Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[OH-].[C:3]([O:7][C:8]([N:10]([CH3:50])[C@@H:11]([CH3:49])[C:12]([NH:14][C@H:15]1[C@H:21]([CH3:22])[O:20][C:19]2[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=2[N:17]([CH2:27][C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]([C:37]3[CH:45]=[CH:44][C:40]([C:41]([O-:43])=[O:42])=[CH:39][C:38]=3[C:46]#[N:47])[N:29]=2)[C:16]1=[O:48])=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[C:3]([O:7][C:8]([N:10]([CH3:50])[C@@H:11]([CH3:49])[C:12]([NH:14][C@H:15]1[C@H:21]([CH3:22])[O:20][C:19]2[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=2[N:17]([CH2:27][C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]([C:37]3[CH:45]=[CH:44][C:40]([C:41]([OH:43])=[O:42])=[CH:39][C:38]=3[C:46]#[N:47])[N:29]=2)[C:16]1=[O:48])=[O:13])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: C[C@@H]1Oc2ccccc2N(Cc2nn(-c3ccc(C(=O)[O-])cc3C#N)c3ccccc23)C(=O)[C@H]1NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1Oc2ccccc2N(Cc2nn(-c3ccc(C(=O)O)cc3C#N)c3ccccc23)C(=O)[C@H]1NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C
Yield: 97.7 %

Procedure:
LiOH (1 N, 448 μl, 448 μmol, Eq: 1.3) was added to a solution of 4-(3-(((2S,3S)-3-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-2-methyl-4-oxo-3,4-dihydrobenzo[b][1,4]oxazepin-5(2H)-yl)methyl)-1H-indazol-1-yl)-3-cyanobenzoate (230 mg, 345 μmol, Eq: 1.00) in THF (7 mL) at 0° C. and H2O (3 mL) was added. After 7 h the mixture was acidified with citric acid to pH 4-5 and was extracted with EtOAc. The combined extracts were washed with H2O, dried over Na2SO4 and concentrated to give 4-(3-(((2S,3S)-3-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-2-methyl-4-oxo-3,4-dihydrobenzo[b][1,4]oxazepin-5(2H)-yl)methyl)-1H-indazol-1-yl)-3-cyanobenzoic acid (220 mg, 97.7%) which was used without purification.
Reaction SMILES: [C:1]([S:4][C@@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[CH:7]([C:8](=O)[CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:24])[CH2:6]1)(=[O:3])[CH3:2].[CH2:26]1COCC1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([S:4][C@@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[CH:7]([C:8](=[CH2:26])[CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:24])[CH2:6]1)(=[O:3])[CH3:2].[SH:4][C@@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[CH:7]([C:8](=[CH2:26])[CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:24])[CH2:6]1
Reactant: C1CCOC1
Reactant: CC(=O)S[C@@H]1CC[C@@]2(C)C(C1)C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CC[C@@H](S)CC12
Product: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CC[C@@H](SC(C)=O)CC12
Temperature: 25 °C
Yield: 35 %
Yield: 35 %

Procedure:
To a stirred solution of 3α-acetylthioandrostane-6,17-dione (Prepn. 78, 600 mg) in THF (8 mL) cooled at −50° C., a solution of ylide prepared from methyltriphenylphosphonium bromide (1.47 g) in THF dry (8 mL) at −50° C. and potassium tert-butoxide (484 mg), was added. After 2 h the temperature was raised to room temperature. The mixture was quenched by addition of 5% NaH2PO4 aqueous solution and extracted with EtOAc (2×60 mL). The combined organic extracts were washed with 5% NaH2PO4 aqueous solution, brine, dried over Na2SO4, and evaporated to dryness. The residue was purified by flash chromatography (n-hexane/EtOAc 9/1) to give 3α-acetylthio-6-methyleneandrostan-17-one (210 mg, 35% yield) and 3α-mercapto-6-methyleneandrostan-17-one (208 mg, 35% yield). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): 3α-acetylthio-6-methyleneandrostane-17-one: δ 4.73 (1H, m), 4.39 (1H, m), 3.96 (1H, m), 2.44-0.84 (20H, m), 2.29 (3H, s), 0.75 (3H, s), 0.66 (3H, s); 3α-mercapto-6-methyleneandrostane-17-one: δ 4.73 (1H, m), 4.38 (1H, m), 3.57 (1H, m), 2.52 (1H, d), 2.45-0.95 (20H, m), 0.76 (3H, s), 0.63 (3H, s).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([S:20][CH3:21])=[C:9]([C:18]#[N:19])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31].[NH4+].[Cl-]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([S:20][CH3:21])=[C:9]([C:18]#[N:19])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([NH:17][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:13][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(SC)c(C#N)c1-c1ccc(N)cc1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1sc(SC)c(C#N)c1-c1ccc(NS(C)(=O)=O)cc1
Reaction time: 8 h
Yield: 25 %

