Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=2[C:6]=1[C:7](Cl)=[O:8].CNCC1C=C2C(=CC=1)C=C(O)C=C2.[CH2:28]([NH:35][CH2:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][CH:46]=1)[CH:43]=[C:42]([OH:47])[CH:41]=[CH:40]2)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(OCC)(=O)C>C(Cl)Cl>[CH2:28]([N:35]([CH2:36][C:37]1[CH:46]=[CH:45][C:44]2[C:39](=[CH:40][CH:41]=[C:42]([OH:47])[CH:43]=2)[CH:38]=1)[C:7]([C:6]1[C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[O:3][C:2]=1[CH3:1])=[O:8])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Oc1ccc2cc(CNCc3ccccc3)ccc2c1
Reactant: Cc1oc2ccccc2c1C(=O)Cl
Agent: CNCc1ccc2cc(O)ccc2c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1oc2ccccc2c1C(=O)N(Cc1ccccc1)Cc1ccc2cc(O)ccc2c1
Yield: 30 %

Procedure:
Prepared in the same manner as described in step 2 of Example 32, and replacing 2-ethyl-benzofuran-3-carbonyl chloride with 2-methyl-benzofuran-3-carbonyl chloride, prepared in step 2 of Example 20 and 6-methylaminomethyl-naphthalen-2-ol with 6-(benzylamino-methyl)-naphthalen-2-ol, prepared in step 3 of Example 48. Chromatography of the crude oil on 400 g silica gel (230-400 mesh) using 2-3% ethyl acetate in methylene chloride as the eluent gave 2-methyl-benzofuran-3-carboxylic acid benzyl-(6-hydroxy-naphthalen-2ylmethyl)-amide (0.71 g, 30%) as a yellow solid, mp 190-193° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:29])([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:3][CH2:4][CH2:5]C1C=C(S([O-])(=O)=O)C=CC=1C.[CH2:30]([O:32][C:33](=[O:41])[C:34]1[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=1)[CH3:31].C1(C)C=CC=CC=1.CCCCCCC>ClCCl>[CH2:30]([O:32][C:33](=[O:41])[C:34]1[CH:39]=[CH:38][C:37]([NH:40][CH2:5][CH2:4][CH2:3][Si:2]([CH3:29])([CH3:1])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:36][CH:35]=1)[CH3:31]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CCCCCCCCCCCC[Si](C)(C)CCCc1cc(S(=O)(=O)[O-])ccc1C
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCCCCCCCCCC[Si](C)(C)CCCNc1ccc(C(=O)OCC)cc1

Procedure:
Under nitrogen, 26.8 g of 4,4-dimethyl-4-sila-n-hexadecyl-p-toluenesulphonate, mixed with 35 g (in excess) of ethyl-p-aminobenzoate is heated at 123° to 128° for 4 hrs. The hot mixture is diluted with about 120 ml. of toluene and allowed to cool. The solution is then further diluted with dichloromethane. The resulting mixture is then washed with about 50 ml. of dilute aqueous sodium hydroxide, then washed with brine, and then dried over anh. sodium sulfate, filtered, and the filtrate concentrated by evaporating to obtain an oily residue. Heptane is added to the residue and upon standing two crops of solids (ethyl-p-aminobenzoate) are removed by filtering. The filtrate is concentrated to give an oily product which is placed on a chromatographic column, eluted with ethyl acetate/dichloromethane (5/95) to obtain several high quality fractions, which upon recrystallization from heptane, cooling to -20° gives refined title product, m.p. (39)--40°-41°. Additional crops of product are obtained from other fractions.
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10](C(=O)C)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:16]([OH:19])(=[O:18])[CH3:17].S(=O)(=O)(O)O>O>[CH2:1]([C:7]1[CH:8]=[CH:9][C:10]([CH2:17][C:16]([OH:19])=[O:18])=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CC(=O)O
Reactant: CCCCCCc1ccc(C(C)=O)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCCCc1ccc(CC(=O)O)cc1
Temperature: 150 °C
Yield: 66.3 %

