Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)#[N:23]>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]([OH:18])[CH2:19][N:33]4[CH2:32][CH2:31][N:30]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=5[C:22]#[N:23])[CH2:35][CH2:34]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: N#Cc1ccccc1N1CCNCC1
Reactant: Fc1ccc2c(-c3ccc(OC[C@@H]4CO4)cc3)noc2c1
Solvent: CN(C)C=O
Solvent: CCO
Product: N#Cc1ccccc1N1CCN(C[C@H](O)COc2ccc(-c3noc4cc(F)ccc34)cc2)CC1

Procedure:
The title compound is prepared from a mixture of (S)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 1-(2-cyanophenyl)piperazine in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=473.
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:48])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:47])[CH2:12][CH2:13][C@@:14]3([C:30](=[O:46])[NH:31][C@H:32]4[CH2:35][C@@H:34]([C:36]([N:38]5[CH2:43][CH2:42][O:41][CH2:40][CH2:39]5)=[O:37])[C:33]4([CH3:45])[CH3:44])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:50])[CH3:49])(=O)C.[OH-].[Na+]>CO.C1COCC1>[CH3:44][C:33]1([CH3:45])[C@H:34]([C:36]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)=[O:37])[CH2:35][C@@H:32]1[NH:31][C:30]([C@:14]12[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]1[C@@H:16]1[C@@:11]([CH3:47])([CH2:12][CH2:13]2)[C@@:10]2([CH3:48])[C@@H:19]([C@:20]3([CH3:23])[C@@H:7]([CH2:8][CH2:9]2)[C:6]([CH3:49])([CH3:50])[C@@H:5]([OH:4])[CH2:22][CH2:21]3)[CH2:18][CH2:17]1)=[O:46]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@H]3C[C@@H](C(=O)N4CCOCC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@H]3C[C@@H](C(=O)N4CCOCC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.6 %

Procedure:
To a solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((1S,3R)-2,2-dimethyl-3-(morpholine-4-carbonyl)cyclobutylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl acetate (Example 7, 0.380 g, 0.55 mmol) in MeOH:THF (2:1) (6 ml) NaOH (2N, 2 ml) was added at about 0° C. and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC) the volatiles was evaporated and the aqueous layer was extracted with ethyl acetate and dried with Na2SO4. The solvent was evaporated and purified by silica gel column (100-200 mesh, elution 15% EtOAc in hexane) to afford the title compound as an off white solid. Wt: 0.320 g: Yield: 89.6%; 1H NMR (300 MHz, CDCl3): δ 5.88 (d, 1H, J=8.1 Hz), 4.73 (s, 1H), 4.58 (s, 1H), 4.18-4.07 (m, 1H), 3.80-3.41 (m, 7H), 3.21-3.08 (m, 2H), 2.91-2.83 (m, 1H), 2.50-2.29 (m, 3H), 1.98-1.87 (m, 2H), 1.80-1.10 (m, 26H), 0.95-0.92 (s, 12H), 0.99-0.68 (s, 9H); Mass: [M+1]+ 651 (100%), [M+Na]+ 673 (70%); IR (KBr, cm−1): 3367, 2856, 2926, 1714, 1634, 1493, 1463, 1375, 1270, 1241, 1115, 1040, 983, 884, 756, 665; M.R: 262.5° C.-267.8° C.; HPLC: 90.7%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:8]2[CH:16]=[CH:15][NH:14][C:9]=2[N:10]=[C:11](Cl)[N:12]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]([CH3:28])[C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=1.C[Si](Cl)(C)C>C(O)CCC>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:8]2[CH:16]=[CH:15][NH:14][C:9]=2[N:10]=[C:11]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]([CH3:28])[C:25](=[O:27])[CH3:26])=[CH:22][CH:23]=2)[N:12]=1
Reactant: NCCCCNc1nc(Cl)nc2[nH]ccc12
Reactant: CC(=O)N(C)c1ccc(N)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CC(=O)N(C)c1ccc(Nc2nc(NCCCCN)c3cc[nH]c3n2)cc1
Temperature: 116 °C
Yield: 5.2 %

