Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([S:8]([N:11]2[C:19]3[C:14](=[C:15]([O:33][CH3:34])[CH:16]=[C:17]([C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[C:25]([F:32])[CH:24]=4)=[O:21])[CH:18]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:7]=1.Cl[C:38]1C=CC(OC)=C(S(Cl)(=O)=O)[CH:43]=1>>[CH2:38]([O:28][C:27](=[O:29])[C:26]1[CH:30]=[CH:31][C:23]([NH:22][C:20]([C:17]2[CH:18]=[C:19]3[C:14]([CH2:13][CH2:12][N:11]3[S:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:35][CH3:36])(=[O:10])=[O:9])=[C:15]([O:33][CH3:34])[CH:16]=2)=[O:21])=[CH:24][C:25]=1[F:32])[CH3:43]
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCc2c(OC)cc(C(=O)Nc3ccc(C(=O)O)c(F)c3)cc21
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Product: CCOC(=O)c1ccc(NC(=O)c2cc(OC)c3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CC3)cc1F

Procedure:
4-{[1-(5-Chloro-2-methoxy-benzenesulfonyl)-4-methoxy-2,3-dihydro-1H-indole-6-carbonyl]-amino}-2-fluoro-benzoic acid, m/z (ES+): 535.33 (M+H+.), was prepared in analogy to example 14, steps 1 to 6. Step 5 was performed using 5-chloro-2-methoxy-benzenesulfonyl chloride and yielded 4-{[1-(5-chloro-2-methoxy-benzenesulfonyl)-4-methoxy-2,3-dihydro-1H-indole-6-carbonyl]-amino}-2-fluoro-benzoic acid ethyl ester, which was hydrolyzed in step 6.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[OH:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl.[Cl:15][CH2:16][CH2:17][CH2:18][C:19](=N)OCC>ClC(Cl)Cl>[Cl:15][CH2:16][CH2:17][CH2:18][C:19]1[O:13][C:12]2[CH:11]=[CH:10][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][C:2]=2[N:1]=1
Reactant: CCOC(=O)c1ccc(O)c(N)c1
Reactant: CCOC(=N)CCCCl
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc2oc(CCCCl)nc2c1
Temperature: 20 °C
Reaction time: 24 h
Yield: 74.7 %

Procedure:
A mixture of 9 parts of ethyl 3-amino-4-hydroxybenzoate, 10.2 parts of ethyl 4-chlorobutanimidate hydrochloride and 150 parts of trichloromethane was stirred for 24 hours at 20° C. The separated organic layer was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The eluent of the desired fraction was evaporated, yielding 10 parts (74.7%) of ethyl 2-(3-chloropropyl)-5-benzoxazolecarboxylate as a residue (interm. 25).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:9]([N+:24]([O-])=[O:25])[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.CN(C)C=O.O.N([O-])=O.[Na+]>O>[Cl:1][C:2]1[C:3]([C:9](=[N:24][OH:25])[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:21])([F:20])[F:22])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(NCC(c1ncc(Cl)cc1Cl)[N+](=O)[O-])c1ccccc1C(F)(F)F
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=NO)c1ncc(Cl)cc1Cl)c1ccccc1C(F)(F)F
Temperature: 60 °C
Reaction time: 18 h
Yield: 43.9 %