Procedure:
12.0 g (39.3 mmol) of 1-(4-hexylphenyl)ethanone was dissolved in 23.6 g (393 mmol) of glacial acetic acid mixed with 4.95 g (275 mmol) of water and 5.79 g (58.9 mmol) of sulfuric acid and heated at 150° C. for 6.5 hours under reflux. After completion of the reaction, the reaction solution was diluted with 400 mL of water and extracted with ethyl acetate. The resulting organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate:hexane (1:20 to 1:4) as the eluent to give 5.74 g of the desired product as white crystals.
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][CH:6]=[N:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(CC)CC)C.[C:22]([O:28][CH2:29][CH2:30][CH2:31]Br)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>CN(C=O)C>[N:3]1[CH:8]=[CH:7][CH:6]=[N:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:31][CH2:30][CH2:29][O:28][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:11][CH2:10]1
Reactant: CC(C)(C)C(=O)OCCCBr
Reactant: c1cnc(N2CCNCC2)nc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)OCCCN1CCN(c2ncccn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 164.1 %

Procedure:
To a stirred solution of N-(2-pyrimidinyl)piperazine dihydrochloride (4.25 g, 0.0179 mol) and triethylamine (6.06 g, 0.06 mol) in DMF was added 3-bromopropyl pivalate (4.0 g, 0.0179 mol) and the solution was stirred overnight at room temperature. The solvent was evaporated and the residue dissolved in CH2Cl2. The CH2Cl2 extract was washed with water, dried (anhydrous Na2SO4) and evaporated to afford 9.0 g of crude title compound. Purification by HPLC and conversion to the dihydrochloride with ethereal HCl yielded the product, mp. 178°-180° C.
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][C:17]([C:19](O)=O)=[CH:18][C:12]=3[N:11]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([N:31]4[CH2:35][CH:34]=[CH:33][CH2:32]4)=[O:30])=[CH:25][CH:24]=3)[C:10](=[O:36])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C([N:41](CC)CC)C.ClC(OCC)=O.N.[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O>C1COCC1>[Cl:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][C:17]([C:19]#[N:41])=[CH:18][C:12]=3[N:11]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([N:31]4[CH2:32][CH2:33][CH2:34][CH2:35]4)=[O:30])=[CH:25][CH:24]=3)[C:10](=[O:36])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccc2c(c1)N(Cc1ccc(C(=O)N3CC=CC3)cc1)C(=O)CN(C(=O)c1ccc(Cl)cc1)C2
Agent: CCOC(=O)Cl
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: N
Solvent: C1CCOC1
Product: N#Cc1ccc2c(c1)N(Cc1ccc(C(=O)N3CCCC3)cc1)C(=O)CN(C(=O)c1ccc(Cl)cc1)C2
Reaction time: 0.5 h

Procedure:
1.8 g (3.5 mmol) of 4-(4-chlorobenzoyl)-2-oxo-1-[4(2,5-dihydro-1H-pyrrol-1-ylcarbonyl)benzyl]-2,3,4,5-tetrahydro-1H-benzo[e][1,4]-diazepine-8-carboxylic acid was dissolved in 10 ml of THF. 0.73 ml (5.3 mmol) of triethylamine and 0.40 ml (4.1 mmol) of ethyl chloroformate were added to the obtained solution, and they were stirred or 30 minutes. 10 ml of aqueous ammonia was added to the reaction mixture. The temperature was elevated to room temperature, and the obtained mixture was stirred overnight. After the treatment with ethyl acetate as the extracting solvent by ah ordinary method, the solvent was evaporated and 1.35 g (2.63 mmol) of the obtained elide product was dissolved in 20 ml of dichloromethane. 760 mg (3.19 mmol) of (methoxycarbonylsulfamoyl)-triethylammonium hydroxide was added to the obtained solution, and the obtained mixture was stirred overnight. After the treatment with dichloromethane as the extracting solvent by an ordinary method, the solvent was evaporated, and the obtained crude product was treated in the same manner as in step 3 in Example 1 to obtain the title compound.
Reaction SMILES: [CH3:1]N(C=O)C.[Br:6][C:7]1[C:12]([OH:13])=[CH:11][C:10]([Cl:14])=[CH:9][N:8]=1.[H-].[Na+].CI>O>[Br:6][C:7]1[C:12]([O:13][CH3:1])=[CH:11][C:10]([Cl:14])=[CH:9][N:8]=1
Reactant: Oc1cc(Cl)cnc1Br
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COc1cc(Cl)cnc1Br

