Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=CC=CC=1C(Cl)=O.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[C:28]([F:33])[CH:27]=1.[F:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]([N:43]=[C:44]=[S:45])=[O:42]>C1(C)C=CC=CC=1.C(O)C>[F:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]([N:43]=[C:44]=[S:45])=[O:42].[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:44]([NH:43][C:41](=[O:42])[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[F:34])=[S:45])=[C:28]([F:33])[CH:27]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: O=C(Cl)c1ccccc1F
Agent: O=C(N=C=S)c1ccccc1F
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4F)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
2-Fluoro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2-fluoro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2-fluoro-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then 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 (63 mg, yield 80%).
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]([OH:18])=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.Cl.[NH2:26][CH:27]1[CH2:36][CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([Br:37])[CH:33]=2)[C:28]1=[O:38].C(N(C(C)C)CC)(C)C>ClCCl.N1C(F)=NC(F)=NC=1F>[Br:37][C:32]1[CH:33]=[C:34]2[C:29](=[CH:30][CH:31]=1)[C:28](=[O:38])[CH:27]([NH:26][C:16]([C:10]1[O:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:11]=1[C:12]([F:13])([F:14])[F:15])=[O:18])[CH2:36][CH2:35]2
Reactant: NC1CCc2cc(Br)ccc2C1=O
Reactant: O=C(O)c1onc(-c2ccccc2)c1C(F)(F)F
Agent: Cl
Agent: Fc1nc(F)nc(F)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(NC1CCc2cc(Br)ccc2C1=O)c1onc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h
Yield: 73.8 %

Procedure:
To 3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxylic acid (Intermediate I-3D, 0.465 g, 1.808 mmol) in dichloromethane (5 mL) was added pyridine (0.175 ml, 2.170 mmol) followed by cyanuric fluoride (0.188 ml, 2.172 μmol) at room temperature. The reaction mixture was stirred at room temperature for 20 h., and partitioned between dichloromethane (30 mL) and cold 0.5N HCl (15 mL). The dichloromethane layer was separated, dried over sodium sulfate, and concentrated to afford an orange-red solid. The solid was dissolved in dichloromethane (5 mL) and added dropwise over a period of 2 min. to 2-amino-6-bromo-3,4-dihydronaphthalen-1(2H)-one hydrochloride (Preparation 82B, 0.5 g, 1.808 mmol) in dichloromethane (5.00 mL) and diisopropylethylamine (0.789 ml, 4.52 mmol) at 0° C. The reaction mixture was allowed to come to room temperature over a period of 20 min., stirred at room temperature for 2 h., and partitioned between dichloromethane (30 mL) and cold 0.5N HCl (10 mL). The dichloromethane layer was separated, dried over sodium sulfate, and concentrated. The resulting solid was triturated with ether (15 mL), sonicated for 5 min. and filtered to yield N-(6-bromo-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxamide (0.640 g, 1.335 mmol, 73.9% yield) as a light tan solid. LC/MS M+1=480.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[N+:17]([O-:19])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=O.[BH4-].[Na+].O>C(O)(=O)C>[CH2:1]([S:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N+:17]([O-:19])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])/C=C/c1ccc(SCc2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])CCc1ccc(SCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
To a solution of 1-benzylsulfanyl-4-((E)-2-nitro-vinyl)-benzene (950 mg, 3.5 mmol) described in Manufacturing Example 205-1-3 in acetic acid (0.6 mL) and dimethyl sulfoxide (10 mL) was added sodium borohydride (212 mg, 5.6 mmol) while the internal temperature was held at 30° C. or lower, which was stirred for 30 minutes at room temperature. The mixture was cooled with ice water, water was added, which was stirred for another 30 minutes. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (936 mg). The title compound was used in the following reaction without any further purification.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([CH2:18][CH2:19][CH3:20])[CH:11]=[C:12]([C:13]([O:15]CC)=[O:14])[C:7]=2[CH:6]=[N:5]1)[CH3:3].[OH-].[Na+]>C(O)C.C1COCC1>[CH3:3][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([CH2:18][CH2:19][CH3:20])[CH:11]=[C:12]([C:13]([OH:15])=[O:14])[C:7]=2[CH:6]=[N:5]1)[CH3:1]
Reactant: CCCc1cc(C(=O)OCC)c2cnn(C(C)C)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCc1cc(C(=O)O)c2cnn(C(C)C)c2n1
Temperature: 40 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a solution of ethyl 1-(1-methylethyl)-6-propyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (180 mg, 0.654 mmol) in ethanol (5 mL) and THF (1 mL) was added sodium hydroxide (1.090 mL, 3.27 mmol), and the mixture was stirred at 40° C. for 1 h. The volatiles were removed under reduced pressure. The aqueous phase was acidified to pH 3 with aq. 1N HCl. The solid precipitate formed was collected by filtration and dried under high vacuum to give 144 mg (89%) of product, which was used for next reaction without further purification. LCMS E-S (M+H)=248.1 1H NMR (400 MHz, DMSO-d6) δ ppm 0.82-1.12 (m, 3 H), 1.50 (d, J=6.6 Hz, 6 H), 1.78 (m, 2 H), 2.80-3.11 (m, 2 H), 5.09-5.38 (m, 1 H), 7.47-7.72 (s, 1 H), 8.18-8.46 (s, 1 H), 13.82 (s, 1 H).