Procedure:
Combine 3-(4-Aminophenyl)-4-cyano-5-methylsulfanyl-thiophene-2-carboxylic acid ethyl ester (0.1 g, 1.0 eq) in CH2Cl2 (5 mL) and stir. Add triethylamine (1.5 eq) and methanesulfonyl chloride (1.0 eq) at room temperature. Stir the mixture overnight. Add a saturated solution of NH4Cl and extract with CH2Cl2 (2×50 mL). Dry over NaSO4, filter and evaporate to dryness. Purification by chromatography (hexane:ethyl acetate 4:1) provides the title compound (0.028 g, Yield 25%). MS (ES+, m/e): 397 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[C:20](=[O:22])[CH2:19][CH2:18]2.C(=O)([O-])[O-].[K+].[K+]>[Cu]I.CN1CCCC1=O>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([NH:12][C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:21]=2[C:20](=[O:22])[CH2:19][CH2:18]3)[CH:3]=1
Reactant: Nc1cccc2c1C(=O)CC2
Reactant: Brc1cnc2ccccc2c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=C1CCc2cccc(Nc3cnc4ccccc4c3)c21
Temperature: 200 °C
Reaction time: 2 h
Yield: 27.8 %

Procedure:
0.43 g of 3-bromoquinoline, 0.29 g of 7-aminoindan-1-one, 0.08 g of copper (I) iodide, 0.41 g of potassium carbonate, and 4 ml of N-methylpyrrolidone were mixed, and then the mixture was stirred for 2 hours at 200° C. The resultant mixture was purified by silica gel column chromatography to obtain 0.15 g of 7-(quinolin-3-ylamino)-indan-1-one (Compound Number 50).
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([Br:9])=[N:7][CH:8]=1)#N.[H-].C([Al+]CC(C)C)C(C)C.[OH:20]S(O)(=O)=O>C1(C)C=CC=CC=1.C(Cl)Cl.CO>[Br:9][C:6]1[N:7]=[CH:8][C:3]([CH:1]=[O:20])=[N:4][CH:5]=1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1cnc(Br)cn1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: O=Cc1cnc(Br)cn1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 28 %

Procedure:
To a solution of 5-cyano-2-bromopyrazine (1.02 g, 5.54 mmol) in anhydrous toluene (15 mL) at −78° C. was added 1 M diisobutyl aluminum hydride (8.32 mmol) in CH2Cl2 (8.3 mL). The reaction mixture was stirred at −78° C. for 15 min, warmed to room temperature, stirred for 26 h, and then diluted with MeOH (4 mL) and stirred for 30 min at room temperature before addition of 10% H2SO4 (55 mL). The resulting solution was stirred for 1.75 h and extracted with EtOAc (100 mL, 50 mL). After solvent removal at reduced pressure, the residue was chromatographed (11% to 14% EtOAc/hexane) to give 289 mg (28%) of 5-bromo-pyrazine-2-carbaldehyde as an orange solid, mp 56-58° C. IR 2960, 1654, 1546, 1111 cm−1; 1H NMR (CDCl3) δ 8.83 (d, J=1.24 Hz, 1H, 6-PyrH), 8.91 (d, J=1.24 Hz, 1H, 3-PyrH), 10.13 ppm (s, 1H, CHO). HRMS calcd C5H3BrN2O [M+H]+ 186.9501. found 186.9496.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[F:13][C:14]([F:22])([F:21])[CH:15]([OH:20])[C:16]([F:19])([F:18])[F:17].C(N(CC)C(C)C)(C)C.[F:32][C:33]1[CH:34]=[C:35]([C:39]2[CH:40]=[CH:41][C:42]([CH2:45][N:46]3[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]3)=[N:43][CH:44]=2)[CH:36]=[CH:37][CH:38]=1>O.ClCCl>[F:32][C:33]1[CH:34]=[C:35]([C:39]2[CH:40]=[CH:41][C:42]([CH2:45][N:46]3[CH2:51][CH2:50][N:49]([C:5]([O:20][CH:15]([C:16]([F:19])([F:18])[F:17])[C:14]([F:22])([F:21])[F:13])=[O:11])[CH2:48][CH2:47]3)=[N:43][CH:44]=2)[CH:36]=[CH:37][CH:38]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Fc1cccc(-c2ccc(CN3CCNCC3)nc2)c1
Reactant: OC(C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: O=C(OC(C(F)(F)F)C(F)(F)F)N1CCN(Cc2ccc(-c3cccc(F)c3)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 160.2 %