Procedure:
To a DMF (60 mL) solution containing 2-bromo-5-chloro-3-hydroxypyridine (19.95 g, 95.7 mmol) at 0° C. was added NaH (2.53 g, 105.3 mmol) portion wise. After the cessation of H2 evolution, CH3I (14.26 g, 100.5 mmol) was added dropwise and the reaction stirred ~16 h. Water (1.9 mL) was added and the solvent removed under reduced pressure. The concentrate was triturated with 5 portions of CH2Cl2. The combined organic phases were washed with sat. NaCl solution, dried with K2CO3, filtered, and concentrated in vacuo. Silica gel chromatography (95:5 Hexane:EtOAc) of the concentrate afforded the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][S:16]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=2[O:29][CH3:30])(=[O:18])=[O:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1([Li])C=CC=CC=1.[CH3:38][C:39]([CH3:41])=[O:40].C(O)(=O)C>C1COCC1.C(OCC)(=O)C>[CH3:30][O:29][C:22]1[CH:23]=[C:24]([O:27][CH3:28])[CH:25]=[CH:26][C:21]=1[CH2:20][NH:19][S:16]([CH:15]([C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:14][CH:13]=1)[C:39]([OH:40])([CH3:41])[CH3:38])(=[O:18])=[O:17]
Reactant: COc1ccc(CNS(=O)(=O)Cc2ccc(OCc3ccccc3)cc2)c(OC)c1
Reactant: CC(C)=O
Agent: [Li]c1ccccc1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(CNS(=O)(=O)C(c2ccc(OCc3ccccc3)cc2)C(C)(C)O)c(OC)c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Under inert gas, 3.22 g of C-(4-benzyloxyphenyl)-N-(2,4-dimethoxybenzyl)methanesulfonamide were initially charged in 70 ml of THF, and then, at a temperature of −78° C., 12.50 ml of a 1.8 N phenyllithium solution were added dropwise. The reaction mixture was allowed to come to 0° C. and stirred briefly, then cooled again to −78° C., and 4.00 ml of acetone were added dropwise. The mixture was allowed to come to −20° C. within 15 minutes, admixed with 1.29 ml of acetic acid and 100 ml of ethyl acetate, and washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution. The organic phase was dried over MgSO4 and concentrated by rotary evaporation. The crude product was purified by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined and concentrated by rotary evaporation. This gave the product (3.65 g) with a molecular weight of 485.6 g/mol (C26H31NO6S).
Reaction SMILES: [CH3:1][S:2]([NH:5][CH:6]1[CH2:10][CH2:9][CH:8]([NH:11][C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[C:31]5[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=5)[N:25]([CH3:33])[N:24]=4)[N:21]=3)[N:16](COCC[Si](C)(C)C)[CH:15]=2)=[O:13])[CH2:7]1)(=[O:4])=[O:3].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[CH3:1][S:2]([NH:5][CH:6]1[CH2:10][CH2:9][CH:8]([NH:11][C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[C:31]5[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=5)[N:25]([CH3:33])[N:24]=4)[N:21]=3)[NH:16][CH:15]=2)=[O:13])[CH2:7]1)(=[O:4])=[O:3]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)NC2CCC(NS(C)(=O)=O)C2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Solvent: ClCCl
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4CCC(NS(C)(=O)=O)C4)c3n2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
In a round-bottomed flask, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (3-methanesulfonylamino-cyclopentyl)-amide (109 mg, 0.176 mmol) was dissolved in dichloromethane (0.9 ml) and trifluoroacetic acid (0.54 ml, 7.0 mmol) was added. The orange solution was stirred at room temperature for 2 h then concentrated. The residue was dissolved in dichloromethane (0.9 ml) and ethylenediamine (0.7 ml, 10.5 mmol) was added. The yellow solution was stirred at room temperature for 1.5 h then quenched with water and diluted with ethyl acetate. The resultant suspension was filtered, washed with hot water and ethyl acetate and dried under high vacuum to provide 76 mg (88%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (3-methanesulfonylamino-cyclopentyl)-amide as an off-white powder. MS: (M+H)+=488; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.30 (br. s, 1H), 9.11 (s, 1H), 8.42-8.52 (m, 2H), 8.17 (d, J=7.2 Hz, 1H), 8.02 (s, 1H), 7.41 (dd, J=8.7, 1.5 Hz, 1H), 7.31 (d, J=7.2 Hz, 1H), 4.27-4.40 (m, 1H), 4.18 (s, 3H), 3.67-3.82 (m, 1H), 2.92 (s, 3H), 2.53-2.63 (m, 1H), 1.97-2.20 (m, 2H), 1.65-1.81 (m, 2H), 1.55 (dt, J=12.3, 9.0 Hz, 1H).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][CH:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[C:25](Cl)=[O:26]>C1COCC1>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([C:25](=[O:26])[C:14]([CH3:19])([CH3:13])[C:15]([O:17][CH3:18])=[O:16])[CH:28]=[CH:29][C:30]=1[O:31][CH3:32]
Reactant: COC(=O)C(C)C
Reactant: COc1ccc(C(=O)Cl)cc1OC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)C(=O)c1ccc(OC)c(OC)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
124 ml of diisopropylamine is dissolved in 500 ml of THF under a blanket of dry nitrogen and cooled to 0° C. and 550 ml n-BuLi (1.6M in hexane) is added drop wise. Next, the mixture is cooled to minus 40° C., using an acetone/N2 bath, and 100 ml methyl 2-methylproponate is added. The resulting mixture is stirred for an additional 15 min at minus 40° C., after which 160.5 g of 3,4-dimethoxybenzoyl chloride dissolved in 750 ml of THF is added drop wise in 60 min during which the temperature is kept below minus 40° C. The cooling bath is removed and stirring is continued for 60 min at RT. 150 ml of 4M hydrochloric acid is added and the THF layer is separated and washed with 100 ml of water, 200 ml 1M of sodium carbonate and 100 ml of brine, dried over MgSO4 and concentrated in vacuo.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[S:12]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13]1.C([O-])(O)=O.[Na+]>COCCOC.O.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>[S:12]1[CH:16]=[CH:15][C:14]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=2)=[CH:13]1
Reactant: OB(O)c1ccsc1
Reactant: O=C(O)Cc1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(O)Cc1ccc(-c2ccsc2)cc1
Yield: 51.3 %