Procedure:
To 14.00 g of N-[2-(3,5-dichloropyridin-2-yl)-2-nitroethyl]-2-(trifluoromethyl)benzamide in 70 ml of a mixture of N,N-dimethylformamide-water (7:1), 16.62 g of sodium nitrite was added, and the mixture was stirred at 60° C. for 18 hours. After completion of the reaction, the reaction mixture was allowed to cool to room temperature, poured into 100 ml of water and extracted with ethyl acetate (100 ml×2). The resulting organic layers were combined, washed with water (50 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 3:7 to 1:1) as the eluent to obtain 5.90 g of the desired product as pale yellow crystals.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([I:9])=[CH:4][N:3]=1.Cl.[NH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([OH:18])[CH2:14][CH2:13]1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[F:8][C:7]1[C:2]([NH:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([OH:18])[CH2:14][CH2:13]2)=[N:3][CH:4]=[C:5]([I:9])[CH:6]=1
Reactant: Fc1cc(I)cnc1F
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: O[C@H]1CC[C@H](Nc2ncc(I)cc2F)CC1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
2,3-Difluoro-5-iodopyridine (300 mg, 1.24 mmol) was dissolved in dioxane (3 ml) and trans-4-aminocyclohexanol hydrochloride (227 mg, 1.49 mmol, 1.2 equiv.) and Cs2CO3 (1.01 g, 3.11 mmol, 2.5 equiv.) were added at room temperature. The mixture was stirred for 3 hours at 100° C. The reaction mixture was evaporated and treated with sat. NaHCO3 solution and extracted twice with a small volume of CH2Cl2. The organic layers were loaded directly to silica gel column and the crude material was purified by flash chromatography on silica gel (20 gr, ethyl acetate/heptane gradient, 0:100 to 0:100). The desired trans-4-(3-fluoro-5-iodopyridin-2-ylamino)cyclohexanol (65 mg, 16% yield) was obtained as a white solid, MS: m/e=337.1 (M+H+).
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][C:9](=[S:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][C:20]1[C:27]([CH3:28])=[C:26]([CH3:29])[C:25]([CH3:30])=[C:24]([CH3:31])[C:21]=1[CH2:22][Cl:23]>CCO>[ClH:23].[CH3:22][C:21]1[C:20]([CH3:19])=[C:27]([CH3:28])[C:26]([CH3:29])=[C:25]([CH3:30])[C:24]=1[CH2:31][S:18][C:9]1[NH:8][C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@H:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1
Reactant: Cc1c(C)c(C)c(CCl)c(C)c1C
Reactant: S=C1N[C@H](c2ccccc2)[C@H](c2ccccc2)N1
Solvent: CCO
Product: Cc1c(C)c(C)c(CSC2=N[C@@H](c3ccccc3)[C@@H](c3ccccc3)N2)c(C)c1C
Product: Cl
Temperature: 25 °C
Yield: 52.5 %

Procedure:
A mixture of intermediate 25 (200 mg, 0.786 mmol) and 2,3,4,5,6-pentamethylbenzyl chloride (309 mg, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C. for 24 h. The reaction mixture is cooled to RT, evaporated to dryness, and the residue suspended in Et2O. The insoluble material is filtered to give 186 mg of the product 234. 1H NMR (DMSO-d6) δ 11.20 (s, 2 H), 7.25-6.95 (m, 10 H), 5.85 (s, 2 H), 4.84 (s, 2 H), 2.38 (s, 6 H), 2.20 (s, 9 H); MS: m/z 415 (M++1).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:6][C@@H:5]([C:7]([O-:9])=[O:8])[CH2:4][O:3]1.[Na+].OP(O)(O)=O.[Na+].[Cl-]>O.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:10])[O:6][C@@H:5]([C:7]([OH:9])=[O:8])[CH2:4][O:3]1
Reactant: CC1(C)OC[C@H](C(=O)[O-])O1
Agent: O=P(O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(C)OC[C@H](C(=O)O)O1
Temperature: 0 °C

Procedure:
Sodium (R)-(+)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (1.03 g, 6.1 mmol) was dissolved in a mixture of water (1.2 ml) and ethyl acetate (1.2 ml) and cooled to 0° C. 2 M aqueous H3PO4 solution (7 ml) was added until the reaction mixture reached pH 2. After that the reaction mixture was saturated with NaCl and the reaction mixture was extracted with ethyl acetate (3×20 ml). The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure. The product (0.73 g, 4.9 mmol, 81%) was used in the next step without any further purification.
Reaction SMILES: [CH3:1]C1C=CC(C2C=NN(C)C=2)=C(C=1)C(OC)=O.Cl[C:19]1[N:24]=[C:23]([C:25]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:26]=2[C:27]([O:29][CH3:30])=[O:28])[CH:22]=[CH:21][N:20]=1.CB1OB(C)OB(C)O1>>[CH3:35][C:32]1[CH:33]=[CH:34][C:25]([C:23]2[CH:22]=[CH:21][N:20]=[C:19]([CH3:1])[N:24]=2)=[C:26]([CH:31]=1)[C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)c1cc(C)ccc1-c1ccnc(Cl)n1
Reactant: COC(=O)c1cc(C)ccc1-c1cnn(C)c1
Agent: CB1OB(C)OB(C)O1
Product: COC(=O)c1cc(C)ccc1-c1ccnc(C)n1

