Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14].Cl.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[O:26])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[F:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]([CH:27]2[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:16])[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N+:13]([O-:15])=[O:14])[CH2:29][CH2:28]2)=[O:26])=[CH:23][CH:24]=1
Reactant: O=C(NCCCBr)c1ccccc1[N+](=O)[O-]
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: O=C(NCCCN1CCC(C(=O)c2ccc(F)cc2)CC1)c1ccccc1[N+](=O)[O-]
Yield: 87 %

Procedure:
A mixture of 14.4 parts of N-(3-bromopropyl)-2-nitrobenzamide, 12.2 parts of (4-fluorophenyl) (4-piperidinyl)methanone hydrochloride, 16 parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone is stirred and refluxed for 3 hours using a water-separator. The reaction mixture is cooled, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 18 parts (87%) of N-[3-[4-(4-fluorobenzoyl)-1-piperidinyl]propyl]-2-nitrobenzamide as an oily residue.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[NH2:11].[CH3:13][C:14]([CH3:19])([CH3:18])[C:15](Cl)=[O:16]>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:15](=[O:16])[C:14]([CH3:19])([CH3:18])[CH3:13])[C:5]=1[NH2:11]
Reactant: COC(=O)c1cccc(N)c1N
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)c1cccc(NC(=O)C(C)(C)C)c1N
Reaction time: 16 h
Yield: 78.3 %

Procedure:
To a solution of 2,3-diaminobenzoic acid methyl ester (2.3 g, 13.8 mmol) in pyridine (40 mL) at room temperature was added 2,2-dimethylpropionyl chloride (1.7 g, 14.0 mmol). The solution was stirred at for 16 h, evaporated, and the residue partitioned between ethyl acetate (100 mL) and 1M aqueous hydrochloric acid (100 mL). The organic phase was separated, washed with 1M aqueous hydrochloric acid (100 mL), dried over sodium sulfate and evaporated to afford the title compound as a dark oil (2.7 g, 10.8 mmol, 78%) which was used without further purification. (m/z): [M+H]+ calcd for C13H18N2O3 251.14; found 250.8
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([N:10]=[C:11]=[S:12])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[C:30]([CH3:35])[C:29]=1[CH3:36].C1(C)C=CC=CC=1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[C:8]([NH:10][C:11]([NH:32][C:31]1[CH:33]=[CH:34][C:28]([O:27][C:18]2[C:17]3[C:22](=[CH:23][C:24]([O:25][CH3:26])=[C:15]([O:14][CH3:13])[CH:16]=3)[N:21]=[CH:20][CH:19]=2)=[C:29]([CH3:36])[C:30]=1[CH3:35])=[S:12])=[O:9]
Reactant: O=C(N=C=S)c1cccc(Cl)c1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(Cl)c4)c(C)c3C)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
Commercially available 3-chloro-1-benzenecarbonyl isothiocyanate (50 μl) was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (70 mg, yield 87%).
Reaction SMILES: [NH2-].[Na+:2].[CH2:3]([Si:6]([NH:9][Si:10]([CH3:15])([CH3:14])[CH2:11][CH2:12][CH3:13])([CH3:8])[CH3:7])[CH2:4][CH3:5]>C1C=CC=CC=1>[CH2:11]([Si:10]([N-:9][Si:6]([CH3:8])([CH3:7])[CH2:3][CH2:4][CH3:5])([CH3:14])[CH3:15])[CH2:12][CH3:13].[Na+:2]
Reactant: CCC[Si](C)(C)N[Si](C)(C)CCC
Agent: [NH2-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCC[Si](C)(C)[N-][Si](C)(C)CCC