Procedure:
A mixture of N-(4-aminobutyl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-amine (63 mg, 0.26 mmol), N-(4-aminophenyl)-N-methylacetamide (81 mg, 0.49 mmol) and trimethylsilyl chloride (0.067 mL, 0.52 mmol) in nBuOH (3 mL) was heated at 116° C. for 4 h. It was then purified by HPLC to give the titled compound (5 mg). MS 368.2 (M+H); UV 203.8, 268.7, 301.9 nm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Cl:10]Cl>N(C(C)(C)C#N)=NC(C)(C)C#N.C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][Cl:10]
Reactant: Cc1ccc(Cl)cc1Cl
Reactant: ClCl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CC#N
Product: ClCc1ccc(Cl)cc1Cl
Reaction time: 0.5 h

Procedure:
1 Mol of 2,4-dichloro-methylbenzene and 322 g of acetonitrile are heated to reflux. 0.8 g of azobisisobutyronitrile is added and this addition is repeated every half hour. Chlorine gas is simultaneously introduced in a slight excess. 0.75 Mol of product is obtained after 2 hours.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:13]N(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.CO>[CH3:13][O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)Cc1cccc(Br)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Product: COC(=O)Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3-bromophenylacetic acid (2.0 g, 9.3 mmol) and 4-dimethylamino pyridine (1.1 g, 9.3 mmol) in methanol (20 mL) was treated with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDAC) (2.1 g, 11 mmol). Reaction stirred for 16 hours at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was taken up in ethyl acetate and washed with water, saturated sodium bicarbonate, 1N phosphoric acid, and brine before drying over Na2SO4, filtering, and concentrating under reduced pressure to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[O:31][C:30]([CH3:32])=[N:29][C:28]=1[C:33](O)=[O:34]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:33]([C:28]3[N:29]=[C:30]([CH3:32])[O:31][C:27]=3[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[O:20][CH3:19])=[O:34])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: COc1ccccc1-c1oc(C)nc1C(=O)O
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: COc1ccccc1-c1oc(C)nc1C(=O)Nc1cnn(Cc2ccc(C(C)=O)o2)c1

Procedure:
Following general procedure B followed by either C or D, 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(2-methoxy-phenyl)-2-methyl-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=0.92 min; [M+H]+=421.00.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([C:20]([N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=O)=[CH:14]2.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[N:22]1([CH2:20][C:15]2[NH:16][C:17]3[C:13]([CH:14]=2)=[CH:12][C:11]([O:10][C:2]2[S:1][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=2)=[CH:19][CH:18]=3)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C(c1cc2cc(Oc3nc4ccccc4s3)ccc2[nH]1)N1CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc2sc(Oc3ccc4[nH]c(CN5CCCCC5)cc4c3)nc2c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 53.6 %

Procedure:
To a cooled (−78° C.) solution of [5-(benzothiazol-2-yloxy)-1H-indol-2-yl]-piperidin-1-yl-methanone (150 mg, 0.40 mmol) in THF (5 mL) was added LAH (2 M in THF, 0.2 mL, 18 mg, 0.40 mmol) and the reaction mixture was stirred (−78° C., 1 h) and allowed to warm (rt, 1 h). The reaction mixture was cooled (0° C.) and treated with H2O (5 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (3×15 mL). The organic layer was dried, filtered and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography using MeOH:DCM (0-8%) to provide the title compound as a colorless foam (78 mg, 54%). MS (ESI): mass calcd. for O21H21N3OS, 363.1; m/z found, 364.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.64 (s, 1H), 7.77-7.70 (m, 1H), 7.61 (dd, J=7.9, 0.7, 1H), 7.48 (d, J=2.3, 1H), 7.40-7.32 (m, 2H), 7.22 (dd, J=11.0, 4.3, 1H), 7.10 (dd, J=8.7, 2.4, 1H), 6.35 (s, 1H), 3.62 (s, 2H), 2.60-2.30 (m, 4H), 1.65-1.54 (m, 4H), 1.53-1.41 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:16]2[CH:17]=[C:18]([CH:24]=[CH:25][C:26]([O:28]CC)=[O:27])[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.Cl.Cl[CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>>[CH3:23][O:22][C:21]1[CH:20]=[CH:19][C:18]([CH:24]=[CH:25][C:26]([OH:28])=[O:27])=[CH:17][C:16]=1[C:3]1[C:2]([O:1][CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[CH:11][C:10]2[C:9]([CH3:13])([CH3:12])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]=2[CH:4]=1
Reactant: ClCCN1CCOCC1
Reactant: CCOC(=O)C=Cc1ccc(OC)c(-c2cc3c(cc2O)C(C)(C)CCC3(C)C)c1
Agent: Cl
Product: COc1ccc(C=CC(=O)O)cc1-c1cc2c(cc1OCCN1CCOCC1)C(C)(C)CCC2(C)C
Yield: 89.4 %

