Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:9][O-:10].[Na+]>>[CH2:7]([O:6][C:1](=[O:5])[CH:2]([CH:9]=[O:10])[CH2:3][CH3:4])[CH3:8]
Reactant: CCCC(=O)OCC
Reactant: C[O-]
Agent: [Na+]
Product: CCOC(=O)C(C=O)CC
Yield: 70.6 %

Procedure:
1200 g Ethyl butyrate was reacted with 130 g 85% sodium methylate substantially as in Example 1 to produce 245 g 2-formylbutyric acid ethyl ester (85% yield) boiling at 60°-64° C./14 torr. n20D =1.4300.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([O:17][C:18]3[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=3[CH3:25])=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[N:12]=2)=[CH:4][CH:3]=1.[CH2:26](N(CC)CC)[CH3:27].C(Br)C.O>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([O:17][C:18]3[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=3[CH3:25])=[C:11]([CH2:13][C:14]([O:16][CH2:26][CH3:27])=[O:15])[N:12]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C)c(Oc2oc(-c3ccc(Cl)cc3)nc2CC(=O)O)c1
Reactant: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCBr
Product: CCOC(=O)Cc1nc(-c2ccc(Cl)cc2)oc1Oc1cc(C)ccc1C
Reaction time: 1.5 h

Procedure:
To a solution of 0.80 g of 2-p-chlorophenyl-5-(2,5-dimethylphenoxy)-4-oxazoleacetic acid in 8 ml of dimethylformamide were added 1 ml of triethylamine and 1.5 ml of ethyl bromide. The mixture was stirred at 35°-40° C. for 90 minutes. The reaction mixture was poured into water and ethyl acetate and shaken with a separate funnel. The organic layer was successively washed with water, diluted hydrochloric acid and water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The white crystalline residue was recrystallized from n-hexane to give 0.68 g of the title compound as white fine needles, melting at 122°-123.5° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:6](=[O:7])[O:5][C:4]2[CH:8]=[CH:9][C:10]3[C:15]([C:3]1=2)=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3.[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:16][C:13]1[CH:14]=[C:15]2[C:10]([CH:9]=[CH:8][C:4]3[O:5][C:6](=[O:7])[C:2]([CH3:17])([CH3:1])[C:3]=32)=[CH:11][CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2ccc3c(c2c1)C(C)(C)C(=O)O3
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)C(=O)Oc2ccc3ccc(CBr)cc3c21

Procedure:
A mixture of 1,1,8-trimethyl-2(1H)-naphtho[2,1-b]furanone (1.13 g), N-bromosuccinimide (0.98 g), benzoyl peroxide (0.05 g) and carbon tetrachloride (30 ml) was heated under reflux for 1.5 h and filtered, and the filtrate was evaporated to dryness under reduced pressure, to give 8-bromomethyl-1,1-dimethyl-2[1H]-naphtho[2,1-b]furanone, which was used without further purification.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([CH3:39])=[N:13][C:14]2[N:15]([N:29]=[C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:31]=2C)[C:16]=1[C:17]1[C:18]([CH3:28])=[C:19]2[C:24](=[C:25]([F:27])[CH:26]=1)[O:23][CH2:22][CH2:21][CH2:20]2)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[Br:40]N1C(=O)CCC1=O>C(#N)C>[Br:40][C:31]1[C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:29][N:15]2[C:16]([C:17]3[C:18]([CH3:28])=[C:19]4[C:24](=[C:25]([F:27])[CH:26]=3)[O:23][CH2:22][CH2:21][CH2:20]4)=[C:11]([CH:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:7]([O:9][CH3:10])=[O:8])[C:12]([CH3:39])=[N:13][C:14]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2c(C)c(-c3ccccc3)nn2c1-c1cc(F)c2c(c1C)CCCO2
Solvent: CC#N
Product: COC(=O)C(OC(C)(C)C)c1c(C)nc2c(Br)c(-c3ccccc3)nn2c1-c1cc(F)c2c(c1C)CCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.1 %