Procedure:
Sodium bis(n-propyldimethylsilyl)amide was prepared as follows: Sodium amide (1.26 g, 0.0322 mol) was placed in dry benzene and bis(n-propyldimethylsilyl)amine (7.00 g, 0.0322 mol) was added. The mixture was stirred and refluxed for several hours. The benzene solution was filtered through celite and then the benzene was evaporated under vacuum, leaving 6.31 g (82%) of a yellow liquid product, sodium bis(n-propyldimethylsilyl)amide. Its viscosity was measured to be 7.1×104 centipoise at 40° C. It was distilled at a temperature of 213° C. and a pressure of 0.3 torr.
Reaction SMILES: [NH2:1][OH:2].[C:3]1([CH:9]([N:16]([S:24]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH2:17][CH2:18][C:19](OCC)=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl>C(OCC)C>[OH:2][NH:1][C:19](=[O:20])[CH2:18][CH2:17][N:16]([CH:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[S:24]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)(=[O:26])=[O:25]
Reactant: NO
Reactant: CCOC(=O)CCN(C(c1ccccc1)c1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Agent: Cl
Solvent: CCOCC
Product: COc1ccc(S(=O)(=O)N(CCC(=O)NO)C(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
Freshly prepared hydroxylamine reagent (8 mL; 8 mmol) was added to ethyl 3-[(diphenylmethyl)-(4-methoxybenzene-sulfonyl)-amino]-propionate (563 mg; 1.24 mmol) and the resulting mixture stirred overnight at room temperature. The mixture was poured into 1 N HCl (100 mL) and extracted with CH2Cl2 (2×50 mL). The combined extracts were washed with saturated aqueous NaCl (100 mL), dried over MgSO4, and evaporated under reduced pressure to give crude product. Trituration with diethyl ether afforded 262 mg (48%) of the title compound as a white solid. 300 MHz 1H-NMR (DMSO-d6): δ 1.81 (m, 2H), 3.40(m, 2H), 3.84 (s, 3H), 6.31 (s, 1H), 7.02 (m, 6H), 7.28 (m, 6H), 7.71 (d, 2H), 8.59 (s, 1H), 10.23 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([NH:14][NH2:15])=[O:13])[CH:6]=[CH:5]2.[F:23][C:24]([F:37])([F:36])[O:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.C1(S(Cl)(=O)=O)C=CC=CC=1>>[NH:14]([C:12]([CH:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][S:32]([C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]([F:23])([F:36])[F:37])=[CH:31][CH:30]=3)(=[O:34])=[O:33])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1)[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:13])[NH2:15]
Reactant: NNC(=O)C(Cc1ccccc1)n1ccc2cc(N)ccc21
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Agent: O=S(=O)(Cl)c1ccccc1
Product: NNC(=O)C(Cc1ccccc1)n1ccc2cc(NS(=O)(=O)c3ccc(OC(F)(F)F)cc3)ccc21

Procedure:
N-[1-(1-Hydrazinocarbonyl-2-phenyl-ethyl)-1H-indol-5-yl]-4-trifluoromethoxy-benzenesulfonamide was prepared from 2-(5-amino-indol-1-yl)-3-phenyl-propionic acid hydrazide following the procedure of Example 2 Step 1 substituting 4-trifluoro methoxy-benzene sulfonyl chloride for benzenesulfonyl chloride: MS (ESI) m/z 519, MS (ESI) m/z 517.
Reaction SMILES: [CH2:1]([C:5]1[C:12]([C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([Cl:28])[CH:19]=3)[O:15][N:14]=2)=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]#[N:8])[CH2:2][CH:3]=C.[O:29]=O.CSC.Cl>C(Cl)Cl.C1COCC1>[NH2:8][CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:12]([C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([Cl:28])[CH:19]=3)[O:15][N:14]=2)[C:5]=1[CH2:1][CH2:2][CH2:3][OH:29]
Reactant: O=O
Reactant: C=CCCc1c(C#N)cccc1-c1noc(-c2ccc(OC(C)C)c(Cl)c2)n1
Agent: Cl
Solvent: CSC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc(CN)c3CCCO)no2)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 18.9 %

