Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[N:9][C:8]2[CH:7]=[C:6]([N:17]([CH2:21][CH2:22][Cl:23])[CH2:18][CH2:19][Cl:20])[CH:5]=[CH:4][C:3]1=2.Cl.[CH3:25][CH:26](O)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].C1(N=C=NC2CCCCC2)CCCCC1>CN(C1C=CN=CC=1)C>[CH3:36][CH:35]([O:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]1[N:2]([CH3:1])[C:3]2[CH:4]=[CH:5][C:6]([N:17]([CH2:18][CH2:19][Cl:20])[CH2:21][CH2:22][Cl:23])=[CH:7][C:8]=2[N:9]=1)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH3:25]
Reactant: CCCCCCCCCCC(C)O
Reactant: Cn1c(CCCC(=O)O)nc2cc(N(CCCl)CCCl)ccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CCCCCCCCCCC(C)OC(=O)CCCc1nc2cc(N(CCCl)CCCl)ccc2n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.1 %

Procedure:
A 250 mL three neck round bottom flask was equipped with an overhead stirrer, thermocouple, temperature controller and nitrogen sweep then charged with 10.0 g (25.34 mmol) of bendamustine hydrochloride, 4.77 g (5.75 mL, 25.6 mmol, 1.01 eq) of 2-dodecanol, 5.3 g (25.6 mmol, 1.01 eq) of dicyclohexylcarbodiimide (DCC), 100 mL of MDC and 0.31 g (2.54 mmol, 0.1 eq) of DMAP. The reaction was stirred at room temperature overnight at which time an in process analysis indicated the reaction was complete. Solids were removed by vacuum filtration and washed with 25 mL of MDC. The filtrate was diluted with 200 mL of MDC then washed with 4% aqueous sodium bicarbonate solution (1×500 mL) before drying over sodium sulfate, filtering and concentrating to dryness in vacuo to an off-white solid. This solid was triturated with 25 mL of MDC and the solid impurities were removed by vacuum filtration and washed with 5 mL of MDC. The filtrate was concentrated to dryness in vacuo to yield the crude product which was shown to contain residual 2-dodecanol by 1H NMR. The crude product was chromatographed using 100 g of silica gel 60, 230-400 mesh, eluting with first 1 L of heptanes, then 500 mL of 3:1 heptane/EtOAc, 500 of 2:1 heptane/EtOAc and finally 500 mL of 1:1 heptane/EtOAc collecting 100 mL fractions. Product containing fractions were combined and concentrated to dryness in vacuo to yield 5.35 g (10.16 mmol, 40%) of the product as a light purple viscous oil with an HPLC purity of 99.5A %. 1H NMR (400 MHz, DMSO-d6) δ 7.31 (d, J=8.76 Hz, 1H), 6.93 (d, J=2.28 Hz, 1H), 6.78 (dd, J=2.36, 8.76 Hz, 1H), 4.8 (m, 1H), 3.7 (s, 8H), 3.65 (s, 3H), 2.82 (t, J=7.4 Hz, 2H), 2.42 (t, J=7.36 Hz, 2H), 2.00 (m, 2H), 1.50 (m, 2H), 1.25 (s, b, 16H), 1.14 (d, J=6.24, 2H), 0.84 (t, J=6.68 Hz, 3H).
Reaction SMILES: C[O:2][C:3](=[O:35])[CH:4]([CH2:27][C@H:28]1[CH2:33][CH2:32][C@@H:31]([OH:34])[CH2:30][CH2:29]1)[CH2:5][CH2:6][NH:7][C@@H:8]1[C@@H:17]([O:18][CH3:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:20](=[O:22])[NH2:21])=[CH:13][CH:14]=2)[C:9]1([CH2:25][CH3:26])[CH2:23][CH3:24].O.[OH-].[Na+]>CO.CC(O)=O>[C:20]([C:12]1[CH:11]=[C:10]2[C:15]([CH2:16][C@H:17]([O:18][CH3:19])[C@@H:8]([NH:7][CH2:6][CH2:5][CH:4]([CH2:27][C@H:28]3[CH2:33][CH2:32][C@@H:31]([OH:34])[CH2:30][CH2:29]3)[C:3]([OH:35])=[O:2])[C:9]2([CH2:23][CH3:24])[CH2:25][CH3:26])=[CH:14][CH:13]=1)(=[O:22])[NH2:21]
Reactant: CCC1(CC)c2cc(C(N)=O)ccc2C[C@H](OC)[C@H]1NCCC(C[C@H]1CC[C@@H](O)CC1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CCC1(CC)c2cc(C(N)=O)ccc2C[C@H](OC)[C@H]1NCCC(C[C@H]1CC[C@@H](O)CC1)C(=O)O
Temperature: 50 °C
Reaction time: 15 h