Procedure:
In a manner similar to that of Example 16(a), by reaction of 1.4 g (3.4 mmol) of ethyl 3-[3-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyphenyl]acrylate obtained in Example 13(f) with 760 mg (4.08 mmol) of 4-(2-chloroethyl)-morpholine hydrochloride, 1.5 g (85%) of the expected compound was obtained in the form of a yellow oil.
Reaction SMILES: [CH2:1]=[CH:2][CH:3](O)/[CH:4]=[CH:5]/[C:6]#[C:7][CH2:8][C:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].P(Br)(Br)[Br:18]>CCOCC>[Br:18][CH2:1]/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[C:6]#[C:7][CH2:8][C:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: BrP(Br)Br
Reactant: C=CC(O)/C=C/C#CCC#CCCCCC
Solvent: CCOCC
Product: CCCCCC#CCC#C/C=C/C=C/CBr

Procedure:
A solution of (E)-1,4-pentadecadien-6,9-diyn-3-ol (8.5 g) in ether (200 mL) was cooled to -40° and treated over 5 min with phosphorous tribromide (3.7 mL) dissolved in ether (70 mL). The cooling bath was removed and the reaction mixture was warmed to 0° over 1 hour and then poured onto ice. The ether extract was then washed with water, sodium carbonate solution (10 mL) and dried (MgSO4). Removal of the solvents and purification of the residue by liquid chromatography (two columns, hexane) gave (E,E)-1-bromo-2,4-pentadecadien-6,9-diyne as pure material (7.8 g).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH:9]=[C:10]([C:14]([O-:16])=O)[C:11]([O-:13])=[O:12])=[CH:4][CH:3]=1.[C:17]1(OC2C=CC=CC=2)C=CC=C[CH:18]=1>C(OCC)(=O)C>[Br:1][C:2]1[N:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:17][CH3:18])=[O:12])=[C:14]2[OH:16]
Reactant: O=C([O-])C(=CNc1ccc(Br)nc1)C(=O)[O-]
Reactant: c1ccc(Oc2ccccc2)cc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc2ccc(Br)nc2c1O

Procedure:
Diethyl(2-(((6-bromopyridin-3-yl)amino)methylene)malonate (36 g, 0.105 mol) was added to boiling diphenyl ether (185 mL) in batches over 5 min, and reacted under reflux for 45 min. After confirming a disappearance of the raw materials by a thin layer chromatography plate (ethyl acetate:petroleum ether=1:3), cooled and poured into petroleum ether to precipitate a solid. The reaction mixture was suction filtered to give 17.1 g of a khaki solid.
Reaction SMILES: [N:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][C:10](=[O:14])[NH:11]2)=[CH:6][CH:5]=1)=[C:2]=[S:3].[C:15]([NH:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)(=[O:17])[CH3:16]>C1COCC1>[C:15]([NH:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:2](=[S:3])[NH:1][C:4]2[CH:13]=[C:12]3[C:7]([CH2:8][CH2:9][C:10](=[O:14])[NH:11]3)=[CH:6][CH:5]=2)=[CH:21][CH:20]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)Nc1ccc(N)cc1
Reactant: O=C1CCc2ccc(N=C=S)cc2N1
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(NC(=S)Nc2ccc3c(c2)NC(=O)CC3)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution containing 0.8 g of 7-isothiocyanato-3,4-dihydro-2(1H)quinolone and 0.59 g of 4-acetamidoaniline in 10 ml of THF was stirred for 5 h at room temperature. The product was filtered, dried and used as such to the next step. Yield 0.45 g (32%).
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[CH2:20]([NH2:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:26][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: NC(=O)c1cnc(Oc2ccc(C=O)cc2F)cn1
Reactant: CCCCCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCNCc1ccc(Oc2cnc(C(N)=O)cn2)c(F)c1
Reaction time: 8 h
Yield: 62.1 %