Procedure:
Through a solution of 2-(3-buten-1-yl)-3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)benzonitrile (Preparation 22) (8.26 g, 20.97 mmol) in DCM (125 ml) under Ar at −78° C. was bubbled Ar then O2 (5 min each). The ozonoliser (model 502; 75 lh−1; 0.3 A) was switched on and the orange solution ozonolised until it had turned an opaque green-grey colour (3 hrs). The ozonoliser was switched off, and O2, then Ar bubbled though the solution (10 min each). The solution was allowed to warm to RT under Ar, then concentrated in vacuo to give an opaque yellow oil. This was redissolved in dry THF (200 ml), BH3.DMS (9.96 ml, 105 mmol) added (CARE: gas evolution), and the solution stirred at RT for 18 hrs and then at 40° C. for 3 hrs. The reaction was cooled to 0° C., then 0.1M aqueous HCl (150 ml) was added cautiously (CARE: gas evolution), then allowed to stir at RT for 18 hrs. The solution was passed directly down an SCX-2 column (50 g), washing with MeOH. The product was eluted with 0.5M NH3 in MeOH; concentration in vacuo gave an orange foam 3-[2-(aminomethyl)-6-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)phenyl]-1-propanol (2.73 g, 3.95 mmol, 18.9% yield). 1H NMR (400 MHz, CDCl3) δ (inter alia) 8.23 (1H, d), 8.05 (1H, dd), 7.86 (1H, d), 7.46 (1H, d), 7.34 (1H, t), 7.06 (1H, d), 4.72 (1H, sept), 4.03 (2H, s), 3.47 (2H, t), 3.27 (2H, t), 1.78 (2H, quin), 1.45 (6H, d); MS (ES) C21H2435ClN3O3 requires 401; found 402 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5](/[CH:10]=[CH:11]/[CH:12]=[CH:13]/[C:14]([NH:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[NH:27][CH:26]=3)[CH2:21][CH2:20]2)=[O:15])=[CH:4][C:3]=1[O:34][CH3:35].[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([O:1][C:2]1[C:3]([O:34][CH3:35])=[CH:4][C:5](/[CH:10]=[CH:11]/[CH:12]=[CH:13]/[C:14]([NH:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[NH:27][CH:26]=3)[CH2:21][CH2:20]2)=[O:15])=[CH:6][C:7]=1[O:8][CH3:9])(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: COc1cc(/C=C/C=C/C(=O)NCCN2CCC(c3c[nH]c4ccccc34)CC2)cc(OC)c1O
Product: COc1cc(/C=C/C=C/C(=O)NCCN2CCC(c3c[nH]c4ccccc34)CC2)cc(OC)c1OC(C)=O
Temperature: 0 °C

Procedure:
To a mixture of 1-[2-{5-(4-hydroxy-3, 5-dimethoxyphenyl)-(2E, 4E)-2, 4-pentadienoylamino}ethyl]-4-(3-indolyl)piperidine (1 g) and pryidine (10 ml) was added slowly acetyl chloride (0.48 ml) at 5° to 10° C. After hour, the reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off and the residue was subjected to column chromatography on silica gel and eluted with a mixture of chloroform and methanol (10:1 V/V). The fractions containing the object compound were combined and concentrated under reduced pressure. The residue was treated with a mixture of fumaric acid (83 mg) and methanol (8 ml) and concentrated under reduced pressure to give white crystals. The crystals were recrystallized from ethanol to give 1-[2-{5-(4-acetoxy-3, 5-dimethoxyphenyl)-(2E, 4E)-2, 4-pentadienoylamino}ethyl]-4-(3-indolyl)piperidine 1/2fumarate (0.25 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[N:4][CH:3]=1.F[P-](F)(F)(F)(F)F.[CH3:18][N+:19](C)=[C:20](N(C)C)ON1C2N=CC=CC=2N=N1.CNC.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.ClCCl.C1COCC1.C(OCC)(=O)C>[CH3:18][N:19]([CH3:20])[C:8]([C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[N:7]=1)=[O:10]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1cncc(Cl)n1
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1cncc(Cl)n1
Reaction time: 18 h
Yield: 59.3 %

Procedure:
1.000 g (6.31 mmol) of 6-chloro-pyrazine-2-carboxylic acid were dissolved in 75 mL of 50% v/v acetonitrile in dichloromethane containing. 2.810 g (7.48 mmol) of N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate were added, then 8.0 mL (16 mmol) of 2 M dimethylamine in anhydrous THF was added and stirring was continued for 18 h. The resulting solution was distributed between ethyl acetate and a 2 M aqueous solution of sodium carbonate. The organic phase was washed with brine, dried over sodium sulfate and evaporated. The resulting crude was purified by flash chromatography on silica gel using a gradient of ethyl acetate and hexanes to afford 695 mg (3.74 mmol, 59%) of 6-chloro-pyrazine-2-carboxylic acid dimethylamide as a pale yellow oil. 1H-NMR [500 MHz, d6-DMSO] δ: 8.91 (s, 1H), 8.84 (s, 1H), 3.04 (s, 3H), 2.98 (s, 3H); MS [MH+] m/z: 186.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([OH:11])=[N:5][NH:6]2.[CH3:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19](Cl)=[O:20])[CH2:15][CH2:14]1>N1C=CC=CC=1>[CH3:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:11][C:4]2[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[F:1])[NH:6][N:5]=2)=[O:20])[CH2:15][CH2:14]1
Reactant: Oc1n[nH]c2cccc(F)c12
Reactant: CC1CCN(C(=O)Cl)CC1
Solvent: c1ccncc1
Product: CC1CCN(C(=O)Oc2n[nH]c3cccc(F)c23)CC1
Reaction time: 8 h

