Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:16][N:17]=1)(=[O:12])=[O:11])[CH3:2].[N:25]1([CH2:34][C:35](O)=[O:36])[CH:33]=[C:31]([CH3:32])[C:29](=[O:30])[NH:28][C:26]1=[O:27]>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:16][N:17]=1)(=[O:12])=[O:11])[C:35](=[O:36])[CH2:34][N:25]1[CH:33]=[C:31]([CH3:32])[C:29](=[O:30])[NH:28][C:26]1=[O:27])[CH3:2]
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nnc(-c2ccccc2)s1
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nnc(-c2ccccc2)s1)C(=O)Cn1cc(C)c(=O)[nH]c1=O

Procedure:
The title compound was synthesized by the reaction of N-[2-(5-phenyl-1,3,4-thiadiazole-2-sulfonylamino)-ethyl]-glycine ethyl ester with (thymin-1-yl)-acetic acid as per the procedure of example 13. 1H NMR (500 MHz; DMSO-d6) δ 11.28 (s, 0.6H), 11.26 (s, 0.4H), 9.08 (brs, 1H), 8.05 (d, 2H), 7.66–7.57 (m, 3H), 7.32 (s, 0.6H), 7.24 (s, 0.4H), 4.65 (s, 1.2H), 4.47 (s, 0.8H), 4.32 (s, 0.8H), 4.16 (q, 0.8H), 4.06 (q, 1.2H), 4.04 (s, 1.2H), 3.56 (t, 1.2H), 3.43–3.38 (m, 2H), 3.24 (t, 0.8H), 1.73 (s, 3H), 1.21 (t, 1.2H), 1.16 (t, 1.8H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.Cl.[CH3:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[NH:40]N>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:40][C:35]3[C:36]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:37][CH:38]=[CH:39][C:34]=3[CH3:33])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1NN
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(Br)cc3)CC2)c1
Agent: Cl
Product: Cc1cccc2c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c(-c3ccc(Br)cc3)[nH]c12

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(4-bromophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-(2-methylphenyl)hydrazine hydrochloride: ESMS m/e: 572 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[CH2:24]O>>[CH3:15][O:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[CH2:24][O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: COc1cc(C)ccc1CO
Product: COc1cc(C)ccc1COc1ccnn1-c1cc(C#N)ccn1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (2-methoxy-4-methylphenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 3.37 (3H, s), 3.89 (3H, s), 5.23 (2H, s), 5.80 (1H, d, J=2.0 Hz), 6.76-6.79 (2H, m), 7.24-7.26 (1H, m), 7.37 (1H, dd, J=1.2 Hz, 4.8 Hz), 7.58 (1H, d, J=1.6 Hz), 8.08 (1H, s), 8.70 (1H, d, J=4.4 Hz). [M+H] Calc'd for C18H16N4O2, 321; Found, 321.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[CH2:13][N:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[N:15]1.C(N(C(C)C)CC)(C)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[CH3:32][S:33]([O:1][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[CH2:13][N:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[N:15]1)(=[O:35])=[O:34]
Reactant: OCCn1c(Cn2nnc3ccccc32)nc2ccccc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCCn1c(Cn2nnc3ccccc32)nc2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.3 %