Procedure:
A mixture of 4-bromophenylacetic acid (1.08 g, 5 mmol), 3-thiopheneboronic acid (0.7 g, 5.5 mmol), NaHCO3 (1.68 g, 20 mmol), and dichlorobis(triphenylphosphine)palladium (0.35 g, 0.5 mmol) in DME-water (21 mL-7 mL) was heated at reflux temperature for 2 hours under nitrogen. After cooling, the reaction mixture was partitioned between Et2O (80 mL) and saturated aqueous NaHCO3 (30 mL). The organic layer was washed with saturated aqueous NaHCO3 (30 mL) again. The combined aqueous layer was acidified with 2N HCl solution and the whole extracted with CH2Cl2 (50 mL×3). The combined organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography (SiO2) eluting with ethyl acetate/hexane (1/1) to give the subtitle compound (0.56 g, 51% yield).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[CH:22]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:21]2)[C:5](=[O:19])[N:6]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:11](OC)=[O:12])[CH:7]=1.C([O-])=O.[NH4+].C([N:46](CC)[CH:47]([CH3:49])[CH3:48])(C)C>[Pd].C(O)C>[CH:47]1([NH:46][C:11](=[O:12])[C:10]2[CH:15]=[CH:16][C:17]([CH3:18])=[C:8]([N:6]3[CH:7]=[CH:2][N:3]=[C:4]([N:20]4[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]5[CH2:29][CH2:30][CH2:31][CH2:32]5)[CH:22]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[CH2:21]4)[C:5]3=[O:19])[CH:9]=2)[CH2:49][CH2:48]1
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)c1ccc(C)c(-n2cc(Br)nc(N3CCN(CCN4CCCC4)C(c4ccccc4)C3)c2=O)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(N2CCN(CCN3CCCC3)C(c3ccccc3)C2)c1=O
Temperature: 70 °C