Procedure:
To a solution of methyl 2-(tert-butoxy)-2-(7-(8-fluoro-5-methylchroman-6-yl)-3,5-dimethyl-2-phenylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (350 mg, 0.676 mmol) in acetonitrile (20 mL) was added N-bromosuccinimide (119 mg, 0.676 mmol). The reaction mixture was stirred at r.t. for 1 h. The solvent was evaported and the residue was purified by silica gel chromatography to afford (210 mg, 52%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]=[O:11])=[C:7]([CH3:12])[C:6]=2[CH:13]=1.[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][OH:11])=[C:7]([CH3:12])[C:6]=2[CH:13]=1
Reactant: Cc1c(C=O)oc2ccc(Cl)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1c(CO)oc2ccc(Cl)cc12
Reaction time: 1 h
Yield: 88.4 %

Procedure:
To a solution of 5-chloro-3-methyl benzofuran-2-carboxaldehyde (5.55 mmol, 1.08 g) in ethanol (25 mL) was added portion-wise sodium borohydride (16.6 mmol, 630 mg). After one hour, the ethanol was evaporated and the residue was partitioned between CHCl3 and H2O. The CHCl3 layer was collected, filtered, dried, and evaporated to dryness to obtain 5-chloro-3-methyl benzofuran 2-methanol (88%, 965 mg); mp 112° C.-113° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]([CH2:16][CH2:17][CH:18]=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:21]1[C:23]2([CH2:28][CH2:27][NH:26][CH2:25][CH:24]2[OH:29])[CH2:22]1.B.N1C=CC=CC=1>ClCCCl.CCO.CC(O)=O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]([CH2:16][CH2:17][CH2:18][N:26]2[CH2:27][CH2:28][C:23]3([CH2:21][CH2:22]3)[CH:24]([OH:29])[CH2:25]2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)N(CCC=O)CC1
Reactant: OC1CNCCC12CC2
Agent: B
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(=O)N(CCCN2CCC3(CC3)C(O)C2)CC1
Yield: 93.6 %

Procedure:
5-Oxo-4-(3-oxo-propyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (intermediate 61) (0.19 g, 0.7 mmol) was reacted with (−)-6-Aza-spiro[2.5]octan-4-ol hydrochloride (intermediate 83) (0.12 g, 0.7 mmol) in DCE:EtOH (1:1, 6 ml), AcOH (0.18 ml) and pyridine-borane complex (0.18 ml, 8M in pyridine, 1.4 mmol) for 20 minutes. The reaction was then concentrated, redissolved in CH2Cl2 and washed with sat. NaHCO3, dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography (CH2Cl2:MeOH 8:2) to afford the title product (0.25 g, 91%) as a gum. MS: 382.4 (MH+).
Reaction SMILES: C(OC([N:8]1[C:12]([CH2:13][C@H:14]([N:35]([CH3:45])[C:36](C(OC(C)(C)C)=O)=[O:37])[C:15]([NH:17][C@@H:18]([CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[C@@H:19]([OH:27])[CH2:20][C@@H:21]([CH:24]([CH3:26])[CH3:25])[CH:22]=[CH2:23])=[O:16])=[CH:11][N:10]=[CH:9]1)=O)(C)(C)C.CCOCC>Cl.O1CCOCC1>[CH3:45][N:35]([C@@H:14]([CH2:13][C:12]1[N:8]=[CH:9][NH:10][CH:11]=1)[C:15]([NH:17][C@@H:18]([CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[C@@H:19]([OH:27])[CH2:20][C@@H:21]([CH:24]([CH3:25])[CH3:26])[CH:22]=[CH2:23])=[O:16])[CH:36]=[O:37]
Reactant: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cncn1C(=O)OC(C)(C)C)N(C)C(=O)C(=O)OC(C)(C)C)C(C)C
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)N(C)C=O)C(C)C
Reaction time: 5 h
Yield: 59.2 %

