Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>CN(C)C=O>[N+:1]([C:4]1[C:5]2[C:9]([CH:10]=[CH:11][CH:12]=1)=[N:8][N:7]([CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)[CH:6]=2)([O-:3])=[O:2]
Reactant: ClCCN1CCCC1
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc2nn(CCN3CCCC3)cc12
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
4-Nitroindazole (3.00 g, 18.4 mmol) was dissolved in 60 mL of N,N-dimethylformamide and potassium carbonate (7.50 g, 54.3 mmol) was added. The mixture was stirred for 30 minutes and then 1-(2-chloro-ethyl)-pyrrolidine hydrochloride (4.80 g 28.2 mmol) was added. The reaction mixture was heated to 60° C. for 6 hours, cooled to room temperature and the mixture filtered through a plug of silica gel which was rinsed with triethylamine/ethyl acetate (1/4). The filtrate was concentrated in vacuo to remove N,N-dimethylformamide and the residue purified by flash chromatography (silica gel, triethylamine/ethyl acetate 1/30). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.64 (m, 4H), 2.48 (m, 4H), 3.01 (t, 2H, J=6.44), 4.67 (t, 2H, J=6.44), 7.49 (t, 1H, J=8.14), 8.19 (d, 2H, J=7.80), 8.92 (s, 1H); MS (DCI/NH3) m/z 261 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:20]=[CH:19][C:14]([NH:15][CH2:16][C:17]#[N:18])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N-:21]=[N+:22]=[N-:23].[Na+].[Cl-].[NH4+]>[Cl-].[Li+].CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]2[CH:20]=[CH:19][C:14]([NH:15][CH2:16][C:17]3[NH:23][N:22]=[N:21][N:18]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCNc1ccc(S(=O)(=O)c2ccc(Cl)cc2)cc1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccc(Cl)cc1)c1ccc(NCc2nnn[nH]2)cc1
Yield: 77.1 %

Procedure:
A reaction mixture comprising 6.14 g of [p-(p-chlorophenylsulfonyl)anilino]acetonitrile, 1.43 g of sodium azide, 30 mg of lithium chloride, 1.18 g of ammonium chloride and 10 ml of dimethylformamide was stirred at 90° C. for 34 hours and then filtered. The solvent was removed in vacuo, the residue suspended in 50 ml of water and acidified with hydrochloric acid to pH2. The resulting solid was collected and recrystallized from acetic acid, giving 5.4 g of the desired product as tan crystals, mp 102°-105° C.
Reaction SMILES: [N:1]12[CH2:11][CH2:10][CH2:9][CH:8]1[CH2:7][CH:6]1[CH:2]2[CH2:3][N:4](C(OCC)=O)[CH2:5]1.C(=O)([O-])[O-].[K+].[K+]>Cl>[N:1]12[CH2:11][CH2:10][CH2:9][CH:8]1[CH2:7][CH:6]1[CH:2]2[CH2:3][NH:4][CH2:5]1
Reactant: CCOC(=O)N1CC2CC3CCCN3C2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C1CC2CC3CNCC3N2C1

Procedure:
9 g (40 mmol) of ethyl 1,4-diazatricyclo[6.3.0.02,6 ]undecane-4-carboxylate are heated under reflux overnight with 50 ml of concentrated hydrochloric acid. The mixture is rendered alkaline with potassium carbonate and extracted ten times using 50 ml of chloroform each time, the extracts are dried over potassium carbonate and concentrated, and the residue is distilled.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH2:11][C:12]#[N:13])(=[O:10])=[O:9].Br[CH2:15][CH2:16][CH2:17][CH2:18]Br.[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C:11]1([C:12]#[N:13])[CH2:18][CH2:17][CH2:16][CH2:15]1)(=[O:10])=[O:9]
Reactant: BrCCCCBr
Reactant: N#CCS(=O)(=O)c1ccccc1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: N#CC1(S(=O)(=O)c2ccccc2Br)CCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 41.2 %