Procedure:
1-[1-(2-Hydroxylethyl)-1-H-benzimidazol-2-ylmethyl)-1H-benzotriazole (300 mg, 1.02 mmol) was suspended in anhydrous methylene chloride and cooled to 0° C. with an ice bath. Diisopropylethylamine (0.36 ml, 2.05 mmol) and methanesulfonyl chloride (0.16 mL, 2.05 mmol) were slowly added. The reaction was stirred at 0° C. for 1 hour during which the solution became clear. The solvent was stripped under vacuum, and the residue was purified by flash chromatography (EtOAc) to give 221 mg (58%) of the title compound as a white solid.
Reaction SMILES: C(Cl)(=O)C.C1([C@H](OC(=O)[NH:15][C@@H:16]2[C@@H:25]([O:26][CH3:27])[CH2:24][C:23]3[C:18](=[CH:19][C:20]([C:28](=[O:30])[NH2:29])=[CH:21][CH:22]=3)[C:17]2([CH2:33][CH3:34])[CH2:31][CH3:32])C)C=CC=CC=1>C(O)C>[NH2:15][C@H:16]1[C:17]([CH2:31][CH3:32])([CH2:33][CH3:34])[C:18]2[CH:19]=[C:20]([C:28]([NH2:29])=[O:30])[CH:21]=[CH:22][C:23]=2[CH2:24][C@@H:25]1[O:26][CH3:27]
Reactant: CCC1(CC)c2cc(C(N)=O)ccc2C[C@H](OC)[C@H]1NC(=O)O[C@H](C)c1ccccc1
Solvent: CCO
Solvent: CC(=O)Cl
Product: CCC1(CC)c2cc(C(N)=O)ccc2C[C@H](OC)[C@H]1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
Acetyl chloride (193 mL, 2710 mmol) was added dropwise to ethanol (260 mL, 4500 mmol) at −5° C. over 40 min keeping the internal temperature below 30° C. The resulting solution was added over 5 min, at 10° C., to a mixture of ((2S,3S)-7-carbamoyl-1,1-diethyl-3-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamic acid (R)-1-phenyl-ethyl ester (49.0 g, 115 mmol) and ethanol (200 mL). The reaction mixture was stirred at room temperature overnight, and concentrated to ˜100 mL by rotary evaporation. Ethyl acetate (100 mL) was added and the resulting slurry was stirred at 0° C. for 30 min and filtered. The filter cake was washed with ethyl acetate and dried to yield the hydrochloride salt of the title compound (30 g, >99% purity). The volume of the filtrate was reduced almost to dryness. Isopropyl alcohol (20 mL) was added and the resulting thick slurry was stirred for 30 min and filtered. The filter cake was washed with ethyl acetate (2×20 mL) and dried under vacuum overnight to yield additional title compound (5.5 g, >97% purity). 1H NMR (DMSO-d6): δ (ppm) 0.49 (t, 3H), 0.63 (t, 3H), 1.62 (q, 2H), 1.89 (m, 1H), 2.09 (m, 1H), 2.60 (dd, 1H), 3.22 (m, 1H), 3.41 (s, 3H), 3.50 (dd, 1H), 3.82 (q, 1H), 7.19 (d, 1H), 7.31 (br, 1H), 7.70 (d, 1H), 7.71 (s, 1H), 7.98 (br, 1H), 8.15 (br, 3H).
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[N:13]([CH2:30][C:31]([F:34])([F:33])[F:32])C(=O)C1C=C(C(F)(F)F)N=C(C(F)(F)F)C=1.[F:36]C1C=CC=CC=1B(O)O>CCCCCCC.CCOC(C)=O>[F:36][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[NH:13][CH2:30][C:31]([F:34])([F:33])[F:32]
Reactant: OB(O)c1ccccc1F
Reactant: Cc1ccccc1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Fc1ccccc1-c1ccncc1NCC(F)(F)F

Procedure:
The title compound was prepared from (4-iodo-pyridin-3-yl)-(2,2,2-trifluoro-ethyl)-amine (example 150, intermediate b) and 2-fluorophenylboronic acid (CAS RN 1193-03-9) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Light brown solid (85%). MS (ESI): m/z=271.09 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([C:18]([F:21])([F:20])[F:19])[O:10][N:9]=2)=[CH:4][CH:3]=1.Cl[C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][N:24]=1>>[CH3:30][O:29][C:27](=[O:28])[C:26]1[CH:31]=[CH:32][C:23]([N:16]2[CH:17]=[C:13]([C:12]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[N:9][O:10][C:11]=3[C:18]([F:21])([F:19])[F:20])[N:14]=[CH:15]2)=[N:24][CH:25]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: Fc1ccc(-c2noc(C(F)(F)F)c2-c2c[nH]cn2)cc1
Product: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3C(F)(F)F)c2)nc1
Yield: 71 %