Procedure:
The title compound was synthesized following the same general protocol as described for methyl 5-methyl-2-(1-methyl-1H-pyrazol-4-yl)benzoate in Example A1, using methyl 2-(2-chloropyrimidin-4-yl)-5-methylbenzoate and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane. ESI-MS (m/z): 243 [M+1]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](Br)=[CH:13][C:12]([CH:16]2[O:20][CH2:19][CH2:18][O:17]2)=[C:11]([CH3:21])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[CH2:33]([O:40][C@@H:41]1[C@@H:47]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C@H:46]([O:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[C@@H:45]([CH2:64][O:65][CH2:66][C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[O:44][C:42]1=[O:43])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:33]([O:40][C@@H:41]1[C@@H:47]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C@H:46]([O:56][CH2:57][C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=2)[C@@H:45]([CH2:64][O:65][CH2:66][C:67]2[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=2)[O:44][C:42]1([C:14]1[CH:13]=[C:12]([CH:16]2[O:20][CH2:19][CH2:18][O:17]2)[C:11]([CH3:21])=[CH:10][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[OH:43])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=C1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: Cc1cc(OCc2ccccc2)c(Br)cc1C1OCCO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(OCc2ccccc2)c(C2(O)O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1C1OCCO1
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
To a tetrahydrofuran solution (36 mL) of 2-[4-(benzyloxy)-5-bromo-2-methylphenyl]-1,3-dioxolane (5.82 g, 16.6 mmol) was added dropwise under nitrogen atmosphere at −78° C. a 2.67 M n-butyllithium solution in hexane (6.40 mL, 16.6 mmol), and the mixture was stirred for 30 minutes at the same temperature. Then a tetrahydrofuran solution (18 mL) of 2,3,4,6-tetra-O-benzyl-D-glucono-1,5-lactone (8.16 g, 15.1 mmol) was added dropwise, and the mixture was stirred for 20 minutes at the same temperature. To the reaction solution was added a saturated aqueous solution of ammonium chloride, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine, and dried with anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was evaporated under reduced pressure. Thus obtained residue was purified with silica gel column chromatography (hexane:ethyl acetate=3:1 to 2:1) to obtain the title compound (10.7 g, 87%) as a yellow oily compound.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl.[NH2:20][OH:21]>CO.C(OCC)(=O)C>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[N:20][OH:21])[CH2:3][CH2:2]1
Reactant: O=C1CCOc2ccccc21
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CO
Product: ON=C1CCOc2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 146 %

Procedure:
To a solution of 4-chromanone (10 g, 67.6 mmol) in methanol (150 mL) was added triethylamine (15 mL, 108.1 mmol) and hydroxylamine hydrochloride (7.5 g, 108.1 mmol). The mixture was stirred at rt for 16 hrs. The solvent was evaporated giving a residue which was dissolved in ethyl acetate and extracted with water. The organic layer was separated and dried over anhydrous sodium sulfate. Evaporation of the filtrate afforded chroman-4-one oxime (16.1 g, 100%) as a white crystalline solid. MS: 164.0 (M+H)+; tR=1.99 min (method 1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]=[C:20]=[O:21])=[CH:14][CH:13]=1.CCCCCC>C1COCC1>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][NH:19][C:20]([NH:1][C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[CH:5][NH:6]3)=[O:21])=[CH:16][CH:17]=1
Reactant: Nc1cccc2[nH]ccc12
Reactant: O=C=NCc1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(NCc1ccc(Br)cc1)Nc1cccc2[nH]ccc12

Procedure:
4-aminoindole (0.13 g, 1 mmol) in THF (3 mL) was treated with 1-bromo-4-(isocyanatomethyl)benzene (0.23 g, 1.1 mmol) for 3 hours at ambient temperature. Hexane was added to the reaction mixture to precipitate 0.26 g of the title compound as a tan solid. mp 198° C.; 1H NMR (300 MHz, DMSO-d6) δ 4.30 (d, 2H), 6.51 (t, 1H), 6.89 (t, 1H), 6.95 (d, 2H), 7.29 (t, 1H), 7.31 (d, 2H), 7.55 (d, 2H), 7.62 (dd, 1H), 8.3 (s, 1H), 11.04 (s, 1H); MS (DCI+) m/z 346 (M+H); Anal. Calcd. For C16H14N3BrO: C, 55.83; H, 4.10; N, 12.21. Found: C, 55.71; H, 4.12; N, 12.01.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:6][CH2:5][C:4](=[O:7])[N:3]1[CH2:8][C:9]([O:11]CC)=O.[CH3:15][C@H:16]1[CH2:21][CH2:20][CH2:19][C@@H:18]([CH3:22])[N:17]1[CH2:23][CH2:24][CH2:25][NH2:26]>>[CH3:15][C@H:16]1[CH2:21][CH2:20][CH2:19][C@@H:18]([CH3:22])[N:17]1[CH2:23][CH2:24][CH2:25][NH:26][C:9](=[O:11])[CH2:8][N:3]1[C:4](=[O:7])[CH2:5][CH2:6][C:2]1([CH3:1])[CH3:14]
Reactant: C[C@@H]1CCC[C@H](C)N1CCCN
Reactant: CCOC(=O)CN1C(=O)CCC1(C)C
Product: C[C@@H]1CCC[C@H](C)N1CCCNC(=O)CN1C(=O)CCC1(C)C