Procedure:
A mixture of 2-(2-bromophenylsulfonyl)acetonitrile (4.4 g, 17 mmol), tetrabutylammonium bromide (0.82 g, 2.6 mmol), 1,4-dibromobutane (3.85 g, 17.8 mmol) and NaOH (14 mL, 5 N) in DCM (30 mL) was stirred at rt for 5 h, before diluting with DCM (200 mL), washing with water (2×80 mL) and brine (60 mL), drying over Na2SO4, filtering, and concentrating to dryness. The residue was treated with IPA (20 mL) and sonicated before isolating the title compound (2.2 g) via vacuum filtration. The filtrate was concentrated to dryness and the resultant residue subjected to FCC to give additional title compound. MS (ESI): mass calcd. for C12H12BrFN3O2S, 312.98; m/z found, 314.0 [M+H]+. 1HNMR (300 MHz, CDCl3) δ 8.28 (dd, J=7.5, 1.5, 1H), 7.85 (dd, J=7.5, 1.5, 1H), 7.62-7.51 (m, 2H), 2.80-2.68 (m, 2H), 2.34-2.22 (m, 2H), 2.02-1.81 (m, 4H).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[O:14][C:15]3[CH:21]=[CH:20][C:19]([C:22]4[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][N:23]=4)=[CH:18][C:16]=3[N:17]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB(C2C=CC3OC(C4CCN(C(OC(C)C)=O)CC4)=NC=3C=2)O1.ClC1C=CC(C(OC)=O)=CN=1.C([O-])([O-])=O.[K+].[K+]>CO>[CH:1]([O:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([C:13]2[O:14][C:15]3[CH:21]=[CH:20][C:19]([C:22]4[CH:31]=[CH:30][C:25]([C:26]([OH:28])=[O:27])=[CH:24][N:23]=4)=[CH:18][C:16]=3[N:17]=2)[CH2:11][CH2:12]1)=[O:6])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(-c2ccc3oc(C4CCN(C(=O)OC(C)C)CC4)nc3c2)nc1
Agent: CC(C)OC(=O)N1CCC(c2nc3cc(B4OC(C)(C)C(C)(C)O4)ccc3o2)CC1
Agent: COC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Solvent: CO
Product: CC(C)OC(=O)N1CCC(c2nc3cc(-c4ccc(C(=O)O)cn4)ccc3o2)CC1
Yield: 41.4 %

Procedure:
Following the General Procedure-2, Methyl 6-{2-(1-(isopropoxycarbonyl)piperidin-4-yl)-benzo[d]oxazol-5-yl]nicotinate (50 mg) was prepared from Intermediate 14 (400 mg, 0.97 mmol) and methyl 6-chloronicotinate (166 mg, 0.97 mmol) as a brown solid. Methyl 6-{2-(1-(isopropoxycarbonyl)piperidin-4-yl)-benzo[d]oxazol-5-yl]nicotinate (35 mg, 0.08 mmol) was dissolved in MeOH (5 ml) and added K2CO3 (22 mg, 0.17 mmol). This mixture was stirred at reflux for overnight. MeOH removed on rotavapour and pH adjusted to 6 using acetic acid to obtain a solid. Solid was filtered and dried to obtain the titled compound (20 mg) as a grey solid. M. P.: 239-242° C. MS (m/z): 410.4 [M+H]+.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[N:5][CH:6]=[C:7]3[CH2:12][CH2:11][C:10](=[CH:13][C:14]#[N:15])[C:8]3=2)[O:3][CH2:2]1.N.C(O)C>C(O)C.[Co]>[CH2:1]1[C:9]2[C:4](=[N:5][CH:6]=[C:7]3[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][NH2:15])[C:8]3=2)[O:3][CH2:2]1
Reactant: N#CC=C1CCc2cnc3c(c21)CCO3
Agent: [Co]
Agent: N
Solvent: CCO
Product: NCCC1CCc2cnc3c(c21)CCO3
Temperature: 25 °C
Reaction time: 30 h

Procedure:
To a solution of 1,2,6,7-tetrahydro-8H-cyclopenta[d]furo[2,3-b]pyridin-8-ylideneacetonitrile (500 mg, 2.52 mmol) in ethanol (16 mL) were added Raney cobalt (1 g) and 2M ammonia/ethanol solution (8 mL), and the mixture was stirred at room temperature for 30 hr under a hydrogen atmosphere. The catalyst was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (20 mL), palladium-carbon powder (100 mg) was added, and the mixture was stirred at room temperature for 12 hr under a hydrogen atmosphere. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound. The obtained title compound was used for the reaction in Examples 25, 26, 27 and 28 without purification.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:10]([F:13])([F:12])[F:11])=[C:5]([C:7]([OH:9])=O)[N:6]=1.Cl.[CH3:15][NH:16][O:17][CH3:18].CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>ClCCl>[CH3:18][O:17][N:16]([CH3:15])[C:7]([C:5]1[N:6]=[C:2]([CH3:1])[O:3][C:4]=1[C:10]([F:13])([F:12])[F:11])=[O:9]
Reactant: Cc1nc(C(=O)O)c(C(F)(F)F)o1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)c1nc(C)oc1C(F)(F)F
Reaction time: 16 h
Yield: 91.7 %