Procedure:
A 100 mL round-bottom flask was charged with triphosgene (66.0 mg, 0.220 mmol, 0.30 equiv), dichloromethane (20 mL), 1,1,1,3,3,3-hexafluoropropan-2-ol (124 mg, 0.740 mmol, 1.00 equiv). N,N-Diisopropylethylamine (181 mg, 1.40 mmol, 1.90 equiv) was added dropwise. The resulting solution was stirred for 2 h at room temperature. 1-[[5-(3-Fluorophenyl)pyridin-2-yl]methyl]piperazine (200 mg, 0.740 mmol, 1.00 equiv) was added. The resulting solution was stirred overnight at room temperature and then diluted with water (5 mL). The resulting mixture was extracted with dichloromethane (3×5 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product (352 mg) was purified by preparative HPLC using the following gradient conditions: 20% CH3CN/80% Phase A increasing to 80% CH3CN over 10 min, then to 100% CH3CN over 0.1 min, holding at 100% CH3CN for 1.9 min, then reducing to 20% CH3CN over 0.1 min, and holding at 20% for 1.9 min, on a Waters 2767-5 Chromatograph. Column: Xbridge Prep C18, 19*150 mm 5 um; Mobile phase: Phase A: aqueous NH4HCO3 (0.05%); Phase B: CH3CN; Detector, UV220 & 254 nm. Purification resulted in 164 mg (48% yield) of 1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[5-(3-fluorophenyl)pyridin-2-yl]methyl]piperazine-1-carboxylate as a white solid. 1H NMR 300 MHz (CDCl3) δ 8.79 (s, 1H), 7.84-7.87 (m, 1H), 7.42-7.49 (m, 2H), 7.36 (d, J=7.8 Hz, 1H), 7.29-7.30 (m, 1H), 7.08-7.14 (m, 1H), 5.69-5.82 (m, 1H), 3.84 (s, 2H), 3.62 (br, 4H), 2.58 (br, 4H). LCMS (ESI, m/z): 466 [M+H]+.
Reaction SMILES: Cl.O.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.[CH2:10](N(CC)CC)C.CN1CCOCC1.[CH3:24][O:25][C:26]1[CH:31]=[C:30]([CH3:32])[C:29]([S:33]([N:36]2[CH2:40][CH2:39][CH2:38][CH:37]2[CH2:41][O:42][CH2:43][C:44]([OH:46])=O)(=[O:35])=[O:34])=[C:28]([CH3:47])[CH:27]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH3:47])[C:29]([S:33]([N:36]2[CH2:40][CH2:39][CH2:10][CH2:38][CH:37]2[CH2:41][O:42][CH2:43][C:44]([N:3]2[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]2)=[O:46])(=[O:35])=[O:34])=[C:30]([CH3:32])[CH:31]=1
Reactant: O=C1CCNCC1
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCC2COCC(=O)O)c(C)c1
Reactant: CCN(CC)CC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: COc1cc(C)c(S(=O)(=O)N2CCCCC2COCC(=O)N2CCC(=O)CC2)c(C)c1
Reaction time: 72 h