Procedure:
100 mg (0.66 mmol) of 4-fluoro-1H-indazol-3-ol and 116.8 mg (0.72 mmol) of 4-methylpiperidine-1-carbonyl chloride (Example 2) in 10 ml of pyridine were heated under reflux for 4 h and left to stand overnight. Addition of 24 mg of 4-methyl-piperidine-1-carbonyl chloride was followed by heating under reflux for a further 2 h while the pyridine was distilled off in vacuo, and the residue was dissolved in water and extracted with ethyl acetate. The organic phase was concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 56 mg (31%), M+H+: 278.1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]([C:11]([OH:13])=O)[CH:5]=1)([O-:3])=[O:2].S(Cl)(Cl)=O.[NH2:18][C:19]1[NH:23][N:22]=[N:21][N:20]=1>>[NH:20]1[C:19]([NH:18][C:11]([C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[C:8]([CH3:10])[N:7]=2)=[O:13])=[N:23][N:22]=[N:21]1
Reactant: Nc1nnn[nH]1
Reactant: Cc1cc([N+](=O)[O-])cc(C(=O)O)n1
Solvent: O=S(Cl)Cl
Product: Cc1cc([N+](=O)[O-])cc(C(=O)Nc2nnn[nH]2)n1
Yield: 40.1 %

Procedure:
1.44 g of 4-nitro-6-methyl-2-pyridinecarboxylic acid, 27 ml of thionyl chloride and 0.79 g of 5-aminotetrazole are treated in the same manner as described in Example 1. The crude product thus obtained is washed with ethanol, whereby 0.79 g of N-(5-tetrazolyl)-4-nitro-6-methyl-2-pyridinecarboxamide is obtained.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([S:7]([OH:9])=[O:8])=[CH:3][CH:2]=1.[Li].[S:12]([CH2:16][CH2:17][NH:18][C:19](=[O:22])[CH2:20]Br)([OH:15])(=[O:14])=[O:13].O>C(O)C>[CH3:10][C:1]1[CH:6]=[CH:5][C:4]([S:7]([CH2:20][C:19]([NH:18][CH2:17][CH2:16][S:12]([OH:15])(=[O:14])=[O:13])=[O:22])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)O)cc1
Reactant: O=C(CBr)NCCS(=O)(=O)O
Agent: [Li]
Solvent: CCO
Solvent: O
Product: Cc1ccc(S(=O)(=O)CC(=O)NCCS(=O)(=O)O)cc1
Reaction time: 4 h
Yield: 89 %

Procedure:
To a 5-liter flask equipped with a mechanical stirrer and reflux condenser was added p-toluenesulfinic acid, lithium salt (309 g), N-(2-sulfoethyl)-2-bromoacetamide, lithium salt (527 g), water (180 ml), and ethyl alcohol (3380 ml). The resulting suspension was heated to reflux. After about an hour of reflux, nearly all of the reactants had dissolved. Reflux was continued another four hours, and the solution was filtered hot through a Celite pad to remove some haziness. The solution was cooled overnight to room temperature. The solid that formed was collected and washed with 1 liter of 95% ethyl alcohol/water. The white solid was air dried and then dried at high vacuum, providing 554 g (89% yield) of 2-(4-methylphenyl)sulfonyl-N-(2-sulfoethyl)acetamide, lithium salt (Intermediate 1). HPLC analysis showed no detectable impurities. Ion chromatography indicated 0.035 weight % bromide and 1.8 weight % lithium. The material exhibited an acceptable proton spectrum.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][CH2:16][C:17]([OH:19])=[O:18].C(=O)([O-])[O-].[K+].[K+]>O.CS(C)=O>[N+:12]([C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[NH:15][CH2:16][C:17]([OH:19])=[O:18])([O-:14])=[O:13]
Reactant: NCC(=O)O
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)CNc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 6 h