Procedure:
From 10 g. of ethyl 2,2-dimethyl-5-oxopyrrolidineacetate, (British Pat. No. 1,309,692) and 10.5 g. of cis-3-(2,6-dimethyl-1-piperidinyl)propylamine, following the procedure of Example 9, there is obtained cis-N-[3-(2,6-dimethyl-1-piperidinyl)propyl]-2,2-dimethyl-5-oxo-1-pyrrolidineacetamide; m.p. 86°-87° C. after crystallization from isooctane.
Reaction SMILES: [H][H].[CH3:3][CH:4]([C:7]([CH3:12])([CH3:11])[CH2:8][C:9]#[N:10])[C:5]#[N:6].N>C(O)C>[CH3:3][CH:4]([C:7]([CH3:12])([CH3:11])[CH2:8][CH2:9][NH2:10])[CH2:5][NH2:6]
Reactant: CC(C#N)C(C)(C)CC#N
Reactant: [H][H]
Agent: N
Solvent: CCO
Product: CC(CN)C(C)(C)CCN
Temperature: 105 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
After scavenging with nitrogen and then with hydrogen, commercial hydrogen is introduced under a pressure of 170 atm and then the autoclave is heated to about 105° C. for six hours. Thereafter the autoclave is cooled, the pressure is released and the autoclave is charged with a solution of 68 grams of 2,3,3-trimethylglutaronitrile dissolved in 30 mls abs. ethanol, the scavenging with nitrogen is repeated, there are charged 160 grams of anhydrous ammonia and finally commercial hydrogen is introduced under a pressure of 165 atm approx. The autoclave, which is fitted with a magnetic stirrer, is heated to about 105° C.-108° C. the hydrogen pressure being restored as hydrogen is gradually being absorbed. After about 2 hrs. the pressure does not decrease any more and the above specified temperature is maintained for three additional hours, whereafter the autoclave is allowed to cool. The catalyst is filtered off, the solvent is distilled off and, on the raw production of the reaction, the yield in terms of 2,3,3-trimethyl pentamethylene diamine is determined by gaschromatographic methods in the presence of an internal standard (yield 65%-70%). The diamine is then purified by fractionation and, under a pressure of about 12 Torr. it boils at 105° C.-106° C.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([C:20]3[C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[N:23][N:22]([CH3:31])[N:21]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O>[ClH:19].[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[C:20]1[C:24]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[N:23][N:22]([CH3:31])[N:21]=1
Reactant: Cn1nc(-c2ccccc2)c(-c2c(Cl)ccc3c2CCN(C(=O)OC(C)(C)C)CC3)n1
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: Cn1nc(-c2ccccc2)c(-c2c(Cl)ccc3c2CCNCC3)n1
Yield: 177.6 %