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:12]=[CH:11][C:10]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:9]=3[CH:8]([C:18]3[C:19](=[O:25])[NH:20][C:21](=[O:24])[NH:22][CH:23]=3)[C:6]=2[N:7]=1)[CH3:2].C[Si](N([Si](C)(C)C)C(=O)C(F)(F)F)(C)C.[CH2:41]([O:43][C:44]([C:46]1[O:47][C:48]([CH2:51]Br)=[CH:49][CH:50]=1)=[O:45])[CH3:42].CO>ClCCCl.C(#N)C>[CH2:1]([C:3]1[O:4][C:5]2[CH:12]=[CH:11][C:10]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:9]=3[CH:8]([C:18]3[C:19](=[O:25])[NH:20][C:21](=[O:24])[N:22]([CH2:51][C:48]4[O:47][C:46]([C:44]([O:43][CH2:41][CH3:42])=[O:45])=[CH:50][CH:49]=4)[CH:23]=3)[C:6]=2[N:7]=1)[CH3:2]
Reactant: CCc1nc2c(o1)C=Cc1cc(C)ccc1C2c1c[nH]c(=O)[nH]c1=O
Reactant: CCOC(=O)c1ccc(CBr)o1
Agent: C[Si](C)(C)N(C(=O)C(F)(F)F)[Si](C)(C)C
Solvent: CO
Solvent: ClCCCl
Solvent: CC#N
Product: CCOC(=O)c1ccc(Cn2cc(C3c4ccc(C)cc4C=Cc4oc(CC)nc43)c(=O)[nH]c2=O)o1
Temperature: 25 °C

Procedure:
To a slurry of the product of step (vii) (1.42 g) in dry 1,2-dichloroethane (15 ml) was added bis(trimethylsilyl)trifluoroacetamide (3.4 ml). The mixture was heated at reflux for 2 hours until the mixture became a homogeneous solution. The solution was allowed to cool to room temperature and a solution of 5-[bromomethyl]-2-furancarboxylic acid ethyl ester (J. Chem. Soc. Perkin Trans. 1, 1981, 1125, Bull. Chem. Soc. Jpn., 1987, 60, 1807) (1.1 g) in dry acetonitrile (15 ml) was added. The solution was then heated at reflux for 14 hours. The reaction mixture was allowed to cool and methanol (15 ml) was added. The solvents were evaporated under reduced pressure and the residue was triturated with diethyl ether. The resultant solid was collected by filtration and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic phase was dried (MgSO4) and the solvent was evaporated under reduced pressure. Purification was by chromatography eluting with ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](Cl)=[O:17]>C1COCC1>[CH3:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8])=[O:17]
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Reactant: Cc1cccc(C(=O)Cl)c1
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)Nc2ccc(Cl)c(C(=O)O)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
To a stirring solution of 5-amino-2-chlorobenzoic acid (880 mg, 5.1 mmol) in anhydrous THF (45 mL), 3-methylbenzoyl chloride (870 mg, 5.6 mmol) was added slowly. The mixture was stirred at room temperature under argon for overnight. The solvent was removed under reduced pressure and re-crystallized from chloroform to afford the title compound as a white solid (1.2 g, 80%).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]([CH2:18][Br:19])=[CH:14][C:9]=2[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[C:22]1([P:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[Br-:19].[CH3:13][O:12][C:10]([C:9]1[CH:14]=[C:15]([CH:16]=[CH:17][C:8]=1[CH2:7][CH2:6][C:5]1[CH:20]=[CH:21][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:18][P+:28]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:11]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)c1cc(CBr)ccc1CCc1ccc(F)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)ccc1CCc1ccc(F)cc1
Product: [Br-]
Yield: 96 %

Procedure:
A mixture of methyl 2-(4-fluorophenethyl)-5-bromomethylbenzoate (2.5 g; 7.1 mmol) and triphenylphosphine (2.1 g; 7.9 mmol) in toluene (50 ml) was heated at reflux for 3 hours. The solvent was evaporated and the residue was triturated in diethyl ether, filtered and washed three times with diethylether to give 3-methoxycarbonyl-4-[2-(4-fluorophenyl)ethyl]benzyl triphenylphosphonium bromide as a white solid. Yield=96%.