Procedure:
4-piperidone monohydrate hydrochloride (260 mg, 2.692 mmol), triethylamine (0.560 ml, 4.038 mmol) and then 4-methylmorpholine (1.62 ml, 14.805 mmol) were added to a solution of 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)acetic acid (acid structural unit S27) (1.0 g, 2.692 mmol) in N,N-dimethylformamide (20 ml). Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.42 g, 3.230 mmol) was then added to the mixture, and stirring was carried out for 3 d at room temperature. The mixture was then concentrated in vacuo, and the residue was taken up in ethyl acetate (30 ml) and saturated sodium hydrogen carbonate solution (20 ml); the aqueous phase was extracted with ethyl acetate (4×10 ml). The combined organic phases were washed with saturated sodium hydrogen carbonate solution (20 ml) and saturated sodium chloride solution (20 ml), dried (MgSO4), and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) using diethyl ether/dichloromethane/ammonia solution (25% aq.) (100:100:2). Yield: 430 mg (35%); MS, m/z 540.3 (MH+)
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:6][O:7][C:8]2[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=[CH:10][C:9]=2[C:18]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=2[CH2:20][CH2:21][C:22]3=[O:27])[CH2:5][CH2:4]1.C(N(CC)CC)C.[N:35]([CH:38]([CH3:40])[CH3:39])=[C:36]=[O:37].COC1C(OC)=CC=C(C2C=CC=C3C=2CCC3=O)C=1OCC1(COC(=O)NCC)CC1>ClCCl>[CH3:15][O:14][C:13]1[C:12]([O:16][CH3:17])=[CH:11][CH:10]=[C:9]([C:18]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=2[CH2:20][CH2:21][C:22]3=[O:27])[C:8]=1[O:7][CH2:6][C:3]1([CH2:2][O:1][C:36](=[O:37])[NH:35][CH:38]([CH3:40])[CH3:39])[CH2:4][CH2:5]1
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CO)CC2)c1OC
Reactant: CC(C)N=C=O
Agent: CCNC(=O)OCC1(COc2c(-c3cccc4c3CCC4=O)ccc(OC)c2OC)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(COC(=O)NC(C)C)CC2)c1OC

Procedure:
To a stirring solution of 4-[2-(1-Hydroxymethyl-cyclopropylmethoxy)-3,4-dimethoxy-phenyl]-indan-1-one (Compound 177) (200 mg, 0.543 mmol) in dichloromethane (20 mL), were added triethylamine (164 mg, 1.623 mmol) and 2-isocyanatopropane (184 mg, 2.164 mmol) and the resultant reaction mixture was subjected to the conditions used in the preparation of Compound 179 to afford the title compound as a solid.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([O:4][C:5]([NH:7][C@H:8]1[CH2:11][NH:10][C:9]1=[O:12])=[O:6])[CH3:3].Cl[S:15]([N:18]=[C:19]=[O:20])(=[O:17])=[O:16].[NH3:21]>C(#N)C.ClCCl>[NH4+:7].[NH2:21][S:15]([NH:18][C:19]([N:10]1[CH2:11][C@H:8]([NH:7][C:5]([O:4][C:2]([CH3:13])([CH3:1])[CH3:3])=[O:6])[C:9]1=[O:12])=[O:20])(=[O:17])=[O:16]
Reactant: N
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CNC1=O
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CN(C(=O)NS(N)(=O)=O)C1=O
Product: [NH4+]
Reaction time: 0.5 h

Procedure:
(S)-3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-oxoazetidine (5.1 g; see example 15A) was dissolved in a mixture of 160 ml of acetonitrile and 40 ml of dichloromethane. At -50° C. a solution of 5.4 g of chlorosulfonyl isocyanate in 30 ml of dichloromethane was added dropwise (15 minutes). The mixture was kept at -30° C. for 30 minutes. Then 64 ml of a solution of ammonia in acetonitrile (containing 2.4 g of ammonia)was added slowly at -10° to 0° C. The title compound precipitated together with inorganic material and was filtered by suction (crude yield 9.8 g). From the filtrate another crop of 2.7 g of crude title compound was obtained. According to thin-layer chromatography both fractions were of similar purity. The combined material was dissolved in 50 ml of water, adjusted to pH 6.5 by the addition of diluted aqueous ammonia and purified by chromatography on HP-20, eluting with water; 20 ml fractions were taken. Fractions 70-130 contained 2.7 g of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH2:18][CH2:19][O:20]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3](=O)[CH2:4][O:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[CH:15]=[CH:14][S:13][C:12]=2[CH:16]=1.Cl.O.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[S:13]1[CH:14]=[CH:15][C:11]2[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][O:5][CH2:4][CH2:3][N:2]([CH3:1])[CH2:18][CH2:19][OH:20])=[CH:16][C:12]1=2
Reactant: CN(CCOC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)COCCc1ccc2ccsc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CN(CCO)CCOCCc1ccc2ccsc2c1
Temperature: 5 °C
Yield: 50 %