Procedure:
Stir 3-tert-butoxycarbonyl-7-chloro-6-(2-methyl-5-phenyl-2H-[1,2,3]triazol-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (7.8 mg, 18 μmol) in trifluoroacetic acid (2 mL) at room temperature for 5 h. Concentrate in vacuo and purify the residue by HPLC (Zorbax SB-Phenyl column, 21.2×250 mm; flow rate: 22 mL/min; eluting with 10 to 90% acetonitrile in 0.1% aqueous trifluoroacetic acid). Concentrate in vacuo and elute the residue through a SCX column. Use a method similar to the General Procedure 2-2 and evaporate by lyophylization to obtain the title compound (6 mg, 100%). MS (ES+) m/z: 339 (M+H)+.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:35]2[CH2:46][CH2:45][N:44]3[C:37](=[CH:38][C:39]4[CH2:40][C:41]([CH3:48])([CH3:47])[CH2:42][C:43]=43)[C:36]2=[O:49])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH2:27][NH:28][C:29](=[O:32])[CH:30]=[CH2:31])[N:20]=2)[C:15](=[O:33])[N:14]([CH3:34])[CH:13]=1)(=O)C.[Li+].[OH-]>C1COCC1.CC(O)C.O.O>[CH3:47][C:41]1([CH3:48])[CH2:40][C:39]2[CH:38]=[C:37]3[N:44]([CH2:45][CH2:46][N:35]([C:7]4[C:6]([CH2:5][OH:4])=[C:11]([C:12]5[CH:17]=[C:16]([NH:18][C:19]6[N:20]=[C:21]([O:25][CH2:26][CH2:27][NH:28][C:29](=[O:32])[CH:30]=[CH2:31])[CH:22]=[CH:23][CH:24]=6)[C:15](=[O:33])[N:14]([CH3:34])[CH:13]=5)[CH:10]=[CH:9][N:8]=4)[C:36]3=[O:49])[C:43]=2[CH2:42]1
Reactant: C=CC(=O)NCCOc1cccc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5CC(C)(C)C6)C4=O)c3COC(C)=O)cn(C)c2=O)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: C=CC(=O)NCCOc1cccc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5CC(C)(C)C6)C4=O)c3CO)cn(C)c2=O)n1
Reaction time: 1 h
Yield: 39.4 %

Procedure:
—Step 6: To a solution of 101f (257 mg, 0.387 mmol) in THF/i-PrOH/H2O (5.0/3.0/2.0 mL) was added LiOH (46 mg, 1.95 mmol) at room temperature. The reaction was stirred for 1 h. The mixture was diluted with water (15 mL) and extracted with DCM (15 mL×3). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue solid was purified by reverse-phase prep-HPLC to afford 101 (95 mg, 39% two steps) as a white solid. MS-ESI: [M+H]+ 624.2. 1H NMR (500 MHz, CDCl3) δ 8.74 (d, J=2.0 Hz, 1H), 8.53 (d, J=5.0 Hz, 1H), 9.70 (s, 1H), 7.73 (d, J=2.0 Hz, 1H), 7.50-7.48 (m, 1H), 7.29-7.27 (m, 1H), 6.85 (s, 1H), 6.46-6.44 (m, 2H), 6.27-6.23 (m, 2H), 6.05-6.00 (m, 1H), 5.61-5.59 (m, 1H), 4.98-4.96 (m, 1H), 4.72-4.70 (m, 1H), 4.55-4.53 (m, 1H), 4.39-4.29 (m, 3H), 4.19-4.16 (m, 2H), 3.96-3.94 (m, 1H), 375-3.73 (m, 4H, overlap), 3.64-3.60 (m, 1H), 2.61-2.59 (m, 2H), 2.53-2.51 (m, 2H), 1.30 (s, 6H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10](=O)[CH3:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Cl.[NH2:14][OH:15].C([O-])(=O)C.[Na+]>C(O)C.O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10](=[N:14][OH:15])[CH3:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CC(=O)c1ccc2[nH]ncc2c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=NO)c1ccc2[nH]ncc2c1
Temperature: 80 °C
Reaction time: 15 h
Yield: 71 %

Procedure:
To a suspension of 1-(1H-indazole-5-yl)-ethanone (334 mg, 2.09 mmol) in EtOH-H2O (4:1, 10 ml) were added hydroxylamine hydrochloride (444 mg, 6.39 mmol) and sodium acetate (449 mg, 5.47 mmol). The reaction mixture was stirred at 80° C. for 15 hours and concentrated in vacuo. The residue was stirred with H2O at room temperature for 10 min. The solid obtained was collected by filtration, and rinsed with H2O. After drying, the title compound (260 mg, 71%) was obtained as a white solid. 1H NMR (270 MHz, DMSO-d6) δ ppm 2.22 (3H, s), 7.52 (1H, d, J=8.6 Hz), 7.79 (1H, d, J=8.6 Hz), 7.98 (1H, s), 8.10 (1H, s), 11.05 (1H, s), 13.13 (br.s, 1H). MS (ESI) m/z 176 (M+H)+, 174 (M−H)−.
Reaction SMILES: [CH2:1]([CH2:11][C:12](=[O:14])[CH3:13])/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].[NH4+].[Cl-].[Na+].[Cl-].[CH3:19][O:20][C:21](=O)[O:22]C>>[O:14]=[C:12]([CH2:11][CH2:1][CH:2]=[C:3]([CH3:4])[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])[CH2:13][C:21]([O:20][CH3:19])=[O:22]
Reactant: CC(=O)CC/C=C(\C)CCC=C(C)C
Reactant: COC(=O)OC
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: COC(=O)CC(=O)CCC=C(C)CCC=C(C)C
Reaction time: 1 h