Reaction SMILES: O[C@@H:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@@H:3]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)[CH2:4][NH:5][CH3:6].Cl.C(N(S(F)(F)[F:30])CC)C.O>C(Cl)Cl>[F:30][C@H:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@@H:3]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)[CH2:4][NH:5][CH3:6]
Reactant: CCN(CC)S(F)(F)F
Reactant: CNC[C@H](c1ccc2ccccc2c1)[C@@H](O)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CNC[C@H](c1ccc2ccccc2c1)[C@H](F)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of the (2S,3R)-3-hydroxy-N-methyl-2-(naphthalen-2-yl)-3-phenylpropan-1-amine.HCl (48.6 mg, 0.167 mmol) in 2 mL of DCM was added neat diethylaminosulfur trifluoride (0.073 mL, 0.67 mmol). The reaction mixture was stirred for 1 h at room temperature. Water (10 mL) was added very cautiously (exothermic reaction), and the aqueous reaction mixture was filtered through 0.45μ Teflon filters. The pure product was isolated by reverse phase HPLC (Vydac 2.2×25 cm, C-8, elution with a gradient of 10% B-100% B in 90 min, B=80% aq. CH3CN with 0.1% TFA, A=H2O with 0.1% TFA); FR=8 mL/min; λmax=254 nm; RT==48.5 min). Evaporation of the solvent from product containing HPLC fractions furnished the product as a gummy residue that turned into a white solid after conversion to a hydrochloride salt and drying under high vacuum. Yield 8.9 mg, 18.2%. MCJ001-F-SS: 1H NMR (CD3OD) δ 7.87-7.72 (m, 4H), 7.67 (s, 1H), 7.52-7.43 (m, 3H), 7.32-7.13 (m, 4H), 5.81 (dd, J=46.5, 8.5 Hz, 1H), 3.91-3.65 (m, 4H), 2.72 (s, 3H); MS (ESI): m/z 294.12 (M+1); [α]D20 c 0.03, 9:1 EtOH:H2O). MCJ001-C1-SS: 1H NMR (CD3OD) δ 7.85-7.69 (m, 4H), 7.66 (s, 1H), 7.49-7.41 (m, 3H), 7.33-7.04 (m, 4H), 5.38 (d, J=9.4 Hz, 1H), 4.07-3.-3.07 (m, 4H), 2.69 (s, 3H); MS: m/z 310.30 (M+1)+; [α]D20 c, +9.5 (c 0.335, 9:1 EtOH:H2O)
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:5]2[CH:10]=[C:9]([C:11](O)=[O:12])[NH:8][C:7](=[O:14])[C:6]=12.C(N1C=CN=C1)(N1C=CN=C1)=O.O/[N:41]=[C:42](\[NH2:49])/[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[Ca+2].[Ca+2].[Ca+2]>CN(C)C=O>[CH3:1][C:2]1[NH:3][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:5]2[CH:10]=[C:9]([C:11]3[O:12][N:49]=[C:42]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[N:41]=3)[NH:8][C:7](=[O:14])[C:6]=12
Reactant: N/C(=N\O)c1ccccc1
Reactant: Cc1[nH]c(-c2ccccc2Oc2ccccc2)c2cc(C(=O)O)[nH]c(=O)c12
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=P([O-])([O-])[O-]
Agent: [Ca+2]
Solvent: CN(C)C=O
Product: Cc1[nH]c(-c2ccccc2Oc2ccccc2)c2cc(-c3nc(-c4ccccc4)no3)[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.2 %

Procedure:
A solution of Example 12b (500 μL, 0.005 g, 0.0139 mmol) in N,N-dimethylformamide and a solution of 1,1′-carbonyldiimidazole (500 μL, 0.0113 g, 0.069 mmol) in N,N-dimethylformamide were combined and shaken for 1 hour at ambient temperature. A solution of (Z)—N′-hydroxybenzimidamide (69.4 μL, 0.042 mmol) in N,N-dimethylformamide was added and the resulting mixture was reacted in an Anton Paar Synthos 3000 microwave optimizer at 180° C. for 45 minutes. Upon completion, the crude material was concentrated to dryness and purified by reverse phase HPLC (C8, acetonitrile/water (0.1% ammonium acetate), 25-55%) to yield 0.0027 g (37%) of the title compound as the acetic acid salt. 1H NMR (400 MHz, DMSO-d6/D2O) δ 12.39 (s, 1 H), 10.30 (s, 1 H), 8.09 (m, 2 H), 7.61 (m, 4 H), 7.54 (m, 1 H), 7.41 (m, 1 H), 7.33 (m, 3 H), 7.07 (m, 2 H), 6.95 (d, J=7.93 Hz, 2 H), 2.65 (s, 3 H). MS (ESI+) m/z 461.1 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Cl-].C[CH:12]=[N+:13]=[CH:14]C.Cl[CH2:17]Cl>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:12][N:13]([CH3:14])[CH3:17])=[CH:2]1
Reactant: ClCCl
Reactant: c1ccc2[nH]ccc2c1
Reactant: CC=[N+]=CC
Agent: [Cl-]
Product: CN(C)Cc1c[nH]c2ccccc12

Procedure:
Dissolve the indole (3.54 mmol) and N,N,-dimethylmethyleneammonium chloride (0.372 g, 4.00 mmol) in dichloromethane (15 mL), stir the mixture is at room temperature for 24˜72 h. under nitrogen. Wash with water (5 mL), follow by addition of base to neutralize the acid (3.6 mL, 1M NaOH). Extract with ethyl acetate (2×100 mL), wash with saturated NaCl, then dry over anhydrous magnesium sulfate. Remove the solvent in vacuo to give (1H-Indol-3-ylmethyl)-dimethyl-amine.
Reaction SMILES: [ClH:1].[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].[C:21]([NH:23][C:24]([NH2:26])=[NH:25])#[N:22].[CH3:27][C:28]([CH3:30])=O>>[ClH:1].[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][C:14]1[CH:15]=[C:16]([N:17]2[C:28]([CH3:30])([CH3:27])[N:25]=[C:24]([NH2:26])[N:23]=[C:21]2[NH2:22])[CH:18]=[CH:19][CH:20]=1
Reactant: N#CNC(=N)N
Reactant: Nc1cccc(COc2ccc3ccccc3c2)c1
Reactant: CC(C)=O
Agent: Cl
Product: CC1(C)N=C(N)N=C(N)N1c1cccc(COc2ccc3ccccc3c2)c1

Procedure:
This compound was prepared in a manner analogous to that of Step C of Example 3, using 0.42 gram (0.005 mole) of 3-(naphth-2-yloxymethyl)aniline hydrochloride and 0.33 gram (0.005 mole) of cyanoguanidine in 100 mL of acetone. The solid product was recrystallized from water, yielding 1.54 grams of 1-[3-(naphth-2-yloxymethyl)phenyl]-2,4-diamino-6,6-dimethyl-1,6-dihydro-1,3,5-triazine hydrochloride, mp 172°-174° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C([Cl:4])(=O)C.[N:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][C:13]3([CH2:20][CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]3)[CH2:12]2)=[CH:7][CH:6]=1>C(O)C>[ClH:4].[ClH:4].[ClH:4].[N:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:15][CH2:14][C:13]3([CH2:20][CH2:19][CH2:18][NH:17][CH2:16]3)[CH2:12]2)=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCCC2(CCN(c3ccncc3)C2)C1
Reactant: CC(=O)Cl
Solvent: CCO
Product: Cl