Procedure:
To a solution of 2-methyl-5-trifluoromethyl-oxazole-4-carboxylic acid (500 mg, 2.56 mmole) in dichloromethane (5 ml) was subsequently treated at 22° C. with N,O-dimethylhydroxylamine hydrochloride (262 mg, 2.69 mmole), N-methylmorpholine (0.29 ml, 2.69 mmole) and EDCI.HCl (516 mg, 2.69 mmole) and stirring was continued for 16 h. The mixture was washed with 1 M aqueous HCl and H2O, the organic layer was dried and evaporated to give the title compound (559 mg) as a colorless oil which was used without further purification. MS: m/z=239.0 [M]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:64])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([C:25]3[N:30]=[C:29]([O:31]CC4C=CC=CC=4)[C:28]([C:39]4[CH:63]=[CH:62][C:42]5[NH:43][C:44]([C@@H:46]6[CH2:50][CH2:49][CH2:48][N:47]6[C:51](=[O:61])[C@@H:52]([NH:56][C:57]([O:59][CH3:60])=[O:58])[CH:53]([CH3:55])[CH3:54])=[N:45][C:41]=5[CH:40]=4)=[CH:27][N:26]=3)=[CH:24][C:18]=2[N:17]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:64])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([C:25]3[N:30]=[C:29]([OH:31])[C:28]([C:39]4[CH:63]=[CH:62][C:42]5[NH:43][C:44]([C@@H:46]6[CH2:50][CH2:49][CH2:48][N:47]6[C:51](=[O:61])[C@@H:52]([NH:56][C:57]([O:59][CH3:60])=[O:58])[CH:53]([CH3:55])[CH3:54])=[N:45][C:41]=5[CH:40]=4)=[CH:27][N:26]=3)=[CH:24][C:18]=2[N:17]=1)=[O:10])[CH:6]([CH3:7])[CH3:8]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2cc(-c3ncc(-c4ccc5[nH]c([C@@H]6CCCN6C(=O)[C@@H](NC(=O)OC)C(C)C)nc5c4)c(OCc4ccccc4)n3)ccc2[nH]1)C(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2cc(-c3ncc(-c4ccc5[nH]c([C@@H]6CCCN6C(=O)[C@@H](NC(=O)OC)C(C)C)nc5c4)c(O)n3)ccc2[nH]1)C(C)C
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
To a solution of compound from example 19 (15 mg) in 3 mL of methanol is added Pd—C 10% (5 mg). The reaction is stirred for 30 minutes under hydrogen atmosphere. The reaction mixture is filtered, concentrated to dryness and the residue is purified by reverse phase HPLC to give title compound as a white solid (8 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](O)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[Br-:13].[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CC#N>[Br:13][C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: [Br-]
Reactant: Oc1ccnc2cc(Cl)ccc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: Clc1ccc2c(Br)ccnc2c1
Temperature: 25 °C

Procedure:
A suspension of 7-chloroquinolin-4-ol (10.0 g, 55.7 mmol) and triphenylphosphine dibromide (35.3 g, 83.6 mmol) in CH3CN (370 mL) was refluxed for 16 hours then cooled to room temperature. The resulting precipitate was collected by vacuum filtration and washed with CH3CN (2×70 mL). The precipitate was then partitioned between CH2Cl2 (300 mL) and 1 M NaOH (aq) (300 mL). The aqueous phase was extracted with CH2Cl2 (100 mL). The combined organics were dried over Na2SO4, filtered, and concentrated to afford the title compound as a white solid: 1H NMR (500 MHz, CDCl3): δ 8.67 (d, J=4.7 Hz, 1H); 8.14 (d, J=9.0 Hz, 1H); 8.11 (d, J=2.1 Hz, 1H); 7.70 (d, J=4.7 Hz, 1H); 7.60 (dd, J=9.0, 2.1 Hz, 1H); LC4 1.86 min. (M+H)=244.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.Br[CH2:12][CH2:13][CH2:14][Cl:15]>C(O)C>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:12][CH2:13][CH2:14][Cl:15])[CH2:7][CH2:6]1
Reactant: COCCN1CCNCC1
Reactant: ClCCCBr
Solvent: CCO
Product: COCCN1CCN(CCCCl)CC1
Yield: 49.9 %