Procedure:
To a solution of 4-((2S,3S)-7-carbamoyl-1,1-diethyl-3-methoxy-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-2-(cis-4-hydroxy-cyclohexylmethyl)-butyric acid methyl ester (f2) (56 mg, 0.11 mmol) in MeOH (0.50 mL) was added water (66 μL) and 10 N NaOH (66 μL, 0.66 mmol). The mixture was heated at 50° C. After 15 h, the reaction mixture was cooled to RT, dissolved in 50% aqueous AcOH (6 mL) and purified by preparative HPLC to give the title compound (54 mg) as a lyophylized powder. (m/z): [M+H]+ calcd for C27H42N2O5 475.32. Found 475.2. 1H NMR (CD3OD, 400 mHz) δ (ppm) 7.78 (d, J=1.8 Hz, 1H), 7.72 (dd, J=8.0 Hz, 1.7 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 4.09 (m, 1H), 3.88 (br s, 1H), 3.58 (dd, J=16.6, 5.6 Hz, 1H), 3.52 (s, 3H), 3.52-3.46 (m, 2H) 3.30-3.20 (m, 1H), 2.77 (m, 1H), 2.59 (m, 1H), 2.31 (m, 1H), 2.05-1.92 (m, 2H), 1.79-1.65 (m, 6H), 1.60-1.35 (m, 8H), 0.79 (t, J=7.5 Hz, 3H), 0.70 (dt, J=7.2, 1.6 Hz).
Reaction SMILES: [NH2:1][CH:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[OH:4].[CH2:9](O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[NH2:1][CH:2]([CH:3]([OH:4])[CH3:5])[C:6]([O:8][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH3:9])=[O:7]
Reactant: CCCCCCCCCCCCO
Reactant: CC(O)C(N)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCOC(=O)C(N)C(C)O
Yield: 101.5 %

Procedure:
To a stirred solution of DL-threonine 26 (5 g, 41.9 mmol) in toluene (100 mL) was added 1-dodecanol 2 (7 g, 37.7 mmol) in one lot, followed by pTSA (8.77 g, 46.16 mmol). After addition, the temperature of the reaction mixture was slowly raised to reflux temperature and the water was separated azeotropically. The reaction mixture was monitored by TLC. The reaction mixture was concentrated under vacuum. The obtained residue was taken in ethyl acetate (200 mL) and washed with aqueous 5% Na2CO3 (3×50 mL) followed by brine solution. The organic layer was dried over Na2SO4 and concentrated under vacuum to afford crude 27 (11 g, yield: 91%) as a liquid.
Reaction SMILES: C([O-])(=O)CCCCCCCCCCCCCCCCC.[Al+3:21].C([O-])(=O)CCCCCCCCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCCCCCCCC.[OH:62][C:63]1[CH:64]=[CH:65][CH:66]=[C:67]2[C:72]=1[N:71]=[CH:70][CH:69]=[CH:68]2>C1(C)C=CC=CC=1>[CH:65]1[CH:64]=[C:63]([O-:62])[C:72]2[N:71]=[CH:70][CH:69]=[CH:68][C:67]=2[CH:66]=1.[CH:65]1[CH:64]=[C:63]([O-:62])[C:72]2[N:71]=[CH:70][CH:69]=[CH:68][C:67]=2[CH:66]=1.[CH:65]1[CH:64]=[C:63]([O-:62])[C:72]2[N:71]=[CH:70][CH:69]=[CH:68][C:67]=2[CH:66]=1.[Al+3:21]
Reactant: Oc1cccc2cccnc12
Agent: CCCCCCCCCCCCCCCCCC(=O)[O-]
Agent: [Al+3]
Solvent: Cc1ccccc1
Product: [O-]c1cccc2cccnc12