Product: c1cc(N2CCC3(CCCNC3)C2)ccn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The synthesis was carried out analogously to the synthesis of amine AMN-07. For this, in step (i) tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate was reacted with 4-chloropyridinium chloride (yield: 41%). The Boc protective group was then split off. In step (ii), ethanol (6 ml) and acetyl chloride (0.27 ml, 3.94 mmol) were added to tert-butyl 2-(pyridin-4-yl)-2,7-diazaspiro[4.5]decane-7-carboxylate (0.25 g, 0.788 mmol) and the mixture was stirred at room temperature for 12 h. When the reaction was complete, the solvent was removed in vacuo. Yield: 0.23 g (89%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[C:11](=[S:13])=[S:12].I[CH3:15]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][C:11](=[S:13])[S:12][CH3:15])=[CH:5][CH:4]=1
Reactant: COc1ccc(CN)cc1
Reactant: S=C=S
Reactant: CI
Product: COc1ccc(CNC(=S)SC)cc1

Procedure:
4-Methoxybenzylamine (0.073 mol) was reacted with carbon disulfide (0.073 mol) and iodomethane (0.073 mol) substantially as described in Example 1B above to obtain 7.2 g (43%) as a crystalline solid: mp 67°-70°.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N:7]1([CH2:13][CH2:14][CH2:15][NH2:16])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.Cl[C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[C:20]([Cl:27])[N:19]=1>C1(C)C=CC=CC=1>[Cl:27][C:20]1[N:19]=[C:18]([NH:16][CH2:15][CH2:14][CH2:13][N:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: NCCCN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(Cl)nc1NCCCN1CCCCC1
Temperature: 20 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
Potassium carbonate (540 mg, 1.5 eq) and 3-piperidino-propylamine (420 mg, 1 eq) are added successively to 2,6-dichloro-3-nitropyridine (500 mg, 1 eq) in solution in toluene (10 ml). After stirring for 2 hours at a temperature of approximately 20° C., the mixture is concentrated under reduced pressure at 40° C. then water (20 ml) and dichloromethane (70 ml) are added. After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 then concentrated under reduced pressure at 40° C. Purification of the solid obtained, by flash chromatography on silica gel (eluent: heptane/ethyl acetate 3:7 to 100% ethyl acetate), produces the expected compound in the form of a yellow solid (473 mg; 61% yield).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[C:4]([CH3:12])[C:3]=1[N+:13]([O-:15])=[O:14].[CH2:16]([NH:19][CH2:20][CH2:21][CH3:22])[CH2:17][CH3:18]>C1C=CC=CC=1>[CH3:12][C:4]1[C:3]([N+:13]([O-:15])=[O:14])=[C:2]([C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]=1[CH3:11])[N:19]([CH2:20][CH2:21][CH3:22])[CH2:16][CH2:17][CH3:18]
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1C
Reactant: CCCNCCC
Solvent: c1ccccc1
Product: CCCN(CCC)c1c([N+](=O)[O-])cc(C)c(C)c1[N+](=O)[O-]

Procedure:
Five grams of 1-chloro-3,4-dimethyl-2,6-dinitrobenzene and 5.05 grams of di-n-propylamine are dissolved in benzene and the mixture is refluxed. The benzene is then removed from the mixture by boiling and toluene is added to the remaining residue. The thus-formed mixture is then refluxed, filtered, and the filtrate stripped in vacuo. The residue is treated with hexane and the mixture chilled in dry ice and acetone. The solid from the mixture is collected and dried, it has a melting point of 42° C. to 43.5° C. and is the desired product.