Procedure:
144 grams of N-(2-methoxyethyl)-piperazine and 157.5 grams of 3-bromo-1-chloropropane were dissolved in 500 milliliters of ethanol and refluxed for 2 hours. The ethanol was evaporated, the residue dissolved in water, the aqueous solution made alkaline with sodium hydroxide solution, the solution extracted with ether, the ether solution separated, washed with water, dried and evaporated, 110 grams of 4-(2-methoxyethyl)-1-(3-chloropropyl)-piperazine was thus obtained as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[CH2:6][NH:7][C:8]([C:10]1[C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:12][C:13]([CH3:16])=[N:14][CH:15]=1)=[O:9].[CH3:32]N(C)C=O.CI.O>[Cl-].[Na+].O.C(Cl)Cl>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=1)[CH2:6][N:7]([CH3:32])[C:8]([C:10]1[C:11]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[N:12][C:13]([CH3:16])=[N:14][CH:15]=1)=[O:9]
Reactant: CN(C)C=O
Reactant: Cc1ncc(C(=O)NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(-c2ccccc2)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: CI
Solvent: ClCCl
Solvent: O
Product: Cc1ncc(C(=O)N(C)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(-c2ccccc2)n1
Reaction time: 1 h
Yield: 72.6 %

Procedure:
To a solution of 0.67 g (1.52 mmol) methyl-4-phenyl-pyrimidine-5-carboxylic acid 3,5-bis-trifluoromethyl-benzylamide in 10 ml N,N-dimethylformamide 0.08 g (1.98 mmol) sodiumhydride (60% dispersion in mineral oil) was added and the reaction mixture stirred for 1 hr. After the addition of 0.15 ml (2.4 mmol) methyl iodide at 0°, the reaction mixture was stirred for 3 hrs. at RT. The reaction mixture was distributed between 50 ml H2O, 50 ml brine and 50 ml CH2Cl2. The phases were separated, the aqueous layer washed twice with 50 ml CH2Cl2. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, ethyl acetate/hexane 4:1) to give 0.50 g (72%) 2-methyl-4-phenyl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide as a colorless oil, MS (EI): 453 (M+).
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:14](=[O:16])[CH3:15])[N:4]2[C:8]3[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:7]=3[S:6][C:5]=12.[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[CH:27]=O>>[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[CH:27]=[CH:15][C:14]([C:3]1[N:4]2[C:5]([S:6][C:7]3[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]=32)=[N:1][CH:2]=1)=[O:16]
Reactant: CC(=O)c1cnc2sc3c(n12)CCCCC3
Reactant: O=Cc1ccc2ccccc2c1
Product: O=C(C=Cc1ccc2ccccc2c1)c1cnc2sc3c(n12)CCCCC3

Procedure:
1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)ethanone (Formula O-1), 1.37 g, was condensed with 2-napthaldehyde by non-critical variations of EXAMPLE 15 to yield 3-(2-Napthalenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-2-propene-1-one (Formula O-2), 2.24 g, m.p. 185-188°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I-].[CH2:48]([N+:52]1[N:56]=[C:55]([CH3:57])[S:54][C:53]=1[CH3:58])[CH2:49][CH2:50][CH3:51]>>[CH2:48]([N:52]1[N:56]=[C:55]([CH3:57])[S:54]/[C:53]/1=[CH:58]\[C:5]([C:4]1[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:3]=1[O:2][CH3:1])=[O:7])[CH2:49][CH2:50][CH3:51]
Reactant: CCCC[n+]1nc(C)sc1C
Reactant: COc1ccc(OC)c(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)c1cc(OC)ccc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 2,5-dimethoxybenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-D6/D2O) δ ppm 0.93 (t, 3 H) 1.30-1.36 (m, 2 H) 1.71-1.79 (m, 2 H) 2.47 (s, 3 H) 3.73 (s, 3 H) 3.80 (s, 3 H) 4.11 (t, 2 H) 6.59 (s, 1 H) 6.96-7.00 (m, 1 H) 7.02-7.06 (m, 1 H) 7.22 (d, 1 H); MS (ESI) m/z 335 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=O)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O.Cl.[CH2:23]([O:26][NH2:27])[CH:24]=[CH2:25]>C(O)C>[CH2:23]([O:26][N:27]=[CH:17][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]=1)[CH:24]=[CH2:25]
Reactant: O=Cc1cn(Cc2ccccc2)c2ccccc12
Reactant: C=CCON
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CCON=Cc1cn(Cc2ccccc2)c2ccccc12
Temperature: 25 °C
Yield: 13.1 %