Procedure:
Aluminum stearate, Al[CH3(CH2)16CO2]3, (10.0 g, Fisher Scientific Co., Pittsburgh, Pa., technical grade) was placed in a 250 mL round bottomed flask equipped with a magnetic stir bar and a reflux condenser. Toluene (50 mL) was added to give a white slurry. Separately, a 6.0 g sample of 8-hydroxyquinoline (41.3 mmol) was dissolved in 150 mL of toluene and the solution was gravity filtered through a coarse glass frit into the reaction flask. This removed an insoluble minor impurity found in the 8-hydroxyquinoline. After the addition of the 8-hydroxyquinoline to the aluminum stearate-toluene solution, the reaction flask was heated to reflux by means of an electric heating mantle. As the reaction warmed, but prior to refluxing, a large quantity of a fine yellow solid precipitated. The reaction mixture was refluxed for approximately 72 hours, cooled, and filtered. The yellow filter cake was washed sequentially with two 50 mL portions of toluene and two 50 mL portions of petroleum ether. After vacuum drying, the filter cake provided 5.4 g of tris(8-quinolinolato)aluminum as fine yellow needles. An 1H-NMR of the product precipitated from the toluene reaction mixture showed no significant resonances other than those of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[CH3:27][N:28]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34](B(O)O)[CH:35]=2)[CH:30]=[N:29]1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:34]5[CH:35]=[C:36]6[C:31]([CH:30]=[N:29][N:28]6[CH3:27])=[CH:32][CH:33]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Reactant: Cn1ncc2ccc(B(O)O)cc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccc6cnn(C)c6c5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 1-methyl-indazole-6-boronic acid following a procedure analogous to that described for Intermediate 6. LC (method 3): tR=0.65 min; Mass spectrum (ESI+): m/z=489 [M+H]+.
Reaction SMILES: N1C=CC=CC=1.[C:7]([O:10][CH2:11][C:12]1[CH2:13][S:14][C@@H:15]2[C@H:22]([NH:23][C:24](=[O:34])[C:25](=[N:32][OH:33])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:21](=[O:35])[N:16]2[C:17]=1[C:18]([OH:20])=[O:19])(=[O:9])[CH3:8].[C:36](Cl)(=[O:38])[CH3:37].O>C(OCC)(=O)C.CS(C)=O>[C:36]([O:33][N:32]=[C:25]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:24]([NH:23][C@@H:22]1[C:21](=[O:35])[N:16]2[C:17]([C:18]([OH:20])=[O:19])=[C:12]([CH2:11][O:10][C:7](=[O:9])[CH3:8])[CH2:13][S:14][C@H:15]12)=[O:34])(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)C(=NO)c3ccccc3)[C@H]2SC1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)C(=NOC(C)=O)c3ccccc3)[C@H]2SC1

Procedure:
To a solution of pyridine (1.5 ml) in ethyl acetate (20 ml) was added 3-acetoxymethyl-7β-(2-hydroxyimino-2-phenylacetamido)ceph-3-em-4-carboxylic acid (syn-isomer) (0.5 g.) and the stirred mixture was treated dropwise with a solution of acetyl chloride (1.0 ml.) in ethyl acetate (5 ml.) and stirring continued for ten minutes. The mixture was poured into water, the ethyl acetate phase separated and washed with 2N-hydrochloric acid, water, and extracted with saturated aqueous sodium bicarbonate. The combined aqueous extracts were acidified and extracted with ethyl acetate and the extracts were dried and concentrated to ca. 5 ml. The concentrate was added dropwise with stirring to petroleum (250 ml.) The precipitated solid was collected and dried, giving the title acid (0.32 g; 58%),[α]D + 83° (C 0.8, DMSO),λmax. (pH 6 buffer) 258 nm (ε 20,800), νmax. (Nujol) 3270 (NH), 1780 (β-lactam), 1680 and 1546 cm.-1 (CONH, τ (DMSO-d6) values include -0.10 (doublet J 8 Hz; NH), 2.2 to 2.6 (multiplet; aromatic protons), 7.78 (singlet; =N.O.COCH3), 7.95 (singlet; OCOCH3).
Reaction SMILES: [F:1][CH:2]([F:26])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([CH3:25])[CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:29]=[C:30]([S:34]([NH:37][CH:38]2[CH2:40][CH2:39]2)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[CH:38]1([NH:37][S:34]([C:30]2[CH:29]=[C:28]([NH:27][C:12]([C:11]3[CH:10]=[N:9][N:8]4[C:3]([CH:2]([F:1])[F:26])=[CH:4][C:5]([C:15]5[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[C:17]([CH3:25])[CH:16]=5)=[N:6][C:7]=34)=[O:13])[CH:33]=[CH:32][CH:31]=2)(=[O:36])=[O:35])[CH2:40][CH2:39]1
Reactant: Nc1cccc(S(=O)(=O)NC2CC2)c1
Reactant: Cc1cc(-c2cc(C(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Product: Cc1cc(-c2cc(C(F)F)n3ncc(C(=O)Nc4cccc(S(=O)(=O)NC5CC5)c4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(3-methyl-4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.5) and 3-amino-N-cyclopropyl-benzenesulfonamide [CAS 459434-39-0] according to general procedure II. Light yellow solid. MS (ISP) 564.2 [(M−H)−]; mp 199° C.
Reaction SMILES: N1C=CC=CC=1.CS([Cl:11])(=O)=O.[C:12]([O:16][C:17]([NH:19][CH2:20][CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)O)=[O:18])([CH3:15])([CH3:14])[CH3:13]>C(Cl)Cl>[C:12]([O:16][C:17]([NH:19][CH2:20][CH:21]([Cl:11])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCC(O)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCC(Cl)c1ccccc1
Reaction time: 8 h