Reaction SMILES: [CH2:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11](Cl)=[O:12])[C:5]=2[CH2:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:16]=[C:17]([C@@H:22]([CH2:26][N:27]2[CH:31]=[CH:30][N:29]=[CH:28]2)[CH2:23][CH2:24][OH:25])[CH:18]=[CH:19][C:20]=1[Cl:21].C(N([CH2:37][CH3:38])CC)C>C(#N)C>[CH2:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([O:25][CH2:24][CH2:23][C@@H:22]([C:17]3[CH:18]=[CH:19][C:20]([Cl:21])=[C:15]([Cl:14])[CH:16]=3)[CH2:26][N:27]3[CH:31]=[CH:30][N:29]=[C:28]3[C:11]([C:6]3[C:5]4[CH2:4][CH2:3][CH2:2][CH2:1][C:10]=4[CH:9]=[CH:37][CH:38]=3)=[O:12])=[O:12])[C:5]=2[CH2:4][CH2:3][CH2:2]1
Reactant: OCC[C@H](Cn1ccnc1)c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)c1cccc2c1CCCC2
Reactant: CCN(CC)CC
Solvent: CC#N
Product: O=C(OCC[C@H](Cn1ccnc1C(=O)c1cccc2c1CCCC2)c1ccc(Cl)c(Cl)c1)c1cccc2c1CCCC2
Temperature: 25 °C
Reaction time: 96 h
Yield: 72.7 %

Procedure:
1,2,3,4-Tetrahydro-5-naphthoyl chloride (1.70 g) (see Preparation 36) was added dropwise to a suspension of 3(S)-(3,4-dichlorophenyl)-4-(imidazol-1-yl)butan-1-ol (0.90 g) (see Preparation 99) and triethylamine (1.45 g) in anhydrous acetonitrile (15 ml) and the solution stirred at room temperature for 4 days. The solvent was then removed under reduced pressure to give a residue which was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The phases were separated and the aqueous phase further extracted with ethyl acetate. The organic phases were combined, washed sequentially with water and brine, dried over anhydrous sodium sulphate and the solvent removed under reduced pressure to give a residue which was chromatographed on silica gel eluting with a solvent gradient of 2:1 changing to 0:1, by volume, pentane:ethyl acetate to give 3(S)-(3,4-dichlorophenyl)-4-[2-(1,2,3,4-tetrahydro-5-naphthoyl)imidazol-1-yl]butyl 1,2,3,4-tetrahydro-5-naphthoate (1.38 g) as a gum.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20]([C:22]5([CH2:48][O:49][CH3:50])[CH2:26][CH2:25][N:24]([C:27](=[O:47])[CH2:28][N:29]6[CH2:34][CH:33]=[C:32]([C:35]7[CH:40]=[CH:39][C:38]([C:41]8[N:46]=[CH:45][CH:44]=[CH:43][N:42]=8)=[CH:37][CH:36]=7)[CH2:31][CH2:30]6)[CH2:23]5)=[O:21])[CH:17]=4)[N:12](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:11]=3)[CH:7]=[CH:6][N:5]=2)[CH2:3][CH2:2]1.ClCCl.O>FC(F)(F)C(O)=O>[CH:1]1([C:4]2[CH:9]=[C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20]([C:22]5([CH2:48][O:49][CH3:50])[CH2:26][CH2:25][N:24]([C:27](=[O:47])[CH2:28][N:29]6[CH2:30][CH:31]=[C:32]([C:35]7[CH:36]=[CH:37][C:38]([C:41]8[N:42]=[CH:43][CH:44]=[CH:45][N:46]=8)=[CH:39][CH:40]=7)[CH2:33][CH2:34]6)[CH2:23]5)=[O:21])[CH:17]=4)[NH:12][N:11]=3)[CH:7]=[CH:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: COCC1(C(=O)Nc2ccc3c(c2)c(-c2ccnc(C4CC4)c2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)CCN(C(=O)CN2CC=C(c3ccc(-c4ncccn4)cc3)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: COCC1(C(=O)Nc2ccc3[nH]nc(-c4ccnc(C5CC5)c4)c3c2)CCN(C(=O)CN2CC=C(c3ccc(-c4ncccn4)cc3)CC2)C1
Yield: 105.4 %

Procedure:
3-Methoxymethyl-1-{2-[4-(4-pyrimidin-2-yl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-acetyl}-pyrrolidine-3-carboxylic acid [3-(2-cyclopropyl-pyridin-4-yl)-1-trityl-1H-indazol-5-yl]-amide (570 mg, 0.63 mmol) was dissolved in 4 ml of trifluoroacetic acid (TFA), 10 ml dichloromethane and 2 ml of water and the reaction mixture was stirred for 18 hrs. The reaction mixture was evaporated and chromatographed on silica gel using 3-5% 2N NH3/methanol/dichlormethane to obtain 444 mg of title product. MS (M+1)=669. Retention time (minutes) 2.67.