Procedure:
To a solution of 1-benzyl-1H-indole-3-carbaldehyde (1.086 g, 4.61 mmol) in 4:1 ethanol:2.5 M NaOH solution (16 mL) was added O-allyl hydroxylamine hydrochloride hydrate(0.768 g, 7.17 mmol). The reaction mixture was heated to reflux for 30 minutes and allowed to cool back down to room temperature. The reaction mixture was concentrated to a small volume and the pH of the mixture was then adjusted to 7 using 2 M hydrochloric acid. The mixture was extracted with ethyl acetate. The combined organics were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude oil was purified by flash chromatography through silica gel using ethyl acetate/hexanes (10/90) to give 1-benzyl-1H-indole-3-carbaldehyde O-allyl-oxime (0.176 g, 88%) as a colorless oil. 1H NMR (400 MHz, CDCl3); δ 8.30(s, 1H), 8.15 (m, 1H), 7.24 (m, 7H), 7.10 (d, 2H), 6.10 (m, 1H), 5.30 (m, 4H), 4.68 (d, 2H).
Reaction SMILES: BrC1C=C2C(=CC=1)C[C@@H](NC(=O)C1C=CC(OCC3CC3)=CC=1)CC2.C(=O)=O.C[Li].C([Li])CCC.[CH2:36]([O:40][C:41]1[CH:61]=[CH:60][C:44]([C:45]([NH:47][C@H:48]2[CH2:57][CH2:56][C:55]3[C:50](=[CH:51][CH:52]=[C:53]([CH:58]=[O:59])[CH:54]=3)[CH2:49]2)=[O:46])=[CH:43][CH:42]=1)[CH2:37][CH2:38][CH3:39]>O.C(O)(=O)C.CN(C=O)C.C1COCC1>[CH:37]1([CH2:36][O:40][C:41]2[CH:42]=[CH:43][C:44]([C:45]([NH:47][C@H:48]3[CH2:57][CH2:56][C:55]4[C:50](=[CH:51][CH:52]=[C:53]([CH:58]=[O:59])[CH:54]=4)[CH2:49]3)=[O:46])=[CH:60][CH:61]=2)[CH2:39][CH2:38]1
Reactant: CCCCOc1ccc(C(=O)N[C@H]2CCc3cc(C=O)ccc3C2)cc1
Agent: O=C(N[C@H]1CCc2cc(Br)ccc2C1)c1ccc(OCC2CC2)cc1
Agent: O=C=O
Agent: [Li]C
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1)CC[C@H](NC(=O)c1ccc(OCC3CC3)cc1)C2
Temperature: 25 °C

Procedure:
A mixture of N—((S)-6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)-4-cyclopropylmethoxy-benzamide (5.20 g) and THF (120 ml) was cooled to −78° C. (dry ice bath), and a solution of methyllithium (8.9 ml; 1.6 M in diethyl ether) was added dropwise. One minute after the addition had ended, a solution of butyllithium (5.7 ml; 2.5 M in toluene) was added dropwise. One minute after the addition had ended, DMF (2.85 g) and, after a further 30 seconds, acetic acid (1.5 ml) were added. After warming to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phases were dried over magnesium sulfate and concentrated. The product was thus obtained with the molecular weight of 349.43 (C22H23NO3); MS (ESI): 350 (M+H+). 4-Butoxy-N—((S)-6-formyl-1,2,3,4-tetrahydronaphthalen-2-yl)benzamide can also be prepared analogously.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:7][CH2:8][CH2:9][NH2:10])[CH:4]=[CH:5][N:6]=1.[IH:11].CS[C:14]1[C:22]2[CH:23]=[CH:24][CH:25]=[C:20]3[C:21]=2[C:16](=[CH:17][CH:18]=[CH:19]3)[N:15]=1.C([O-])(=O)C.[Na+]>C(O)C>[IH:11].[CH3:1][C:2]1[N:3]([CH2:7][CH2:8][CH2:9][NH:10][C:14]2[C:22]3[CH:23]=[CH:24][CH:25]=[C:20]4[C:21]=3[C:16](=[CH:17][CH:18]=[CH:19]4)[N:15]=2)[CH:4]=[CH:5][N:6]=1
Reactant: CSC1=Nc2cccc3cccc1c23
Reactant: Cc1nccn1CCCN
Agent: CC(=O)[O-]
Agent: I
Agent: [Na+]
Solvent: CCO
Product: Cc1nccn1CCCNC1=Nc2cccc3cccc1c23
Yield: 15.8 %