Procedure:
A mixture of 3-[5-bromo-2-oxo-3-[3-phenyl-4-[2-(1-pyrrolidinyl)ethyl]-1-piperazinyl]-1(2H)-pyrazinyl]-4-methyl-benzoic acid, methyl ester (50 mg), ammonium formate (322 mg), palladium 10% on carbon (22 mg), N,N-diisopropylethylamine (0.1 mL) and ethanol (2.5 mL) was heated under an atmosphere of nitrogen within a microwave for 30 min. at 70° C. The mixture was filtered and concentrated. Cyclopropylamine (0.3 mL) and water (0.5 mL) were added and the mixture was heated under atmosphere of nitrogen within a microwave for 5 h at 100° C. and concentrated in vacuo. Purification by preparative HPLC (Gemini column, 0.1% TFA: acetonitrile eluent) gave the title compound (30 mg).
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8](Cl)=[N:9][OH:10])[CH:2]=1.O1CCCC1.[C:23]([C:25]1[C:26]([NH2:31])=[N:27][CH:28]=[CH:29][CH:30]=1)#[CH:24].C(N(CC)CC)C>O>[C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:24]=[C:23]([C:25]3[C:26]([NH2:31])=[N:27][CH:28]=[CH:29][CH:30]=3)[O:10][N:9]=2)[CH:2]=1
Reactant: ON=C(Cl)Cc1cccc(-c2ccccc2)c1
Reactant: C#Cc1cccnc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1ncccc1-c1cc(Cc2cccc(-c3ccccc3)c2)no1
Temperature: 55 °C
Reaction time: 2.5 h
Yield: 34.4 %

Procedure:
To a mixture of biphenyl-3-yl-acetohydroximoyl chloride (120 mg) described in Manufacturing Example 85-1-3 and tetrahydrofuran (6 mL) were added 3-ethynyl-pyridin-2-ylamine (28 mg, 0.24 mmol) described in Manufacturing Example 1-2-3 and triethylamine (200 μL, 1.4 mmol) at room temperature, which was stirred for 2.5 hours at 55° C. The reaction mixture was cooled to room temperature and water was added at that temperature, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=2:1) to obtain the title compound (27 mg, 34%).
Reaction SMILES: [CH2:1]([N:3]([CH:11]1[CH2:15][CH2:14][CH:13]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([N+:25]([O-])=O)[CH:23]=3)[NH:18][CH:17]=2)[CH2:12]1)[C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH3:2].O.NN>CO.O.[Ni]>[NH2:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[CH:13]1[CH2:14][CH2:15][CH:11]([N:3]([CH2:1][CH3:2])[C:4](=[O:10])[O:5][C:6]([CH3:7])([CH3:8])[CH3:9])[CH2:12]1
Reactant: CCN(C(=O)OC(C)(C)C)C1CCC(c2c[nH]c3ccc([N+](=O)[O-])cc23)C1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: CCN(C(=O)OC(C)(C)C)C1CCC(c2c[nH]c3ccc(N)cc23)C1
Yield: 97.1 %

Procedure:
To a solution of tert-butyl ethyl(3-(5-nitro-1H-indol-3-yl)cyclopentyl)carbamate (1.40, g 3.75 mmol) in dry MeOH (15 mL) was added Raney-Ni (0.1 g as a slurry in water) and hydrazine hydrate (1.9 mL, 37.5 mmol). The resulting mixture was immersed in a preheated oil bath and refluxed for 15 min. until the solution became clear. The reaction was cooled and filtered trough celite, washed with MeOH (20 mL) and the solvent evaporated. The crude was purified on column chromatography (2% 2N NH3 in MeOH: 98% CH2Cl2) to give the title compound as a brownish solid (1.25 g, quantitative). 1H-NMR (CDCl3) δ 1.11-1.19 (m, 6H), 1.49 (s, 18H), 1.67-1.89 (m, 6H), 1.96-2.12 (m, 4H), 2.13-2.22 (m, 2H), 2.26-2.35 (m, 2H), 3.10-3.28 (m, 4H), 3.37-3.58 (m, 4H), 4.44-4.59 (m, 2H), 6.64 (dd, 1H, J=1.8, 9.0 Hz), 6.67 (dd, 1H, J=2.1, 8.4 Hz), 6.91 (d, 1H, J=2.4 Hz), 6.92 (d, 1H, J=2.1 Hz), 7.14 (d, 1H, J=2.1 Hz), 7.17 (d, 1H, J=2.1 Hz), 7.73 (brs, 2H, NH); E1-MS (m/z, %) 343 (M+, 100).
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[CH:17][CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:30])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>CC(C)=O>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N+:18]([O-:30])=[CH:17][CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3ncccc3c2)CC1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3c(ccc[n+]3[O-])c2)CC1
Temperature: 23 °C
Reaction time: 1.5 h