Procedure:
As described for Example 4, 3-(4-fluoro-phenyl)-4-(1H-imidazol-4-yl)-5-trifluoromethyl-isoxazole (700 mg, 2.4 mmol) instead of 4-(1H-imidazol-4-yl)-3-phenyl-5-trifluoromethyl-isoxazole was converted, using methyl 6-chloronicotinate instead of 4-fluorobenzotrifluoride, to the title compound (720 mg, 71%) which was obtained as a white solid. MS: m/e=433.1 [M+H]+.
Reaction SMILES: [BH4-].[Na+].Cl.[CH2:4]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](OCC)=[O:18])[C:13](=[O:22])[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O>CO>[CH2:4]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][OH:18])[CH:13]([OH:22])[CH2:12]1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCC1CCN(Cc2ccccc2)CC1O
Reaction time: 0.25 h

Procedure:
Sodium borohydride (40 g) was added in portions to a stirred solution of ethyl N-benzyl-3-oxopiperidine-4-carboxylate hydrochloride in methanol (500 mL), over 2 h. Water (300 mL) was added slowly, the mixture stirred for 15 min, and then the organics were evaporated. The resulting residue was partitioned between DCM and water (×3), the combined organic layers dried over anhydrous sodium sulfate, and the solvent evaporated to give the product as a cis trans mixture, used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:9]=[C:10](CC#N)[CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1.O.S(=O)(=O)(O)O.[C:25]([OH:28])(=[O:27])[CH3:26]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[C:12]([CH2:26][C:25]([OH:28])=[O:27])[CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:17][CH:18]=1
Reactant: N#CCc1cccc(C(=O)c2ccc(Cl)cc2)c1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)Cc1cccc(C(=O)c2ccc(Cl)cc2)c1
Reaction time: 2 h

Procedure:
A mixture of 9.61 g of 3-p-chlorobenzoyl phenyl acetonitrile, 75 cc of water, 75 cc of acetic acid and 75 cc of sulfuric acid was refluxed with stirring for 21/2 hours and then cooled and iced for 1 hour. The mixture was vacuum filtered and the precipitate was empasted with water and taken up in 50 cc of a 10% aqueous sodium carbonate solution. The solution was filtered and the filter was washed with water. The pH of the filtrate was adjusted to 5-6 by addition of acetic acid and after being iced for 30 minutes, the mixture was vacuum filtered. The recovered precipitate was washed with water and dried under reduced pressure. The residue was dissolved in 50 cc of refluxing toluene and the solution was treated with activated carbon and filtered. The filter was washed with boiling toluene. The filtrate was cooled and iced for 1 hour and then vacuum filtered. The recovered precipitate was empasted with iced toluene and dried under reduced pressure to obtain 8.37 g of 3-p-chlorobenzoyl phenyl-acetic acid melting at 148° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18](=O)[CH2:19][C:20]#[N:21])=[CH:13][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.NC1C=C[NH:26][N:25]=1.NN>CCO>[N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]3[CH:19]=[C:20]([NH2:21])[NH:25][N:26]=3)=[CH:13][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: Nc1cc[nH]n1
Reactant: N#CCC(=O)Cc1ccc(OCCCN2CCOCC2)cc1
Agent: NN
Solvent: CCO
Product: Nc1cc(Cc2ccc(OCCCN3CCOCC3)cc2)n[nH]1
Temperature: 65 °C