Procedure:
2.1 g of (S)-3-(t-butoxycarbonyl)-α-[1-(t-butoxycarbonyl)-N-methylformamido]-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamide were dissolved in 30 ml of 3N hydrogen chloride in dioxan and the mixture was left to stand at room temperature for 5 hours. 500 ml of ether were added and the precipitate formed was filtered off. The precipitate was washed with ether and dissolved in water. Solid sodium bicarbonate was added to the aqueous solution and the mixture was extracted several times with ethyl acetate, to obtain there was obtained 0.85 g of (S)-α-(N-methylformamido)-N-[(1S,2S,4S)-1-(cyclohexyl-methyl)-2-hydroxy-4-isopropyl-5-hexenyl)imidazole-4-propion-amide which was used directly in the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH:12]=[O:13])[CH:11]=1)[O:8][C:7]([CH3:15])([CH3:14])[CH2:6][C:5]2([CH3:17])[CH3:16].C(N(CC)CC)C.O1CCCC1.[CH3:30][Si:31]([C:34]#[CH:35])([CH3:33])[CH3:32]>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH3:30][Si:31]([C:34]#[C:35][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH:12]=[O:13])[CH:11]=1)[O:8][C:7]([CH3:15])([CH3:14])[CH2:6][C:5]2([CH3:17])[CH3:16])([CH3:33])[CH3:32]
Reactant: C#C[Si](C)(C)C
Reactant: CC1(C)CC(C)(C)c2cc(Br)cc(C=O)c2O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1(C)CC(C)(C)c2cc(C#C[Si](C)(C)C)cc(C=O)c2O1
Yield: 99 %

Procedure:
Following general procedure I and using 6-bromo-2,2,4,4-tetramethyl chroman-8-carbaldehyde (Compound 42, see U.S. Pat. No. 6,303,785, 1.78 g, 5.4 mmol), triethyl amine (5 mL), tetrahydrofuran (10 mL), copper(I)iodide (0.23 g, 1.2 mmol), trimethylsilyl acetylene (3.3 mL, 23 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.843 g, 1.2 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 5% ethyl acetate in hexane as the eluent, the title compound (1.77 g, 99%) was obtained as a pale yellow solid.
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[C:6]2=[N:5][CH:4]=1)#[CH:2].Br[C:27]1[C:28]([F:38])=[CH:29][C:30]([F:37])=[C:31]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:32]=1>>[F:37][C:30]1[CH:29]=[C:28]([F:38])[C:27]([C:2]#[C:1][C:3]2[N:7]3[CH:8]=[C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)[CH:10]=[C:11]([C:12]([F:14])([F:13])[F:15])[C:6]3=[N:5][CH:4]=2)=[CH:32][C:31]=1[S:33]([NH2:36])(=[O:34])=[O:35]
Reactant: NS(=O)(=O)c1cc(Br)c(F)cc1F
Reactant: C#Cc1cnc2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)cn12
Product: NS(=O)(=O)c1cc(C#Cc2cnc3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)cn23)c(F)cc1F

Procedure:
The title compound was prepared from 3-ethynyl-8-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.18) (310 mg, 0.88 mmol) and 5-Bromo-2,4,-difluorobenzenesulfonamide (226 mg, 0.83 mmol) according to general procedure II. Obtained as an off-white solid (56 mg, 12%). MS (ISP) 546.2 [(M+H)+]; mp 306-307° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]([CH3:28])[C:12]([C:14]1[S:27][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13])[C:5](O)=[O:6].[NH2:29][CH2:30][CH:31]([OH:33])[CH3:32]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[NH:29][CH2:30][CH:31]([OH:33])[CH3:32])[CH:8]=[CH:9][C:10]=1[N:11]([CH3:28])[C:12]([C:14]1[S:27][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13]
Reactant: CN(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ccc(C(=O)O)cc1Cl
Reactant: CC(O)CN
Product: CC(O)CNC(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2ccccc2OCC3)c(Cl)c1

Procedure:
3-Chloro-4-(N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)benzoic acid and 1-aminopropan-2-ol were reacted by a procedure similar to that to prepare 137 in Example 47 to give 227. MS: (ESI+) 471.1
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH:27]2[CH2:29][CH2:28]2)[CH:25]=[O:26])[C:5]1=[O:30])[CH:2]=[CH2:3].[CH3:32][Mg]Br>>[CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH:27]2[CH2:28][CH2:29]2)[C@@H:25]([OH:26])[CH3:32])[C:5]1=[O:30])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](C=O)C2CC2)C1=O
Reactant: C[Mg]Br
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](C2CC2)[C@H](C)O)C1=O