Procedure:
4-Chloro-3-nitrobenzotrifluoride (10 grams), glycine (7 grams), and potassium carbonate (10 grams) were mixed in a mixture of 40 ml. each of water and dimethyl sulfoxide. The mixture was heated to 80°-100°C. and held for 6 hours, then poured into 600 ml. of water, acidified, and chilled to 5°C. The mixture was filtered, yielding N-(2-nitro-4-trifluoromethylphenyl)-glycine. The product was dissolved in 5 percent sodium bicarbonate and reprecipitated by acidification. It was separated and recrystallized from a mixture of ethanol and water, m.p., 167°-170°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH:6]([CH3:9])[CH2:7][NH2:8].[F:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:24][CH2:25][CH2:26]OS(C1C=CC(C)=CC=1)(=O)=O.C(N(CC)CC)C.O>C(S(CC)=O)C>[F:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:24][CH2:25][CH2:26][NH:8][CH2:7][CH:6]([O:5][C:4]1[CH:10]=[CH:11][CH:12]=[CH:13][C:3]=1[O:2][CH3:1])[CH3:9]
Reactant: COc1ccccc1OC(C)CN
Reactant: Cc1ccc(S(=O)(=O)OCCCc2c[nH]c3ccc(F)cc23)cc1
Agent: CCS(=O)CC
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccccc1OC(C)CNCCCc1c[nH]c2ccc(F)cc12
Temperature: 90 °C
Reaction time: 8 h
Yield: 23.4 %

Procedure:
A solution of 2-(2-methoxy-phenoxy)propylamine (0.26 g, 1.2 mmol), 5-fluoro-3-(3-p-toluenesulfonyloxypropyl)indole (0.26 g, 0.81 mol) and triethylamine (0.13 g, 1.2 mmol) in anhydrous diethylsulfoxide (20 ml) was allowed to stir for 8 hours at 90° C. The mixture was poured into water (100 ml) and extracted with methylene chloride (3×100 ml). The organic layer was washed with water (3×100 ml), dried over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum. Chromatography (10% methanol-methylene chloride plus ammonium hydroxide) afforded 0.1 g (36%) of product of product as a yellow oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:26][CH2:25][C:5]2[N:6]([CH2:14][C:15]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)(O)[CH2:16][CH3:17])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.CN(C=O)C.S(Cl)(Cl)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][N:2]1[CH2:26][CH2:25][C:5]2[N:6](/[CH:14]=[C:15](\[C:19]3[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=3)/[CH2:16][CH3:17])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CCC(O)(Cn1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CC/C(=C/n1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccncc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-(1,2,3,4-Tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-2-(pyridin-4-yl)butan-2-ol (0.5 g, 1.43 mmol) was dissolved in dry DCM (15 mL) and a drop of DMF was added. The solution was cooled to 0° C. and thionyl chloride (0.5 g, 4.29 mmol) diluted with dry DCM (2 mL) was added dropwise. Stirring was continued for 1 h at 0° C. and then at RT for 2 h. The solution was basified with saturated aqueous sodium bicarbonate and extracted with EtOAc (3×50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by HPLC. 1H NMR (CDCl3, freebase) δ (ppm): 8.36 (d, 2H), 7.16 (s, 1H), 7.0 (d, 1H), 6.90 (d, 1H), 6.85 (d, 2H), 6.75 (s, 1H), 3.70 (s, 2H), 2.78 (t, 2H), 2.65 (q, 2H), 2.50 (s, 3H), 2.42 (m, 2H), 2.40 (s, 3H), 1.18 (t, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:18](O)=[O:19])[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:17]=1>C1COCC1>[OH:19][CH2:18][C:4]1[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:17]=[C:2]([OH:1])[CH:3]=1
Reactant: O=C(O)c1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Solvent: C1CCOC1
Product: OCc1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Temperature: 65 °C
Reaction time: 6 h
Yield: 38.3 %