Procedure:
Place 5-(2-fluoro-4-formylphenoxy)pyrazine-2-carboxamide (Example 737, Part E) (0.400 g, 1.53 mmol), hexylamine (0.170 g, 1.68 mmol) and 3 Å molecular sieves in a vial. Add methanol (7.7 mL), cap and stir overnight. Add NaBH4 (0.058 g, 1.53 mmol) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 0% to 15% (2.0 M NH3 in methanol) in 80% (ethyl acetate in hexanes) to give the title compound (0.329 g, 62%): TOF MS ES+ 347.2 (M+H)+, HRMS calcd for C18H24N4O2F 347.1883 (M+H)+, found 347.1897, time 0.57 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min. 20-95% over 18], tR=11.4 min, 94.8% purity.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:9][CH3:10])[CH:3]=1.Br[C:12]1[S:13][CH:14]=[CH:15][N:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[C:4]([CH2:9][CH3:10])[CH:3]=1
Reactant: CCc1cc(Br)ccc1O
Reactant: Brc1nccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cc(Br)ccc1Oc1nccs1
Temperature: 150 °C
Reaction time: 15 h
Yield: 92.1 %

Procedure:
To a solution of 4-bromo-2-ethyl-phenol (1.00 g, 4.97 mmol) in DMF (40 mL) was added 2-bromothiazole (0.341 mL, 3.82 mmol) and finely crushed K2CO3 (3.17 g, 22.9 mmol). The mixture was stirred at 150° C. for 15 hours, at which time the hot solution was filtered through filter paper. The filtrate was diluted with CH2Cl2 and H2O and then brought to pH 6.0 with 6.0N HCl. The aqueous layer was extracted with CH2Cl2 and the organic layer was washed with H2O and brine. The organic layer was dried over Na2SO4 and concentrated to yield a yellow oil (1.0 g, 92%). 1H NMR (300 MHz, CDCl3): δ 1.19 (t, J=7.6 Hz, 3H), 2.62 (q, J=7.5 Hz, 2H), 6.79 (d, J=3.8 Hz, 1H), 7.10 (d, J=8.5 Hz, 1H), 7.19 (d, J=3.8 Hz, 1H), 7.35 (dd, J=8.7, 2.4 Hz, 1H), 7.43 (d, J=2.4 Hz, 1H).
Reaction SMILES: [C:1]12(O)[CH2:9][CH:5]([C:6]1([CH3:8])[CH3:7])[CH2:4][CH2:3][C:2]2([OH:11])[CH3:10].[CH3:13][CH:14]([CH3:19])[CH2:15][B:16](O)[OH:17]>C(OCC)C>[CH3:13][CH:14]([CH3:19])[CH2:15][B:16]1[O:17][C@@H:3]2[CH2:4][C@@H:5]3[CH2:9][C@H:1]([C@:2]2([CH3:10])[O:11]1)[C:6]3([CH3:8])[CH3:7]
Reactant: CC(C)CB(O)O
Reactant: CC1(O)CCC2CC1(O)C2(C)C
Solvent: CCOCC
Product: CC(C)CB1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.6 %

Procedure:
A mixture of (+)-pinanediol (23.9 g, 0.140 mol) and 2-methylpropylboronic acid (15 g, 0.147 mol) in diethyl ether (300 ml) was stirred at room temperature for 24 h. The mixture was dried over anhydrous sodium sulfate and purified by column chromatography (Silica gel 230-400 mesh), eluting with hexane:ethyl acetate 90:10 mixture. The product was obtained as a clear oil (32.6 g, 94% yield).
Reaction SMILES: C(O)C.C(=O)([O-])[O-].[K+].[K+].Cl.[CH2:11]([O:18][NH2:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O>[CH2:11]([O:18][N:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1
Reactant: NOCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: C(=NOCc1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 112.9 %