Procedure:
A mixture of 3.7 ml of pyridine and 2.2 ml of methanesulfonyl chloride was added dropwise to 35 ml of a solution of 3.5 g of 2-t-butoxycarbonylamino-1-phenylethanol [prepared as described in step (a) above] in methylene chloride and the reaction mixture was allowed to stand overnight at room temperature. The reaction mixture was condensed by evaporation under reduced pressure, and the residue was dissolved in a mixture of ethyl acetate and water. The ethyl acetate layer was separated, washed with water and then washed with an aqueous solution of potassium hydrogen sulfate and with an aqueous solution of sodium bicarbonate. The resulting solution was dried over anhydrous magnesium sulfate. The solvent was then distilled off. The residue was subjected to silica gel column chromatography using a 15:85 by volume mixture of ethyl acetate and cyclohexane as the eluent, to give 0.75 g of the title compound as crystals melting at 57°-59° C.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH3:49])[CH2:30][CH2:31][N:32]([C:42]1[CH:48]=[CH:47][C:45]([NH2:46])=[CH:44][CH:43]=1)[C:33](=[O:41])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH3:49][N:29]([CH3:28])[CH2:30][CH2:31][N:32]([C:42]1[CH:43]=[CH:44][C:45]([NH:46]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:47][CH:48]=1)[C:33](=[O:41])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: CN(C)CCN(C(=O)Cc1ccccc1)c1ccc(N)cc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(CCN(C)C)C(=O)Cc2ccccc2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(N-(2-dimethylamino-ethyl)-N-(phenyl-acetyl)-amino)-aniline Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C35H34N4O4
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.[Mg].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16].OC(C1(O[C@@H]([C@@H]([C@@H](CO)O)O)[C@H](N)[C@@H](O)C1)O)=O.Cl>O1CCCC1>[CH2:16]([C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1)[CH2:15][CH2:14][CH2:13][CH:12]=[CH2:11]
Reactant: Clc1ccc(Cl)cc1
Reactant: C=CCCCCBr
Agent: Cl
Agent: N[C@H]1[C@H]([C@H](O)[C@H](O)CO)OC(O)(C(=O)O)C[C@@H]1O
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CCCCCc1ccc(Cl)cc1
Reaction time: 4 h
Yield: 40 %

Procedure:
A solution containing 294 g (2 Mol) of 1,4-dichlorobenzene in 500 ml of anhydrous tetrahydrofuran was added dropwise at 80° C. under nitrogen over a period of 110 minutes to a stirred suspension of 48.6 g (2.0 Mol) of magnesium turnings. The mixture was subsequently heated at 80° to 84° C. for an additional 2 hours, then decanted off from the excess magnesium. The resultant solution of Grignard compound was added dropwise at 80° C. over a period of 30 minutes to a stirred solution containing 194 g (1.8 Mol) of 6-bromo-1-hexene (commercially available from Fluka GmbH, D-7910 Neu-Ulm) in 200 ml of tetrahydrofuran. The mixture was then stirred at 80° for an additional four hours and poured onto ice. The mixture was acidified using hydrochloric acid and extracted three times using a 1:1 mixture of diethyl ether/methyl tert-butyl ether, and the ether fractions were stirred with activated charcoal and dried over sodium sulfate. After the filtrate had been evaporated, the residue was fractionated under reduced pressure. About 156 g (corresponding to a yield of 40 percent of theory) of 4-(5-hexenyl)-1-chlorobenzene were obtained at a pressure of 13 hPa and at a temperature of 116° to 118° C. 4-(4-pentenyl)-1-chlorobenzene (b.p. 102° to 105° C. at 13 hPa), 4-(11-dodecenyl)-1-chlorobenzene (b.p. 147° to 150° at 0.2 hPa) and 4-(8-nonenyl)-1-chlorobenzene (b.p. 87° C. at 0.3 hPa) can also be prepared in the same manner.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][C:11]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)([N:13]=C=O)[CH2:12][CH:7]2[CH2:6]1)=[O:4].N>Cl>[CH3:1][N:2]([CH3:21])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][C:11]([NH2:13])([CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)[CH2:12][CH:7]2[CH2:6]1)=[O:4]
Reactant: CN(C)C(=O)N1CC2CC(N=C=O)(C3CCCC3)CC2C1
Agent: Cl
Agent: N
Product: CN(C)C(=O)N1CC2CC(N)(C3CCCC3)CC2C1
Yield: 81.8 %