Procedure:
The 4-[4-(3-morpholin-4-yl-propoxy)-phenyl]-3-oxo-butyronitrile is then converted to the appropriate aminopyrazole by the following method: Under Ar(g), 0.095 gms. of the 4-[4-(3-morpholin-4-yl-propoxy)-phenyl]-3-oxo-butyronitrile is dissolved in 2 mL of anhydrous EtOH and then is treated with 0.100 gms. anhydrous hydrazine. The reaction mixture is then heated overnight at 65° C., subsequently, cooled to room temperature and concentrated in vacuo providing 5-[4-(3-morpholin-4-yl-propoxy)-benzyl]-2H-pyrazol-3-ylamine which is use in crude form in the reaction of Example 58.
Reaction SMILES: S([N:11]=[N+:12]=[N-])(C1C=CC(C)=CC=1)(=O)=O.[C:14]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:15][C:16]([CH3:18])=[O:17]>C(Cl)Cl>[N+:11](=[C:15]([C:16](=[O:17])[CH3:18])[C:14]([O:20][CH2:21][CH3:22])=[O:19])=[N-:12]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CCOC(=O)CC(C)=O
Solvent: ClCCl
Product: CCOC(=O)C(=[N+]=[N-])C(C)=O
Temperature: 25 °C
Yield: 91.5 %

Procedure:
Polymer-bound tosylazide (11 g, 15.4 mmol) (typical loading 1.4 mmol/g, prepared according to Merz et al J. Org. Chem. 2001, 66, 2509-2511) was swollen in dry DCM (40 mL). Ethyl acetoacetate (1.0 g, 7.7 mmol, CAS 141-97-9) and TEA (3.2 mL, 23.1 mmol) were dissolved in DCM (10 mL) and added to the polymer containing solution. The resulting mixture was then shaken at RT under nitrogen until the reaction was judged completed by TLC, typically 6 h. The supernatant was filtered off, then the resin was washed with DCM (3×30 mL) to rinse out residual product. The reaction mixture was then evaporated to dryness to afford the title compound (1.1 g, 92%) as yellow oil.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].N1C=CC=CC=1.[CH2:11]([C:13]([C:20]([F:23])([F:22])[F:21])([C:17](F)=[O:18])[C:14](F)=[O:15])[CH3:12]>C(COC)OC>[CH2:11]([C:13]1([C:20]([F:21])([F:22])[F:23])[C:14](=[O:15])[NH:4][C:2](=[O:3])[NH:1][C:17]1=[O:18])[CH3:12]
Reactant: NC(N)=O
Reactant: CCC(C(=O)F)(C(=O)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: COCCOC
Product: CCC1(C(F)(F)F)C(=O)NC(=O)NC1=O
Reaction time: 8 h
Yield: 60.5 %

Procedure:
A mixture of 1.70 g (0.028 mol) of urea, 4.4 g (0.056 mol) of pyridine and 30 ml of glyme was stirred at 25°C while a solution of 5.7 g (0.028 mol) of ethyltrifluoromethylmalonyl fluoride in 20 ml of glyme was added rapidly. The mixture was stirred overnight, solvent was removed under vacuum, and the residue was stirred with 15 ml of water. Filtration provided a solid which was recrystallized from water to give 3.8 g of 5-ethyl-5-trifluoromethylbarbituric acid, mp 210°-211°C. A second crop, 0.2 g, mp 208°-209°C, raised the total to 4.0 g (64%). A sample was recrystallized twice from water for analysis, mp 211°C; ir (KBr): 3.05 and 3.18 (NH), 3.49 (satd. CH), 5.72 and 5.82 (C=O), and 8-8.5 μ (CF); nmr ((CD3)2CO): 1H at ca. 8.5 (very broad (partly exchanged into acetone-d6), 2, NH), 2.37 (quartet with fine structure, JHH = 7.5 Hz, 2, CH2); and 0.94 ppm (triplet, JHH = 7.5 Hz, 3, CH3); 19F at -69.3 ppm (singlet with fine structure, CF3).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[C:19](=[O:31])[N:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:21]([CH3:24])[C:22]=3[CH3:23])=[O:17])=[C:11]([Cl:32])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[C:40](OC(=O)C)(=[O:42])[CH3:41]>>[C:40]([NH:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[C:19](=[O:31])[N:20]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:21]([CH3:24])[C:22]=3[CH3:23])=[O:17])=[C:11]([Cl:32])[CH:10]=2)[CH:5]=[CH:4][N:3]=1)(=[O:42])[CH3:41]
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3)cc2Cl)c(=O)n(-c2ccccc2)n1C
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc(Oc2ccc(NC(=O)c3c(C)n(C)n(-c4ccccc4)c3=O)c(Cl)c2)ccn1
Temperature: 35 °C
Reaction time: 13 h
Yield: 63 %