Procedure:
By the procedure of Example 149, Step A, (S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-2-cyclopropylacetaldehyde (Example 257, Step C, 866 mg, 1.897 mmol) was treated with methyl magnesium bromide to give the diastereomeric alcohols (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2R)-1-cyclopropyl-2-hydroxypropyl)-3-methylpiperidin-2-one and (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2S)-1-cyclopropyl-2-hydroxypropyl)-3-methylpiperidin-2-one as a white foam. MS (ESI) m/z=472 [M+H]+.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[O:13][CH3:14].[BH4-].[Li+].B(OC)(OC)OC>O1CCCC1>[CH3:14][O:13][C:5]1[C:6]([N+:10]([O-:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][OH:2]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1OC
Agent: COB(OC)OC
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1c(CO)cccc1[N+](=O)[O-]
Yield: 76.1 %

Procedure:
A mixture of 2-methoxy-3-nitrobenzoic acid methyl ester (4.82 g), lithium borohydride (298 mg), trimethyl borate (0.27 ml) and anhydrous tetrahydrofuran (200 ml) was heated under reflux for 5 h. The reaction mixture was distilled under reduced pressure and ethyl acetate and water were added to the resulting residue. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and distilled under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=1:1) to give 3.18 g of the titled compound (yield, 76%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][O:8][C:9]1[CH:23]=[CH:22][C:12]2[C:13]([C:16](=[O:21])[C:17](OC)=[O:18])=[CH:14][O:15][C:11]=2[CH:10]=1.[NH4+].[Cl-]>C1COCC1>[CH3:7][O:8][C:9]1[CH:23]=[CH:22][C:12]2[C:13]([CH:16]([OH:21])[CH2:17][OH:18])=[CH:14][O:15][C:11]=2[CH:10]=1
Reactant: COC(=O)C(=O)c1coc2cc(OC)ccc12
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc2c(C(O)CO)coc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
LAH (0.093 g, 2.39 mmol) was added to a mixture of methyl 2-(6-methoxybenzofuran-3-yl)-2-oxoacetate (0.280 g, 1.196 mmol) in THF (10 mL) at 0° C. under N2, and the mixture was stirred overnight at room temperature under N2. An aqueous NH4Cl solution (5 mL) was added, and the reaction mixture was concentrated to half its volume and extracted with EtOAc. The organic layer was washed with brine and water, dried over anhydrous MgSO4, and evaporated to give 1-(6-methoxy-benzofuran-3-yl)-ethane-1,2-diol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=4)[C:24](O)=[O:25])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.Cl.[NH2:31][C:32]1([C:35]([NH:37][S:38]([CH:41]2[CH2:43][CH2:42]2)(=[O:40])=[O:39])=[O:36])[CH2:34][CH2:33]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CO.CN(C=O)C>[CH:41]1([S:38]([NH:37][C:35]([C:32]2([NH:31][C:24]([C:23]3[CH:22]=[C:21]([C:18]4[CH:19]=[CH:20][C:10]5[O:9][C:8]([C:5]6[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=6)=[C:12]([C:13]([NH:14][CH3:15])=[O:16])[C:11]=5[CH:17]=4)[CH:29]=[CH:28][CH:27]=3)=[O:25])[CH2:34][CH2:33]2)=[O:36])(=[O:40])=[O:39])[CH2:43][CH2:42]1
Reactant: NC1(C(=O)NS(=O)(=O)C2CC2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)O)c3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)NC4(C(=O)NS(=O)(=O)C5CC5)CC4)c3)cc12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 51.9 %