Procedure:
Acid 24 (0.030 g, 0.112 mmole) in 5 mL THF was added a solution of Borane-THF complex (2.0 mL, 2.0 mmole) in THF. After stirring at 65° C. for 6 hours, the THF was evaporated and the residue was poured into 2N HCl and extracted with ethyl acetate. The combined organic phases were washed with saturated sodium bicarbonate, water, brine, and dried with magnesium sulfate. The organic phases were concentrated and the residue was separated by HPLC (70:30, H2O/AcCN) to afford 0.011 g (36%) of benzyl alcohol 25 as a white solid: Mp=258–260° C.; 1H NMR (DMSO-d6) δ 9.81 (s, 1H), 9.45 (s, 1H), 7.70 (d, 2 H, J=8.9 Hz), 7.00 (s, 1 H), 6.86 (d, 2 H, J=8.7 Hz), 6.76 (s, 2 H), 5.27 (m, 1 H), 4.75 (d, 2 H, J=5.6 Hz); MS 255 (M−H) −
Reaction SMILES: [C:1]([Si:5]([CH3:29])([CH3:28])[O:6][CH2:7][C@H:8]([CH2:19][N:20]1[CH:25]=[CH:24][C:23](=O)[NH:22][C:21]1=[O:27])[C@H:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH3:10])([CH3:4])([CH3:3])[CH3:2].[NH:30]1[CH:34]=[N:33][CH:32]=[N:31]1>N1C=CC=CC=1>[C:1]([Si:5]([CH3:29])([CH3:28])[O:6][CH2:7][C@H:8]([CH2:19][N:20]1[CH:25]=[CH:24][C:23]([N:30]2[CH:34]=[N:33][CH:32]=[N:31]2)=[N:22][C:21]1=[O:27])[C@H:9]([O:11][Si:12]([C:15]([CH3:17])([CH3:16])[CH3:18])([CH3:13])[CH3:14])[CH3:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: c1nc[nH]n1
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)Cn1ccc(=O)[nH]c1=O
Solvent: c1ccncc1
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)Cn1ccc(-n2cncn2)nc1=O
Temperature: 0 °C
Reaction time: 72 h
Yield: 66.6 %

Procedure:
To a cold (ice/water bath) solution of 42 (2.7 g, 6.08 mmol) and 1,2,4-triazole (5.8 g, 84 mmol) in 37 ml of anhydrous pyridine was added dropwise over 5 min 4.2 g (17.11 mmol) of 4-chlorophenyldichlorophosphate (via syringe). The reaction was allowed to warm up and kept at room temperature for 3 days. The reaction was concentrated and partitioned between ethyl acetate (150 ml) and water (150 ml). The organic phase was washed with 10% citric acid, saturated NaCl and dried over Na2SO4. The crude material (brown oil) obtained after concentration of the extract was chromatographed on silica eluting with a gradient of ethyl acetate (50-66%) in hexane. Concentration of the pure product fractions afforded 2.0 g (66%) of 43 as a light tan solid. 1H NMR (DMSO-d6): δ 9.40 (s, 1H), 8.38 (s, 1H), 8.37 (d, J=7 Hz, 1H), 6.90 (d, J=7 Hz, 1H), 4.05 (m, 2H), 3.83 (m, 1H), 3.60 (d, J=6.3 Hz, 2H), 2.22 (m, 1H), 1.15 (d, J=6 Hz, 3H), 0.81 (s, 9H), 0.79 (s, 9H), 0.01 (s, 6H), −0.04 (s, 6H).
Reaction SMILES: [C:1]([CH2:3][CH:4]1[CH2:7][N:6]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5]1)#[N:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].[H-].[NH4+].[Cl-]>C1COCC1>[NH2:2][CH2:1][CH2:3][CH:4]1[CH2:7][N:6]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:5]1
Reactant: N#CCC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: NCCC1CN(C(c2ccccc2)c2ccccc2)C1
Yield: 86.5 %

Procedure:
5.7 g (21.7 mmol) of 3-cyanomethyl-1-benzhydryl azetidine was added slowly to a suspention of 2.9 g (76.0 mmol) of LiAlH4 in 80 mL of dry THF at roomtemperature. The reaction mixture was refluxed for 4 h. Excess hydride reagent was hydrolyzed by careful addition, with cooling, of NH4Cl(aq), the gelatinous mixture was filtered and the filter cake was washed repeatedly with THF. The solvent was evaporated, the residue was dissolved in diethyl ether, washed with brine and dried with Na2SO4. Evaporation of the solvent gave 5.0 g (87%) of the title compound.