Procedure:
To a suspension of N-(4-((2-aminopyridin-4-yl)oxy)-2-chlorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (125 mg, 0.28 mmol) in acetic anhydride (6.0 mL) was added triethylamine (0.4 mL). The reaction mixture was stirred at 35° C. for 13 hours, then filtered, and the filter cake was washed with petroleum ether (6 mL), MeOH (3 mL), and ethyl acetate (6 mL) respectively to give the title compound as a light blue solid (87 mg, 63%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:14])[CH:12]=2)[N:7]([CH2:15][CH2:16][C:17]2[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=2)[CH:6]=1.[C:24](O)(C(F)(F)F)=O.C=O>C(#N)C>[CH3:1][N:2]1[CH2:3][CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([CH3:14])[CH:12]=3)[N:7]([CH2:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)[C:6]=2[CH2:24]1
Reactant: O=C(O)C(F)(F)F
Reactant: CNCCc1cn(CCc2ccc(C)nc2)c2ccc(C)cc12
Agent: C=O
Solvent: CC#N
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CN(C)CC1
Temperature: 25 °C

Procedure:
N-methyl-2-(5-methyl-1-(2-(6-methylpyridin-3-yl)ethyl)-1H-indol-3-yl)ethanamine (150 mg) was dissolved in acetonitrile (4 mL) containing 5% TFA and the reaction mixture was refluxed. 37% aqueous formaldehyde (0.04 mL) was added and the reaction mixture was refluxed for additional 1.5 h, cooled to 25° C., concentrated under reduced pressure and partitioned between ethyl acetate and saturated aqueous NaHCO3. The organic layer was dried over sodium sulfate, evaporated under reduced pressure and the residue was purified by silica gel chromatography (eluent Methanol: aqueous NH3, 95:5) to obtain 2,3,4,9-tetrahydro-2,6-dimethyl-9-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[3,4-b]indole. The free base was converted into its dihydrochloride salt by treatment of dioxane-HCl. 1H NMR (DMSO): 11.7 (bs, 1H), 8.6 (s, 1H), 8.3 (d, 1H), 7.7 (d, 1H), 7.3 (d, 1H), 7.25 (s, 1H), 6.9 (d, 1H), 4.8 (m, 1H), 4.4 (m, 1H), 4.35 (t, 2H), 3.7 (bs, 1H), 3.55 (s, 3H), 3.5 (m, 1H), 3.4 (bs, 1H), 3.1 (t, 2H), 3.05 (bs, 1H), 2.65 (s, 3H), 2.35 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([CH3:11])=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:12][C:13]1[CH:14]=[C:15]([NH:20][C:21]([NH:23][C:24](=[O:33])[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[S:22])[CH:16]=[CH:17][C:18]=1[OH:19]>>[F:12][C:13]1[CH:14]=[C:15]([NH:20][C:21]([NH:23][C:24](=[O:33])[CH2:25][C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)=[S:22])[CH:16]=[CH:17][C:18]=1[O:19][C:2]1[CH:3]2[C:10]([CH3:11])=[CH:9][S:8][CH:4]2[N:5]=[CH:6][N:7]=1
Reactant: Cc1csc2ncnc(Cl)c12
Reactant: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(O)c(F)c1
Product: CC1=CSC2N=CN=C(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)C12