Procedure:
A mixture of 2.1 g of 3-(2-methyl-1H-imidazol-1-yl)propanamine, 5.0 g of 2-(methylthio)benz[cd]indole hydroiodide, 1.4 g of sodium acetate and 250 ml of ethanol was reacted as described in Example 13, giving 1.0 g of the desired product, mp 153°-155° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.[CH3:13][NH:14][O:15][CH3:16].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([N:14]([O:15][CH3:16])[CH3:13])=[O:5]
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(C)nc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
A mixture of 2-chloro-6-methyl-nicotinic acid (2 g, 12 mmol), N,O-dimethylhydroxylamine hydrochloride (1.14 g, 12 mmol), EDCI (2.68 g, 14 mmol), HOBt (81 mg, 16 mmol) and DIPEA (1 mL) in DCM (100 mL) was stirred at RT overnight. The reaction mixture was then partitioned between water and DCM, the organic layer separated, dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure. The crude residue was purified by flash chromatography (EtOAc/hexane, gradient from 0 to 25% in 25 minutes) to afford 2.4 g of 2-chloro-N-methoxy-6,N-dimethyl-nicotinamide as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C:13](=[O:15])[CH3:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+].C(O)(=O)C>CO>[CH3:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH:13]([OH:15])[CH3:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1nnn(-c2cccc(C)c2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cccc(-n2nnc(C(C)O)n2)c1
Yield: 97.1 %

Procedure:
1-[2-(3-Methylphenyl)-2H-tetrazol-5-yl}ethanone (96.89 g, 479 mmol) in methanol (1000 mL) was cooled in an ice/water bath. Sodium borohydride (29 g, 767 mmol) was added over 1 hour 30 minutes. After stirring for 40 minutes aq. acetic acid (70%, 20 mL) was added and the mixture was concentrated. Dichloromethane (400 mL) was added to the residue and was extracted with saturated aqueous sodium hydrogen carbonate (500 mL). The aqueous layer was extracted with dichloromethane (170 mL), and the combined organic layer was washed with aqueous hydrochloric acid (0.5 M, 250 mL), followed by aqueous hydrogen carbonate (280 mL), then washed with brine (500 mL), dried over sodium sulfate, filtered and concentrated to give the title product (95 g, 97%).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:10](=O)[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:9])(C)(C)C>CC(O)=O.C1(C)C=CC=CC=1>[C:19]1([N:18]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[CH:8]([NH2:7])[CH3:9])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)Nc1ccccc1Nc1ccccc1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(N)c1nc2ccccc2n1-c1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 55.9 %

Procedure:
[1-(2-Phenylaminophenylcarbamoyl)ethyl]carbamic acid tertbutyl ester (400 mg, 1.59 mmol) was suspended in AcOH (4 mL) and the resulting mixture was heated at 80° C. for 12 h whereupon the mixture clarified. The cooled solution was diluted with toluene and volatiles removed under reduced pressure. The resulting residue was stirred with TFA (4 mL) for 2 h and the resulting solution was loaded onto an SCX-2 cartridge which was initially washed with MeOH. The product was eluted with 2M NH3/MeOH and further purified by column chromatography (Si—PCC, gradient 0-6% MeOH in DCM) affording 1-(1-phenyl-1H-benzo[d]imidazol-2-yl)ethanamine as a white crystalline solid (211 mg, 80%). LCMS: RT 0.27 min [M−NH2]+ 221.1. The enantiomers, (S)-1-(1-phenyl-1H-benzo[d]imidazol-2-yl)ethanamine and (R)-1-(1-phenyl-1H-benzo[d]imidazol-2-yl)ethanamine can be resolved and separated. Alternatively, (S)-1-(1-phenyl-1H-benzo[d]imidazol-2-yl)ethanamine can be prepared from enantiopure (S)-2-tertbutoxycarbonylaminopropionic acid.