Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCOCC1.[ClH:7].[OH:8][CH:9]1[CH2:13][O:12][CH2:11][CH:10]1[NH:14][NH:15]C(OC(C)(C)C)=O>CO>[ClH:7].[NH:14]([CH:10]1[CH2:11][O:12][CH2:13][CH:9]1[OH:8])[NH2:15]
Reactant: CC(C)(C)OC(=O)NNC1COCC1O
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NNC1COCC1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 4 M hydrogen chloride-1,4-dioxane solution (50 mL) was added to a solution of t-butyl 2-((3RS,4SR)-4-hydroxytetrahydrofuran-3-yl)hydrazinecarboxylate (5.78 g) in methanol (30 mL) under ice-cooling, and the mixture was then warmed to room temperature and stirred overnight. The reaction mixture was concentrated to give the title compound (5 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([NH2:12])=[CH:10][N:9]=[N:8][CH:7]=1)=[O:5])[CH3:2].[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[C:15]=1[CH2:22][C:23](Cl)=[O:24]>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH2:1]([O:3][C:4]([C:6]1[C:11]([NH:12][C:23](=[O:24])[CH2:22][C:15]2[C:16]([F:21])=[CH:17][C:18]([F:20])=[CH:19][C:14]=2[F:13])=[CH:10][N:9]=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnncc1N
Reactant: O=C(Cl)Cc1c(F)cc(F)cc1F
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cnncc1NC(=O)Cc1c(F)cc(F)cc1F
Temperature: 70 °C
Yield: 101.7 %

Procedure:
5-Aminopyridazine-4-carboxylic acid ethyl ester (1.26 g, prepared according to J. Het. Chem., (1968), 5, 845) was dissolved in dry toluene (125 ml) at 90° C., and DMAP (0.92 g) was added. 2,4,6-Trifluorophenylacetyl chloride (1.75 g of 95% purity material) was added dropwise with stirring at 70° C., and a white solid precipitated. The reaction was stirred at reflux for 5 hours and then filtered hot. The filtrate was evaporated to give 5-[2-(2,4,6-trifluorophenyl)-acetylamino]-pyridazine-4-carboxylic acid ethyl ester as a white solid (2.6 g), m.p. 143-144° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][S:12](O)(=[O:14])=[O:13]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:12]([Cl:11])(=[O:14])=[O:13]
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: O=S(=O)(O)Cl
Product: O=C(O)c1ccc(Br)c(S(=O)(=O)Cl)c1
Temperature: 130 °C
Yield: 79.5 %

Procedure:
4-Bromobenzoic acid (10 g, 49.75 mmol) was added portion wise to chlorosulfonic acid (25 ml, 373.13 mmol) at 0° C. The mixture was heated to 130° C. for 10 hours, until complete consumption of the starting material was observed by LCMS. The reaction mixture was allowed to cool down to ambient temperature, then added drop wise to an ice/water mixture (500 ml). The precipitate was filtered and washed with cold water (2×100 ml). The solid recovered was dissolved in diethyl ether, the solution then dried over sodium sulphate, filtered and concentrated in vacuo to afford the expected product as a beige solid (11.85 g, 79% yield); δH (400 MHz, DMSO) 8.45 (1H, d, 1.7 Hz), 7.72 (1H, d, 2.2 Hz), 7.71 (1H, s); TR=2.08 min.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[CH:13][C:14]([OH:17])=[N:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].CS(O[CH:23]([CH:25]1[CH2:30][CH2:29][N:28]([C:31]2[O:35][N:34]=[C:33]([CH:36]([CH3:38])[CH3:37])[N:32]=2)[CH2:27][CH2:26]1)[CH3:24])(=O)=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:38][CH:36]([C:33]1[N:32]=[C:31]([N:28]2[CH2:27][CH2:26][CH:25]([CH:23]([O:17][C:14]3[CH:13]=[N:12][C:11]([C:8]4[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=4)=[CH:16][N:15]=3)[CH3:24])[CH2:30][CH2:29]2)[O:35][N:34]=1)[CH3:37]
Reactant: CS(=O)(=O)c1ccc(-c2cnc(O)cn2)cc1
Reactant: CC(C)c1noc(N2CCC(C(C)OS(C)(=O)=O)CC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1noc(N2CCC(C(C)Oc3cnc(-c4ccc(S(C)(=O)=O)cc4)cn3)CC2)n1

