,4-dioxane, the mixture was stirred at 55° C. for an hour. The reaction mixture was concentrated under reduced pressure. The resulting residue was added to a mixture of 5 ml of acetic acid and 500 ml of water. The aqueous layer was extracted twice with methylene chloride and the combined extracts were washed with water. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give 13.0 g of methyl 1-(2-cyano-ethyl)-2-indolecarboxylate.