Procedure:
In 20 mL of tetrahydrofuran is dissolved 2.07 g of N1-methyl-N1-[2-(trityloxy)ethyl]-2-(2-benzo[b]-thiophen-6-ylethoxy)-acetamide. The solution is cooled to 5° C., and 7.5 mL of 1 mol/L solution of borane-tetrahydrofuran complex in tetrahydrofuran is dropwise added thereto. After stirring the mixture at ambient temperature overnight, 1.9 mL of 6 mol/L hydrochloric acid is dropwise added, and the resulting mixture is heated under reflux for one hour. After cooling, water and ethyl acetate are added to the reaction mixture, pH is adjusted to 10 with 5 mol/L aqueous solution of sodium hydroxide, and the organic layer is separated. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the residue is purified by column chromatography (eluent: chloroform:methanol=30:1 to 20:1) to obtain 0.54 g of 2-[[2-(2-benzo[b]thiophen-6-ylethoxy)ethyl](methyl)amino]-1-ethanol as an oily product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][C:7](=O)[CH2:8]Br.[C:12]([NH:19][C:20]([NH2:22])=[NH:21])([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[Na+].[I-]>CN(C=O)C>[C:15]([O:14][C:12]([N:19]1[CH:8]=[C:7]([CH2:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:11])[N:21]=[C:20]1[NH2:22])=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)NC(=N)N
Reactant: COC(=O)CCCC(=O)CBr
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Temperature: 25 °C
Yield: 64.8 %

Procedure:
6-bromo-5-oxo-hexanoic acid methyl ester (2.30 g, 10.3 mmol), Boc-guanidine (4.92 g, 30.9 mmol),32 and NaI (3.07 g, 20.6 mmol) were dissolved in DMF (30 mL) and allowed to stir at room temperature. After 24 h the DMF was removed under reduced pressure and the residue was taken up in ethyl acetate (100 mL) and washed with water (3×50 mL) and brine (50 mL) before being dried (Na2SO4), filtered and evaporated to dryness. The resulting oil was purified by flash column chromatography (50-100% EtOAc/Hexanes) to obtain a yellow oil. Trituration of the viscous oil with cold hexanes (20 mL) produced a precipitate, which upon filtration yielded 18 (1.89 g, 65%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 6.53 (s, 1H), 5.6 (br s, 2H), 2.41 (t, 2H, J=7.2 Hz), 2.37 (t, 2H, J=7.2 Hz), 1.93 (quint., 2H, J=7.2 Hz), 1.58 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 174.09, 150.11, 149.61, 138.39, 107.15, 84.81, 51.56, 33.65, 28.18, 27.68, 23.82; HRMS (ESI) calcd for C13H22N3O4 (MH)+ 284.1604. Found 284.1606.
Reaction SMILES: [OH:1][C:2]([C:9]([F:12])([F:11])[F:10])([CH2:7][CH3:8])[C:3]([NH:5][NH2:6])=[O:4].Br[C:14]#[N:15]>O>[NH2:15][C:14]1[O:4][C:3]([C:2]([OH:1])([CH2:7][CH3:8])[C:9]([F:10])([F:11])[F:12])=[N:5][N:6]=1
Reactant: CCC(O)(C(=O)NN)C(F)(F)F
Reactant: N#CBr
Solvent: O
Product: CCC(O)(c1nnc(N)o1)C(F)(F)F
Reaction time: 3 h

Procedure:
To hydrazide (34.07 g, 183 mmol) of step 2 in 275 mL of water was added KHCO3 (18.33 g, 183 mmol) followed by BrCN (19.39 g, 183 mmol) portionwise. After 3 h, the solid was filtered, washed with cold water and dried to afford the title compound. Additional compound could be recovered from the aqueous phase by extraction (ether-hexane, 1:1). 1H NMR (400 MHz, acetone-d6): δ 6.54 (s, 2H), 6.01 (s, 1H), 2.22 (m, 1H), 2.08 (m, 1H) and 0.99 (m, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:30]=[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:28]=[CH:27][C:5]=1[O:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][C:11]=1[N+:24]([O-])=O)([O-])=O.CO.C(Cl)(Cl)Cl.C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O>C(Cl)Cl.[Pt]>[NH2:24][C:11]1[CH:12]=[C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=[CH:15][C:10]=1[O:9][CH2:8][CH2:7][O:6][C:5]1[CH:27]=[CH:28][C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:30][C:4]=1[NH2:1]
Reactant: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1OCCOc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Agent: [Pt]
Agent: O=C1c2ccccc2C(=O)C1(O)O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Nc1cc(OCc2ccccc2)ccc1OCCOc1ccc(OCc2ccccc2)cc1N
Reaction time: 6 h
Yield: 90 %