Procedure:
In a similar manner as described for the preparation of Example 10, the title compound was prepared from commercially available 4-chloro-5-methylthieno[2,3-d]pyrimidine and 1-(3-fluoro-4-hydroxyphenyl)-3-(2-(4-fluorophenyl)acetyl)thiourea (24 mg, 0.075 mmol, Compound A of Example 3). 1H NMR (CDCl3) δ 12.42 (s, 1H), 8.67 (s, 1H), 8.53 (s, 1H), 7.88 (dd, 1H, J=13.8, 2.2 Hz), 7.43 (s, 1H), 7.32 (m, 3 H), 7.09 (m, 3H), 3.72 (S, 2H), 2.67 (s, 3H); MS(ESI+) m/z 471 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[C:12]2[CH:11]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:9]=[CH:8][C:7]=2[CH2:6][CH2:5][CH:4]=1)#[N:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[C:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:9]=[CH:8]2)#[N:2]
Reactant: COC(=O)c1ccc2c(c1)C(C#N)=CCC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2cccc(C#N)c2c1
Temperature: 0 °C
Yield: 72.3 %

Procedure:
Part A--A solution of methyl 8-cyano-5,6-dihydro-2-naphthoate (1.0 g, 0.0047 mol) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (1.07 g, 0.0047 mol) in dioxane (50 mL) was stirred at 120° C. over 16 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. The residue was purified by flash chromatography using ethyl acetate to give methyl 8-cyano-2-naphthoate (0.72 g, 0.0034 mol, 73%) as a tan solid. mp=178°-182° C.; 1H NMR (CDCl3) d 8.95 (s, 1H), 8.3-8.2 (m, 1H), 8.15-8.10 (m, 1H), 8.0-7.95 (m, 2H), 7.7-7.6 (m, 1H), 4.05 (s, 1H).
Reaction SMILES: Cl.[NH:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:4][C:3]1=[O:17].Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]([O:25][C:26]2[CH:27]=[C:28]([CH3:38])[C:29]3[N:33]=[C:32]([CH2:34][O:35][CH3:36])[NH:31][C:30]=3[CH:37]=2)[CH:20]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:36][O:35][CH2:34][C:32]1[NH:31][C:30]2[CH:37]=[C:26]([O:25][C:21]3[N:22]=[CH:23][N:24]=[C:19]([N:14]4[CH2:13][CH2:12][C:5]5([O:4][C:3](=[O:17])[NH:2][C:7]6[N:8]=[CH:9][CH:10]=[CH:11][C:6]5=6)[CH2:16][CH2:15]4)[CH:20]=3)[CH:27]=[C:28]([CH3:38])[C:29]=2[N:33]=1
Reactant: COCc1nc2c(C)cc(Oc3cc(Cl)ncn3)cc2[nH]1
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCc1nc2c(C)cc(Oc3cc(N4CCC5(CC4)OC(=O)Nc4ncccc45)ncn3)cc2[nH]1

Procedure:
49 mg (0.19 mmol) spiro[piperidin-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one hydrochloride, 50 mg (0.16 mmol) 6-(6-chloropyrimidin-4-yloxy)-2-(methoxymethyl)-4-methyl-1H-benzo-[d]imidazole and 0.10 mL (0.57 mmol) DIPEA in 2.0 mL DMF were stirred at 40° C. over the weekend. The reaction mixture was purified by preparative HPLC-MS. The fractions containing product were partially evaporated down i.vac. and neutralised with 4M sodium hydroxide solution. The precipitate formed was suction filtered, washed and dried.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.[Cl:9][C:10]1[S:14][C:13]([S:15]([NH:18][C:19]2[C:24](Br)=[N:23][C:22]([CH3:26])=[CH:21][N:20]=2)(=[O:17])=[O:16])=[CH:12][CH:11]=1>>[Cl:9][C:10]1[S:14][C:13]([S:15]([NH:18][C:19]2[C:24]([O:8][CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[N:23][C:22]([CH3:26])=[CH:21][N:20]=2)(=[O:16])=[O:17])=[CH:12][CH:11]=1
Reactant: Cc1cnc(NS(=O)(=O)c2ccc(Cl)s2)c(Br)n1
Reactant: OCc1cccnc1
Product: Cc1cnc(NS(=O)(=O)c2ccc(Cl)s2)c(OCc2cccnc2)n1