Procedure:
Upon cooling by an ice-water bath, to a solution of 10 mL hydrochloric acid (8 N) was added dropwise 5-cyclopentyl-5-isocyanato-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 16e obtained from the above step. Then the ice-water bath was removed and the reaction mixture was reacted at 50° C. for 15 minutes. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was adjusted to pH>8 with concentrated ammonia and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 5-amino-5-cyclopentyl-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 16f (0.18 g, yield 81.8%) as a yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:11]2([NH2:30])[CH2:19][CH2:18][C:17]3[C:13](=[CH:14][N:15]([S:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)(=[O:22])=[O:21])[N:16]=3)[CH2:12]2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]1[CH:33]=[C:34]([CH2:39][CH2:40][CH:41]2[CH2:43][O:42]2)[CH:35]=[C:36]([F:38])[CH:37]=1>C(O)(C)C>[C:1]([C:5]1[CH:6]=[C:7]([C:11]2([NH:30][CH2:43][CH:41]([OH:42])[CH2:40][CH2:39][C:34]3[CH:35]=[C:36]([F:38])[CH:37]=[C:32]([F:31])[CH:33]=3)[CH2:19][CH2:18][C:17]3[C:13](=[CH:14][N:15]([S:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)(=[O:22])=[O:21])[N:16]=3)[CH2:12]2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1cc(F)cc(CCC2CO2)c1
Reactant: Cc1ccc(S(=O)(=O)n2cc3c(n2)CCC(N)(c2cccc(C(C)(C)C)c2)C3)cc1
Solvent: CC(C)O
Product: Cc1ccc(S(=O)(=O)n2cc3c(n2)CCC(NCC(O)CCc2cc(F)cc(F)c2)(c2cccc(C(C)(C)C)c2)C3)cc1
Temperature: 50 °C
Yield: 41 %

Procedure:
To a sealed tube was added a solution of 5-(3-tert-butyl-phenyl)-2-(toluene-4-sulfonyl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamine (0.41 g, 1.0 mmol) in isopropyl alcohol followed by 2-[2-(3,5-difluoro-phenyl)-ethyl]-oxirane (0.18 g, 1.0 mmol). The reaction was heated at 50° C. overnight and no product was formed. After heating at 100° C. for an additional 3.5 h the reaction was complete. The reaction mixture was concentrated and the crude product was purified by flash chromatography, eluting with 3% methanol in CHCl3 to afford 0.25 g (0.41 mmol, 42%) of 1-[5-(3-tert-butyl-phenyl)-2-(toluene-4-sulfonyl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-4-(3,5-difluoro-phenyl)-butan-2-ol: retention time (min)=2.15, method [1]. MS (ESI) 608.4 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[C:5](=[NH:36])[CH:6](P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH3:2].[C:38](=O)=[O:39]>>[CH2:1]([O:3][C:4](=[O:37])[CH:5]([N:36]=[C:38]=[O:39])[CH2:6][CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH3:2]
Reactant: O=C=O
Reactant: CCOC(=O)C(=N)C(CCNC(=O)OC(C)(C)C)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)C(CCCNC(=O)OC(C)(C)C)N=C=O
Temperature: 50 °C