Procedure:
In a 7 mL scintillation vial were combined 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid (30 mg, 0.077 mmol), 1-amino-N-(cyclopropylsulfonyl)cyclopropanecarboxamide hydrochloride (20 mg, 0.083 mmol), and HATU (40 mg, 0.10 mmol). DMF (0.4 mL) and DIPEA (0.1 mL, 0.57 mmol) were added, the vial was capped, and the solution was stirred at r.t. for 45 min. The reaction was diluted with MeOH, filtered, purified by prep HPLC, and the collected fractions were concentrated on a SPEEDVAC® to afford the title compound (23 mg, 52% yield) as a white powder. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.99 (br. s., 1H) 8.53 (q, J=4.78 Hz, 1H) 8.25 (br. s., 1H) 8.00 (dd, J=8.85, 5.49 Hz, 2H) 7.93 (s, 1H) 7.89 (t, J=7.78 Hz, 2H) 7.72-7.83 (m, 2H) 7.58 (t, J=7.48 Hz, 1H) 7.40 (t, J=8.85 Hz, 2H) 7.07 (br. s., 1H) 2.89-2.98 (m, 1H) 2.87 (d, J=4.58 Hz, 3H) 1.35-1.56 (m, 2H) 0.77-1.28 (m, 6H). LC/MS was performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters MICROMASS®. LC/MS method: solvent A=10% CH3CN/90% H2O/0.1% TFA, solvent B=90% CH3CN/10% H2O/0.1% TFA, start % B=0, final % B=100, gradient time=2 min, stop time=3 min, flow rate=4 ml/min, column: Sunfire C18 5 μm 4.6×50 mm; HPLC Rt=1.59 min, (ES+) m/z (MH+)=576. Analytical HPLC were performed using a Shimadzu-VP instrument with UV detection at 220 nm and 254 nm. Analytical HPLC method: solvent A=5% CH3OH/95% H2O/10 mM NH4HCO3, solvent B=95% CH3OH/5% H2O/10 mM NH4HCO3, start % B=10, final % B=100, gradient time=15 min, stop time=18 min, flow rate=1 ml/min. Column: PHENOMENEX® Gemini C18, 4.6 mm, 3 μm, Rt=15.39 min, purity=100%; column: Waters XBridge phenyl 4.6×150 mm, 3.5 μm, Rt=14.50 min, purity=100%.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][NH:11][C@H:12]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C:13]([NH:15][N:16]1[CH2:20][CH2:19][C@H:18]([N:21]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])[CH2:17]1)=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:41]=O>>[CH3:41][CH:9]([NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:10][NH:11][C@H:12]([CH2:33][C:34]1[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=1)[C:13]([NH:15][N:16]1[CH2:20][CH2:19][C@H:18]([N:21]([CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)[C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])[CH2:17]1)=[O:14]
Reactant: C=O
Reactant: CC(C)C(=O)N(C1CCCCC1)[C@H]1CCN(NC(=O)[C@@H](Cc2ccc(Cl)cc2)NCCNC(=O)OC(C)(C)C)C1
Product: CC(CN[C@H](Cc1ccc(Cl)cc1)C(=O)NN1CC[C@H](N(C(=O)C(C)C)C2CCCCC2)C1)NC(=O)OC(C)(C)C

Procedure:
The title compound was prepared following the procedure described in Step A of Example 3 using (2R)-2-[2-(BOC)aminoethyl]amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide prepared in Step A of Example 360 and formaline.
Reaction SMILES: C(O[C:6]([C:8]1[C:9]([OH:23])=[C:10]2[CH:22]=[CH:21][S:20][C:11]2=[C:12]([C:14]#[C:15][Si](C)(C)C)[N:13]=1)=[O:7])CCC.C[O-].[Na+].CO.[NH2:29][CH2:30][C:31]([OH:33])=[O:32]>>[C:14]([C:12]1[N:13]=[C:8]([C:6]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:7])[C:9]([OH:23])=[C:10]2[CH:22]=[CH:21][S:20][C:11]=12)#[CH:15]
Reactant: NCC(=O)O
Reactant: CCCCOC(=O)c1nc(C#C[Si](C)(C)C)c2sccc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C#Cc1nc(C(=O)NCC(=O)O)c(O)c2ccsc12
Reaction time: 18 h
Yield: 101.4 %