Procedure:
Prepared by the method of Example 20b using pyridine-3-methanol and 5-chloro-N-(3-bromo-5-methyl-2-pyrazinyl)-2-thiophenesulphonamide.
Reaction SMILES: C(O[C:4]([N:6]=[C:7]=[S:8])=[O:5])C.C(OC([C:14]1[NH:15][CH:16]=[CH:17][C:18]=1[NH:19][CH2:20][CH2:21][CH2:22][CH3:23])=O)C.[OH-].[K+].Cl>C1(C)C=CC=CC=1.O>[CH2:20]([N:19]1[C:18]2[CH:17]=[CH:16][NH:15][C:14]=2[C:7](=[S:8])[NH:6][C:4]1=[O:5])[CH2:21][CH2:22][CH3:23]
Reactant: CCOC(=O)N=C=S
Reactant: CCCCNc1cc[nH]c1C(=O)OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCn1c(=O)[nH]c(=S)c2[nH]ccc21
Temperature: 90 °C
Yield: 6.5 %

Procedure:
Ethoxycarbonyl isothiocyanate (0.13 ml, 1.1 mmol) was added to 3-(butylamino)-1H-pyrrole-2-carboxylic acid ethyl ester (0.23 g, 1.1 mmol) in toluene (5 mL) and the mixture was heated at 90° C. for 1 h. The precipitate was filtered off and washed with hexane. The intermediate product was treated with potassium hydroxide (0.55 g, 9.9 mmol) in water (9 mL), and heated to reflux for 15 h. After cooling to ambient temperature, the pH was adjusted to pH 5 with 12 M HCl. The resultant precipitate was collected by filtration and washed with water. The crude product was purified using preparative HPLC to give the title compound (16 mg, 6%) as a solid.
Reaction SMILES: [C:1]([NH:14][C@H:15]([CH2:39][NH:40][C:41](=[O:53])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[CH2:16][S:17][CH2:18][C@H:19]([NH:28]C(=O)OCC1C=CC=CC=1)[C:20]([NH:22][C:23]1([CH2:26][OH:27])[CH2:25][CH2:24]1)=[O:21])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>CCO.[OH-].[OH-].[Pd+2]>[NH2:28][C@H:19]([C:20]([NH:22][C:23]1([CH2:26][OH:27])[CH2:25][CH2:24]1)=[O:21])[CH2:18][S:17][CH2:16][C@H:15]([NH:14][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:39][NH:40][C:41](=[O:53])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52]
Reactant: CCCCCCCCCCCC(=O)NC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)NC1(CO)CC1)NC(=O)CCCCCCCCCCC
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCC(=O)NC[C@H](CSC[C@H](N)C(=O)NC1(CO)CC1)NC(=O)CCCCCCCCCCC

Procedure:
Benzyl(R)-3-((R)-2,3-didodecanamidopropylthio)-1-(1-(hydroxymethyl)cyclopropylamino)-1-oxopropan-2-ylcarbamate (1 eq) was stirred in dry EtOH (0.05 M) under N2 at room temperature. Pd(OH)2 (2.1 eq) was then added in one portion. The reaction was then stirred under hydrogen atmosphere (1 atm) until complete reduction was observed. The crude reaction was filtered twice through celite and cotton, then the organics concentrated and purified by flash chromatography on a COMBIFLASH® system (ISCO) using a gradient of 0-10% MeOH/DCM to afford N,N′—((R)-3-((R)-2-amino-3-(1-(hydroxymethyl)cyclopropylamino)-3-oxopropylthio)propane-1,2-diyl)didodecanamide as an oil. 1H NMR (CDCl3): δ 8.02 (s, 1H), 6.83 (t, 1H), 6.70 (t, 1H), 3.50-3.71 (m, 6H), 3.00-3.12 (m, 3H), 2.88-2.94 (m, 2H), 2.21 (t, 4H), 1.64 (t, 4H), 1.21-1.35 (m, 32H), 0.93 (m, 4H), 0.82 (t, 6H). LRMS [M+H]=628.0.