Procedure:
The obtained mixture was heated to reflux (bath temperature 100°) then, during 1 h, there was added a solution of 0.5M of geranylacetone in 135 g (1.5M) of dimethylcarbonate, where upon the resulting reaction mixture was kept refluxing during 10 min. It was finally poured into a 10% aqueous solution of NH4Cl saturated with NaCl. An ether extraction, followed by the usual work up of the combined organic extracts and fractional distillation gave methyl 3-oxo-7,11-dimethyl-dodeca-6,10-dienoate.
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl[CH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18]1.OS(O)(=O)=O>O>[CH2:8]([NH:15][CH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: ClC1CCc2ccccc21
Reactant: NCc1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(CNC2CCc3ccccc32)cc1
Temperature: 90 °C
Yield: 72.5 %

Procedure:
A mixture of 272 ml of toluene and 199.5 g benzylamine was prepared and heated to 90° C. The chlorindan was added dropwise to the mixture over a 30 minute period. The reaction mixture was heated to 115° C. for ten hours. The reaction mixture was cooled to ambient temperature and 300 ml of water was added. The resulting heterogeneous mixture was then brought to pH 2.2 by the addition of 33% H2SO4. The phases were separated and the organic layer discarded. The pH of the aqueous layer was adjusted to pH 6.0 prior to extraction with 300 ml of toluene. A further 100 ml of toluene was then added and the aqueous phase discarded. The toluene was removed under vacuo from the combined organic layer leaving 104.3 g racemic N-benzyl-1-aminoindan base as an oil (72.5% yield).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C@H:11]([O:14]C2CCCCO2)[CH2:10][C@@H:9]1[CH3:21])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C=CC1C=CC=CC=1.C(C1C=CC=CC=1C=C)=C>CO>[C:1]([N:8]1[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10][C@@H:9]1[CH3:21])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C[C@H]1C[C@@H](OC2CCCCO2)CCN1C(=O)OC(C)(C)C
Agent: C=Cc1ccccc1C=C
Solvent: CO
Solvent: C=Cc1ccccc1
Product: C[C@H]1C[C@@H](O)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A solution of 14.6 g (0.04876 mol) of cis-N-BOC-2-methyl-4-[(tetrahydropyran-2-yl)oxy]piperidine in 120 ml of methanol is treated with 20 g of cationic exchanger Dowex® 50 WX8 (H+ form; 50-100 mesh (50 mesh corresponds to a granular size of c. 300 μm, 100 mesh to c. 150 μm); cationic exchanger based on a styrene/divinylbenzene polymer containing sulfonyl groups; registered trademark of Dow Chemicals Co., USA)), and the mixture is stirred for 22 hours at room temperature. After filtration, washing the ion exchanger with methanol and concentrating the filtrate under vacuum, the title compound is obtained in the form of a viscous oil, Rf =0.16 (silica gel/ethyl acetate:hexane (1:2)).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[F:16].[CH3:17][S:18](Cl)(=[O:20])=[O:19].O>N1C=CC=CC=1.C(OCC)(=O)C>[C:14]([C:11]1[N:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:18]([CH3:17])(=[O:20])=[O:19])=[C:3]([F:16])[CH:4]=2)=[CH:9][CH:10]=1)#[N:15]
Reactant: Cn1c(C#N)ccc1-c1ccc(N)c(F)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: Cn1c(C#N)ccc1-c1ccc(NS(C)(=O)=O)c(F)c1
Reaction time: 4 h
Yield: 79.5 %

Procedure:
5-(4-amino-3-fluorophenyl)-1-methyl-1H-pyrrole-2-carbonitrile (0.15 g, 0.70 mmol) was dissolved in pyridine (1.5 mL), methane sulfonyl chloride (0.05 mL, 0.63 mmol) was added, the mixture was stirred for 4 hours, and then water was added. The mixture diluted with ethyl acetate and the mixture was washed with water, saturated CuSO4, 2N HCl, brine, dried over MgSO4, and concentrated. Flash chromatography (5%-50% ethyl acetate in hexane) afforded N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-fluorophenyl]methane sulfonamide (0.147 g).