Procedure:
To a mixture of ethanol (100 mL), potassium carbonate (8.98 g, 65 mmol), and O-benzylhydroxylamine hydrochloride (10.0 g, 62.7 mmol) was added benzaldehvde (6.65 g, 62.7 mmol). The mixture was refluxed for 5 hours, allowed to cool to room temperature, and diluted with water (500 mL). The aqueous solution was extracted with ethyl acetate (500 mL). The organic layer was washed with water, dried over magnesium sulfate, filtered, and concentrated by rotary evaporation to give the title compound as a yellow oil (14.96 g, 119%).
Reaction SMILES: C1(O[C:8](=[O:25])[NH:9][CH:10]2[CH2:15][CH2:14][C:13]([N:22]([CH3:24])[CH3:23])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)C=CC=CC=1.[F:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[C:30]2[CH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>O1CCOCC1>[CH3:24][N:22]([CH3:23])[C:13]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:11][CH:10]([NH:9][C:8]([N:39]2[CH2:40][CH2:41][CH:36]([C:30]3[C:29]4[C:33](=[CH:34][CH:35]=[C:27]([F:26])[CH:28]=4)[NH:32][CH:31]=3)[CH2:37][CH2:38]2)=[O:25])[CH2:15][CH2:14]1
Reactant: Fc1ccc2[nH]cc(C3CCNCC3)c2c1
Reactant: CN(C)C1(c2ccccc2)CCC(NC(=O)Oc2ccccc2)CC1
Solvent: C1COCCO1
Product: CN(C)C1(c2ccccc2)CCC(NC(=O)N2CCC(c3c[nH]c4ccc(F)cc34)CC2)CC1

Procedure:
The polar diastereoisomer of (4-dimethylamino-4-phenylcyclohexyl)-carbamic acid phenyl ester (322 mg, 0.95 mmole) was added to a solution of 5-fluoro-3-piperidine-4-yl-1H-indole (208 mg, 0.95 mmole) in dioxane (10 ml). The reaction mixture was then boiled under reflux for 32 hours. The reaction mixture was worked up by distilling off dioxane and diluting with water (10 ml). The reaction mixture was adjusted to pH 11 with 5M NaOH and extracted with EE (3×15 ml). The organic phase was dried with Na2SO4 and concentrated by evaporation. The polar diastereoisomer of 4-(5-fluoro-1H-indol-3-yl)piperidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexyl)-amide was recrystallised from methanol (5 ml). It was obtained in a yield of 230 mg (52%) as a colourless solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)(=[O:12])=[O:11])([O-:3])=[O:2]
Reactant: C1CCNC1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
2-Nitrobenzenesulfonyl chloride (4.43 g, 20 mmol) in methylene chloride (20 mL) was added dropwise to the ice-cooled solution of pyrrolidine (8.4 mL, 100 mmol) in methylene chloride (100 mL). The reaction mixture was stirred at room temperature for 2 hours and washed with 3N HCl (2×60 mL) and brine (60 mL). The organic layer was dried (Na2SO4) and concentrated to yield the intermediate nitrobenzene derivative (5.12 g, 100%). 1H NMR (400 MHz, CDCl3) δ: 8.00 (d, 1H), 7.70 (m, 2H), 7.60 (d, 1H), 3.40 (t, 4H), 1.92 (t, 4H), 1.80 (t, 4H).
Reaction SMILES: [C:1]([C:3]1[CH:24]=[CH:23][C:6]([CH2:7][NH:8][C:9](=[O:22])[CH:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[F:21])[O:11][CH3:12])=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:26][OH:27].C(N(CC)CC)C>CO>[F:21][C:14]1[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=1[CH:10]([O:11][CH3:12])[C:9]([NH:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([C:1](=[NH:2])[NH:26][OH:27])=[CH:24][CH:23]=1)=[O:22]
Reactant: COc1ccc(C(OC)C(=O)NCc2ccc(C#N)cc2)c(F)c1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc(C(OC)C(=O)NCc2ccc(C(=N)NO)cc2)c(F)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 97.4 %

Procedure:
(RS)-N-(4-Cyano-benzyl)-2-(2-fluoro-4-methoxy-phenyl)-2-methoxy-acetamide (example 15.2, 251 mg) was dissolved in methanol (7 ml). Hydroxylamine hydrochloride (212 mg) and triethylamine (618 mg) were added. The mixture was stirred for 19 h at rt. The solvent was evaporated. The residue was dissolved in methylene chloride, washed with water, dried and filtered. The solvent was evaporated to give (RS)-2-(2-fluoro-4-methoxy-phenyl)-N-[4-(N-hydroxycarbamimidoyl)-benzyl]-2-methoxy-acetamide (269 mg) as an off-white foam. MS 362.2 ([M+H]+)
Reaction SMILES: [CH:1]([O-])=[O:2].[NH4+].[F:5][C:6]1[CH:27]=[CH:26][CH:25]=[CH:24][C:7]=1[CH:8]=[C:9]1[C:14](=[O:15])[C:13](=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[CH2:12][NH:11][CH2:10]1>C(#N)C>[CH:1]([N:11]1[CH2:10][C:9](=[CH:8][C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[F:5])[C:14](=[O:15])[C:13](=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[CH2:12]1)=[O:2]
Reactant: O=C[O-]
Reactant: O=C1C(=Cc2ccccc2F)CNCC1=Cc1ccccc1F
Agent: [NH4+]
Solvent: CC#N
Product: O=CN1CC(=Cc2ccccc2F)C(=O)C(=Cc2ccccc2F)C1
Yield: 58.3 %