Procedure:
The reaction solution from Example 9 is placed in a Parr® bomb and carbon dioxide (22 g, 0.5 mol) is condensed into the bomb. The bomb is sealed and heated to 50° C. for 12 hours. The bomb is cooled and vented to atmospheric pressure. The solution is transferred from the bomb to a flask and used as is in the next reaction (Example 11).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH:9]2[CH2:14][CH2:13][CH:12]([NH:15][C:16]3[CH:21]=[C:20]([C:22]4[C:30]5[C:25](=[N:26][CH:27]=[C:28]([O:31][CH3:32])[CH:29]=5)[NH:24][CH:23]=4)[CH:19]=[C:18]([Cl:33])[N:17]=3)[CH2:11][CH2:10]2)[CH2:4][CH2:3]1.[C:34]1(=O)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.C([BH3-])#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[Cl:33][C:18]1[N:17]=[C:16]([NH:15][CH:12]2[CH2:11][CH2:10][CH:9]([CH2:8][CH:5]3[CH2:6][CH2:7][CH:2]([NH:1][CH:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)[CH2:3][CH2:4]3)[CH2:14][CH2:13]2)[CH:21]=[C:20]([C:22]2[C:30]3[C:25](=[N:26][CH:27]=[C:28]([O:31][CH3:32])[CH:29]=3)[NH:24][CH:23]=2)[CH:19]=1
Reactant: O=C1CCCCC1
Reactant: COc1cnc2[nH]cc(-c3cc(Cl)nc(NC4CCC(CC5CCC(N)CC5)CC4)c3)c2c1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: COc1cnc2[nH]cc(-c3cc(Cl)nc(NC4CCC(CC5CCC(NC6CCCCC6)CC5)CC4)c3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.4 %

Procedure:
A suspension of Example 237 (80.0 mg, 0.171 mmol) in MeOH (3 mL) was treated with cyclohexanone (0.035 mL, 0.342 mmol). After 30 minutes, sodium cyanoborohydride (21.5 mg, 0.342 mmol) and zinc chloride (0.699 mg, 5.13 μmol) were added. The reaction was stirred at room temperature overnight. The mixture was concentrated. The residue was treated with sat. NaHCO3 and extracted with EtOAc (2×). The combined organic layers were dried and purified by reverse-phase HPLC as described in Example 56 to give the title compound (32.4 mg) as trifluoroacetic acid salts. 1H NMR (400 MHz, CD3OD) ppm 0.96-1.48 (m, 15H), 1.59-1.96 (m, 10H), 2.01-2.17 (m, 5H), 3.12-3.23 (m, 2H), 3.70 (m, 1H), 3.96 (s, 3H), 6.84-7.01 (m, 2H), 7.93 (m, 1H), 7.99 (s, 1H), 8.10 (s, 1H). MS (DCI+) m/z 550.4 (M+H)+.
Reaction SMILES: C(OC([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][C:21]2[N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:23]=[CH:24][N:25]=2)=[CH:14][CH:13]=1)=O)C1C=CC=CC=1>CCOC(C)=O.[Pd]>[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][C:21]2[N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:23]=[CH:24][N:25]=2)=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)n1ccnc1CCCc1ccc(NC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1ccnc1CCCc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
A solution of compound 58 (80 mg, 0.18 mmol) in EtOAc (5 mL) was added Pd/C (10 mg, 10%) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 balloon at room temperature for 2 h. The suspension was filtered and the solid was washed by EtOAc. The filtrates were concentrated to dryness to give compound 59 (38 mg, 70%) as a light yellow oil. The crude product was used directly for the next step without purification. 1H NMR (400 MHz, CDCl3) δ7.32-7.43 (m, 1H), 6.96-7.02 (m, 3H), 6.93 (d, 2H, J=8.3 Hz), 3.17 (t, 2H, J=7.4 Hz), 2.66 (t, 2H, J=7.4 Hz), 2.05-2.13 (m, 2H), 1.62 (s, 9H).
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])\[CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:25][CH:24]=1>>[CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])\[CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][NH:22][C:23]2[CH:24]=[CH:25][C:26]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:27][CH:28]=2)=[CH:9][CH:8]=1
Reactant: CO/N=C(\COc1ccc(C=O)cc1)c1ccccc1C
Reactant: Nc1ccc(CCC(=O)O)cc1
Product: CO/N=C(\COc1ccc(CNc2ccc(CCC(=O)O)cc2)cc1)c1ccccc1C

Procedure:
Compound 6 was synthesized from 4-{[(2Z)-2-(methoxyimino)-2-(2-methylphenyl)ethyl]oxy}benzaldehyde and 3-(4-aminophenyl)propanoic acid by following the procedure described in Scheme 4