Procedure:
A mixture of 4-hydroxy-7-trimethylsilanylethynyl-thieno[2,3-c]pyridine-5-carboxylic acid butyl ester (70 mg, 0.2 mmol) and a 0.5 M solution of sodium methoxide in methanol (10 ml, 5 mmol) was refluxed with stirring for 1 h before glycine (375 mg, 5 mmol) was added. Refluxing and stirring was continued for 18 h before the mixture was concentrated in vacuo. The residue was dissolved in water (20 ml), and the pH of the solution was adjusted to 2-3 by addition of 6 N aqueous HCl. The resulting suspension was extracted with ethyl acetate (1×20 ml). The organic phase was dried over MgSO4 and concentrated in vacuo to give the title compound as a tan solid (56 mg); MS-(+)-ion: M+1=277.1.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[Cl:17][C:18]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:19]=1[NH2:20]>>[Cl:17][C:18]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:19]=1[NH:20][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2
Reactant: Nc1cc(Cl)ccc1Cl
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Product: O=c1[nH]c2nccc(Nc3cc(Cl)ccc3Cl)c2c2ccccc12
Yield: 32.6 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 188 using Compound 83 (100 mg, 0.43 mmol) and 2,5-di-chloroaniline (105 mg, 0.65 mmol) to provide 199 (50 mg, 32% yield) as a white solid. LC-MS (M+H=356, obsd.=356).
Reaction SMILES: [NH:1]1[C:7](=O)[CH2:6][CH2:5][CH2:4][C:3]2[CH:9]=[CH:10][N:11]=[CH:12][C:2]1=2.[H-].[Al+3].[Li+].[H-].[H-].[H-].[H-].[OH-].[NH4+]>O1CCCC1>[NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]2[CH:9]=[CH:10][N:11]=[CH:12][C:2]1=2
Reactant: O=C1CCCc2ccncc2N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1cc2c(cn1)NCCCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.2 %

Procedure:
A solution of 2,3,4,5-tetrahydro-1H-pyrido[3,4-b]azepin-2-one (470 mg) in tetrahydrofuran (20 ml) was treated with lithium aluminum hydride (990 mg) and stirred at room temperature for 30 minutes. The excess hydride was decomposed with 28% ammonium hydroxide at 0° C. The resulting mixture was filtered through a bed of Celite and the Celite was washed with tetrahydrofuran, and the filtrate was concentrated. The residual aqueous layer was extracted with chloroform, dried over sodium sulfate, concentrated and purified by silica gel column chromatography (SiO2; 20 g, 1% methanol in chloroform) to give 2,3,4,5-tetrahydro-1H-pyrido[3,4-b]azepine (370 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(N(CC)CC)C>CCO>[N:11]1([C:2]2[N:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][N:3]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: OB(O)c1cnc(Cl)nc1
Reactant: C1COCCN1
Solvent: CCO
Solvent: CCN(CC)CC
Product: OB(O)c1cnc(N2CCOCC2)nc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 68 %

Procedure:
A mixture of 2-chloropyrimidin-5-ylboronic acid (3 g, 19.0 mmol), morpholine (1.66 mL, 19 mmol) and triethylamine (1.67 mL, 19.19 mmol) in EtOH (20 mL) was stirred at 80° C. for 5 h. LCMS indicated completion of the reaction. The reaction mixture was concentrated in vacuo and the residue was taken up in ethanol (approximately 5 mL). Diethyl ether was added, and the triethylamine hydrochloride salt that crystallised out was filtered and discarded. The filtrate was concentrated in vacuo and water (approximately 10 mL) was added. The mixture was placed in a refrigerator for 1 h, after which time the resulting solid was filtered off, washed with the minimum amount of water and dried by suction, to give the title compound (2.7 g, 68%) as an off-white solid. δH (DMSO-d6) 8.64 (s, 2H), 8.08 (s, 2H), 3.73 (m, 4H), 3.65 (m, 4H). LCMS (ES+) 210 (M+H)+, RT 0.15 minutes.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[S:14](Cl)(=[O:16])=[O:15])([CH3:4])([CH3:3])[CH3:2].[NH4+:18].[OH-]>CCOCC.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[S:14]([NH2:18])(=[O:16])=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: [NH4+]
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1S(=O)(=O)Cl
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)c1ccc([N+](=O)[O-])cc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
To a solution of 2-tert-butyl-5-nitrobenzene-1-sulfonyl chloride (100 mg, 0.36 mmol) in ether (2 mL) was added aqueous NH4OH (128 μL, 3.6 mmol) at 0° C. The mixture was stirred at room temperature overnight, diluted with water and extracted with ether. The combined ether extracts were washed with brine and dried over Na2SO4. After removal of solvent, the residue was purified by column chromatography (0-50% EtOAc-Hexane) to give 2-tert-butyl-5-nitrobenzene-1-sulfonamide (31.6 mg, 34%).