Procedure:
Compound 9 (40 g, 77.5 mmol) is dissolved in 400 mL of CH2Cl2 and 1.5 g 5% platinum on charcoal is added. The reaction is shaken under 40 psi H2 for six hours until the reaction is judged complete using thin layer chromatography (1:9 methanol:chloroform). The product reacts with ninhydrin on a TLC plate to give a ruddy brown product with an Rf of 0.3. The reaction mixture is filtered through diatomaceous earth to remove the catalyst, and the resulting filtrate is evaporated under reduced pressure. The resulting semi-crystalline oil is stirred with 400 mL methanol for two hours while protected from light. The resulting light gray crystals are filtered and dried to give 10 in 90% yield.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([N:15](CC2C=CC(OC)=CC=2)[C:16]2[CH:17]=[N:18][C:19]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:20][CH:21]=2)[N:12]=[CH:11][C:10]=1[CH2:37][C:38]([NH2:40])=[O:39])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:17]=[N:18][C:19]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:20][CH:21]=2)[N:12]=[CH:11][C:10]=1[CH2:37][C:38]([NH2:40])=[O:39])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CN(c2ccc(N3CCOCC3)nc2)c2cc(NCc3ccccc3)c(CC(N)=O)cn2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)Cc1cnc(Nc2ccc(N3CCOCC3)nc2)cc1NCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 3 %

Procedure:
3.0 mg of 4-benzylamino-6-[4-methoxybenzyl-(6-morpholinopyridin-3-yl)amino]pyridine-3-carboxyamide was dissolved in 0.5 mL of methylene chloride, to which 0.5 mg of trifluoroacetic acid was added, stirred at room temperature for 4 hours, and further heated at reflux at 70° C. for 8 hours. After cooling, the solvent was evaporated, saturated sodium bicarbonate in water was added to the residue, extracted with chloroform, the extract was washed with saturated saline, and dried on anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel thin layer chromatography (chloroform:methanol=10:1) and silica gel thin layer chromatography (chloroform:ammonium-saturated methanol=10:1) to obtain 1.2 mg (4 steps, yield 3%) of the title compound as a light brown solid.
Reaction SMILES: C(O[C:4](=[O:17])[CH2:5][C:6]1([CH2:13][N+]([O-])=O)[CH2:10][C@@H:9]([CH3:11])[C@H:8]([CH3:12])[CH2:7]1)C.[CH3:18]O>[Ni]>[CH3:11][C@H:9]1[C@H:8]([CH3:12])[CH2:7][C:6]2([CH2:5][C:4](=[O:17])[CH2:18][CH2:13]2)[CH2:10]1
Reactant: CCOC(=O)CC1(C[N+](=O)[O-])C[C@@H](C)[C@H](C)C1
Reactant: CO
Agent: [Ni]
Product: C[C@@H]1CC2(CCC(=O)C2)C[C@H]1C
Reaction time: 5 h
Yield: 95 %

Procedure:
The nitroester (3) (1.14 g, 4.7 mmol) was dissolved in methanol (50 mL) and shaken over Raney nickel catalyst under an atmosphere of hydrogen (40 psi) at 30° C. After 5 hours, the catalyst was removed by filtration through celite. The solvent was removed in vacuo to give 746 mg (95%) of a pale yellow oil which solidified on standing.
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:15]([C:27]([NH:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[O:28])[CH:14]=1)C(=O)OC(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[CH3:1][NH:2][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[C:15]([CH:14]=1)[C:27]([NH:29][C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1)=[O:28]
Reactant: CN(CCOc1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCOc1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
To the solution of 1,1-dimethylethyl methyl[2-({4-[(phenylmethyl)oxy]-3-[(3-pyridinylamino)carbonyl]phenyl}oxy)ethyl]carbamate (may be prepared as described in Description 75; 140 mg, 0.17 mmol) in dichloromethane (10 ml) was added trifluoroacetic acid (3.0 ml, 38.9 mmol) dropwise. After stirring at 30° C. for 2 h, the pH of the solution was adjusted to 7-8 by adding aqueous NaHCO3 solution. The mixture was extracted with dichloromethane. The dichloromethane layer was washed with brine, dried over Na2SO4, and concentrated to obtain a crude product. The crude product was purified by prep-HPLC (Gilson GX-281, waters X-Bridge 5 μm, 100*30 mm; A: 0.04% NH3.H2O/water, B: CH3CN; 0-6.0 min, 30%-55%; 6-12 min, 95%, RT=7.3 min) to yield the title compound as a white solid. 20 mg.