Procedure:
6-(trans-4-tert-Butyl-cyclohexyloxy)-quinoline (6.11 g, 0.0216 mol) was dissolved in acetone (100 mL, Acros), followed by m-chloroperbenzoic acid (11.7 g, 0.0542 mol, Aldrich) in small portions at RT. The reaction mixture was then stirred at 23° C. for 1.5 hours. Sodium thiosulfate was added, 97.6 mL of a saturated aqueous solution. The reaction mixture was then allowed to stir for 45 minutes. Excess of solvents were removed under vacuum, and the residue was diluted with water and extracted with methylene chloride. Combined organic layers were treated with magnesium sulfate, filtered and evaporated. The residue was taken up in methylene chloride and silica gel was added. The solvents were removed. The residue was then purified via chromatography (SiO2, 0-10% MeOH/DCM) to give the product (Rf=0.19 in 5% methanol/methylene chloride). The appropriate fractions were combined to give the product in 4.99 g yield (77%).
Reaction SMILES: C1C2C(COC(=O)[NH:17][C@H:18]([CH2:27][C:28](=[O:68])[NH:29][C@H:30]([C:57](=[O:67])[NH:58][C:59]3[CH:64]=[CH:63][C:62]([CH2:65][OH:66])=[CH:61][CH:60]=3)[CH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:36]([C:49]3[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=3)([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)C3C(=CC=CC=3)C=2C=CC=1.C(NCC)C>C1COCC1>[OH:66][CH2:65][C:62]1[CH:63]=[CH:64][C:59]([NH:58][C:57](=[O:67])[C@@H:30]([NH:29][C:28](=[O:68])[CH2:27][C@@H:18]([NH2:17])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:36]([C:49]2[CH:50]=[CH:51][C:52]([O:55][CH3:56])=[CH:53][CH:54]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[CH:60][CH:61]=1
Reactant: COc1ccc(C(NCCCC[C@H](NC(=O)C[C@H](Cc2ccc(F)cc2)NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)Nc2ccc(CO)cc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCNCC
Product: COc1ccc(C(NCCCC[C@H](NC(=O)C[C@@H](N)Cc2ccc(F)cc2)C(=O)Nc2ccc(CO)cc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 0 %

Procedure:
In a 50 mL round-bottomed flask, the above prepared {(S)-2-(4-fluoro-phenyl)-1-[((S)-1-(4-hydroxymethyl-phenylcarbamoyl)-5-{[(4-methoxy-phenyl)-diphenyl-methyl]-amino}-pentylcarbamoyl)-methyl]-ethyl}-carbamic acid 9H-fluoren-9-ylmethyl ester (793 mg, 857 mol, Eq: 1.001) was combined with THF (12 ml) to give a brownish solution. At 0°, diethylamine (1.13 g, 1.59 ml, 15.4 mmol, Eq: 18) was added. The reaction was stirred at ambient temperature over night. The mixture was poured onto crashed ice/NH4Cl (pH ˜7), extracted 2× with AcOEt, washed with H2O and brine, dried over Na2SO4, and evaporated to dryness. Flash chromatography SiO2/10% MeOH/0.1% NEt3 in CH2Cl2 yielded 500 mg of the title compound as off-white solid. MS: expected mass: 702.3581, found mass: 702.3578.
Reaction SMILES: [BH4-].[Na+].C[O:4][C:5](=O)[C@H:6]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH3:27])=[CH:21][CH:20]=1)[NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].CO>O1CCCC1>[CH2:11]([O:10][C:8]([NH:7][C@@H:6]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH3:27])=[CH:21][CH:20]=1)[CH2:5][OH:4])=[O:9])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)OC)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1ccc(C[C@@H](CO)NC(=O)OCc2ccccc2)cc1
Reaction time: 2 h

Procedure:
31.80 g (848.4 mmol) of sodium borohydride is added to a solution of 221.41 g (605.9 mmol) of (S)-N-benzyloxycarbonyl-O-ethyltyrosine methyl ester in 1.5 l of tetrahydrofuran at room temperature. 270 ml of methanol is instilled in it with stirring within 2 hours. Then, the tetrahydrofuran is distilled off in a vacuum, the residue is taken up in 1 l of water and extracted three times with 700 ml of ethyl acetate. The combined organic phase is washed with water, dried with sodium sulfate and concentrated. It is recrystallized from ethyl acetate/hexane.