Procedure:
Compound 18 was synthesized by two methods. In the first method, acetic anhydride (3 ml) was added drop-wise to an ice-cold solution of compound 1 (300 mg, 0.96 mmol) in formic acid (6 ml), and the reaction mixture was stirred at room temperature for 16 h. The solvent was distilled-off under vacuum. The solid obtained was recrystallized from chloroform and hexanes to obtain 18 as a yellow solid (148 mg, 45% yield). In the second method, ammonium formate (121 mg, 1.92 mmol) was added to a solution of compound 1 (300 mg, 0.96 mmol) in dry acetonitrile. The mixture was refluxed for 24 h, before evaporating to dryness. The solid was recrystallized from methylene chloride and hexanes to obtain pure 18 as a yellow solid (190 mg, 57% yield). Rf (60:40 ethyl acetate:hexanes)=0.60. 1H NMR (400 MHz, CDCl3): δ 8.16 (s, 1H, CHO), 8.09, 8.06 (2s, 2H, C═CH), 7.60-7.22 (m, 8H, Ar—H), 4.87, 4.66 (2s, 4H). 13C NMR (100 MHz, CDCl3): δ 185.34, 162.14 (d, J=45.6), 160.95, 159.87 (d, J=45.9), 132.85, 132.19 (d, J=25.7), 131.12 (d, J=25.4), 130.78, 124.46 (d, J=3.1), 116.49 (d, J=22.1), 116.18 (d, J=22.3), 46.38 (d, J=5.4), 41.11 (d, J=5.2). ESI Mass calculated for C20H15F2NNaO2 (M+Na)+362.10. found 362.07.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.[CH:9](O)([CH3:11])[CH3:10]>OS(O)(=O)=O>[F:1][C:2]1([CH:9]([CH3:11])[CH3:10])[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH2:3]1
Reactant: Fc1cccc(F)c1
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Product: CC(C)C1(F)C=CC=C(F)C1
Temperature: 65 °C
Reaction time: 4 h
Yield: 55.3 %

Procedure:
To a rapidly stirred mixture of 1,3-Difluorobenzene (31.5 ml, 320 mmol) and 80% H2SO4 (150 ml), Isopropanol (25 ml, 320 mmol) was added at room temperature. The mixture was heated to 65° C. and stirred for four hours. The resulting light brown mixture was cooled to room temperature. The organic layer was separated from the H2SO4 and washed twice with 50 ml saturated NaCl (aqueous). The organic layer was subjected to fractional distillation to give 55.2% (27.6 g, 177 mmol) of the title compound and 27.1% (9.9 g, 86.8 mmol) recovered 1,3- Difluorobenzene.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][N:15]=2)=[O:13])[N:6]=1)=O.O.[NH2:22][NH2:23]>C(O)C>[Cl:20][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([C:12]([NH:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([C:3]([NH:22][NH2:23])=[O:2])[N:6]=2)=[O:13])[CH:19]=1
Reactant: NN
Reactant: COC(=O)c1cccc(NC(=O)c2cc(Cl)ccn2)n1
Solvent: O
Solvent: CCO
Product: NNC(=O)c1cccc(NC(=O)c2cc(Cl)ccn2)n1
Yield: 92 %

Procedure:
The crude 6-[(4-chloro-pyridine-2-carbonyl)-amino]-pyridine-2-carboxylic acid methyl ester from the previous step (25.3 g, 87.8 mmol) was suspended in ethanol (200 mL), and hydrazine hydrate (21.3 mL, 439 mmol) was added. The reaction mixture was refluxed for 4 hours, solvent removed under reduced pressure, and the residue suspended in acetonitrile and collected by filtration. The solids were washed with acetonitrile (2×100 mL) and diethylether (2×100 mL), and dried under reduced pressure to afford 25.3 g (92% yield) of 4-chloro-N-(6-(hydrazinecarbonyl)pyridin-2-yl)picolinamide as a white solid.