Procedure:
The title compound (0.212 g, 26%) was prepared as a white foam from 5-[4-(methylsulfonyl)phenyl]-2-pyrazinol (and tautomers thereof) (prepared as in Example 145, Steps 1-2, 0.43 g, 1.72 mmol), (±)-1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl methanesulfonate (0.74 g, 2.32 mmol) and K2CO3 (0.48 g, 3.44 mmol) in DMF (15 mL) in a manner similar to Example 152, Steps 3. The crude product was purified by chromatography on an ISCO silica gel column using 0 to 25% EtOAc/CH2Cl2, followed by chromatography on a silica gel column eluted with 50% EtOAc/hexanes to give (±)-2-[(1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl)oxy]-5-[4-(methylsulfonyl)phenyl]pyrazine as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.53 (s, 1H), 8.25 (s, 1H), 8.10 (d, 2H, J=8.5 Hz), 8.02 (d, 2H, J=8.5 Hz), 5.20-5.10 (m, 1H), 4.35-4.20 (m, 2H), 3.15-3.00 (m, 5H), 2.91 (septet, 1H, J=7.0 Hz), 2.00-1.80 (m, 3H), 1.60-1.40 (m, 2H), 1.34 (d, 3H, J=6.1 Hz), 1.28 (d, 6H, J=7.1 Hz); LRMS (ESI), m/z 472 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27]([OH:29])=O)[CH:5]=[CH:6][CH:7]=1.[CH3:30][NH:31][CH3:32].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>C(Cl)Cl>[CH3:30][N:31]([CH3:32])[C:27]([CH:9]1[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:24])([CH3:26])[CH3:25])[NH:10]1)=[O:29]
Reactant: CNC
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)C(=O)C1NC(CC(C)(C)C)C(C#N)(c2ccc(Cl)cc2)C1c1cccc(Cl)c1
Yield: 90 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (61.0 mg, 0.14 mmol) prepared in Example 1d was reacted with dimethylamine (1.0 M in THF, 2 mL), HATU (106.0 mg, 0.28 mmol) and iPr2NEt (38.8 mg, 0.30 mmol) in CH2Cl2 (2 mL) at rt overnight to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid dimethyl amide (57.8 mg, 90.0%).
Reaction SMILES: [CH3:1][C@@:2]12[C@H:11]3[CH2:12][CH2:13][C@:14]4([CH3:20])[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]4[C@@H:10]3[CH2:9][CH2:8][C@H:7]1[CH2:6][C@@H:5]([OH:21])[CH2:4][CH2:3]2.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>N1C=CC=CC=1>[S:28]([O:21][C@H:5]1[CH2:4][CH2:3][C@@:2]2([CH3:1])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:11]2[CH2:12][CH2:13][C@@:14]2([CH3:20])[C@H:15]3[CH2:16][CH2:17][C:18]2=[O:19])[CH2:6]1)([C:25]1[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=1)(=[O:30])=[O:29]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@]12CC[C@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O[C@H]2CC[C@@]3(C)[C@@H](CC[C@@H]4[C@@H]3CC[C@]3(C)C(=O)CC[C@@H]43)C2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87 %

Procedure:
In a 25 mL round bottom flask, trans-androsterone (1.00 g, 3.44 mmol) and p-toluenesulfonyl chloride (1.51 g, 7.91 mmol) was dissolved in in pyridine (4.30 mL). The reaction mixture was stirred continuously at room temperature. After 24 h, the reaction mixture was quenched by adding H2O (10 mL) and it was extracted with CH2Cl2 (3×20 mL). All organic layers were collected, combined together and washed over HCl (3×20 mL, 2 M), brine solution (3×20 mL), and H2O (3×20 mL), dried over Na2SO4, and concentrated under reduced pressure afforded 3β-tosyloxy-5α-androstan-17-one (1.33 g, 87%) as a white solid. 1H NMR (300 MHz, CDCl3): d 7.79 (dt, J=8.3, 1.9 Hz, 2H), 7.33 (dd, J=8.0, 0.5 Hz, 2H), 4.42 (h, J=5.9 Hz, 1H), 2.44 (s, 3H), 2.38-2.47 (m, 1H), 1.99-2.11 (m, 1H), 1.86-1.95 (m, 1H), 1.78-1.80 (m, 1H), 1.71-1.77 (m, 2H), 1.65-1.69 (m, 1H), 1.56-1.64 (m, 3H), 1.44-1.55 (m, 3H), 1.30-1.31 (m, 1H), 1.28-1.29 (m, 2H), 1.22-1.24 (m, 1H), 1.18-1.20 (m, 1H), 1.04-1.16 (m, 1H), 0.85-1.00 (m, 2H), 0.84 (s, 3H), 0.80 (s, 1H), 0.60-0.69 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:11][C:7]=2[C:6]([N:21]2[CH2:26][CH2:25][S:24][CH2:23][CH2:22]2)=[CH:5][CH:4]=1.I([O-])(=O)(=O)=[O:28].[Na+].O.ClCCl>O1CCOCC1>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:11][C:7]=2[C:6]([N:21]2[CH2:22][CH2:23][S:24](=[O:28])[CH2:25][CH2:26]2)=[CH:5][CH:4]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COc1ccc(N2CCSCC2)c2sc(NC(=O)c3ccccc3)nc12
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(N2CCS(=O)CC2)c2sc(NC(=O)c3ccccc3)nc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 21 %

Procedure:
To a solution of N-(4-methoxy-7-thiomorpholin-4-yl-benzothiazol-2-yl)-benzamide (80 mg, 0.21 mmol) in [1,4]dioxane (3 ml) was added sodium periodate (89 mg, 0.42 mmol) and the mixture stirred for 20 h at ambient temperature. To this mixture water (10 ml) and dichloromethane (10 ml) were added, the phases were separated and the aqueous layer extracted twice with dichloromethane. The combined organic extracts were dryed with Na2SO4 and the solvent evaporated. Recrystallization from hot THF afforded the title compound as white solid (21%), MS: m/e=402 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[C:4]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH:5]=[CH:6][CH:7]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[C:4]2[C:5]([C:11](=[O:13])[CH2:10][CH2:9][NH:8]2)=[CH:6][CH:7]=1
Reactant: O=C(O)CCNc1cccc(Cl)c1[N+](=O)[O-]
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Cc1ccccc1
Product: O=C1CCNc2c1ccc(Cl)c2[N+](=O)[O-]
Yield: 50.2 %

Procedure:
A mixture of 3-(3-chloro-2-nitrophenylamino)propionic acid (21.5 g), which was synthesized according to the method of Giovanni Pappalardo et al. (Ann. Chim. (Rome), 55, 182 (1965)), phosphorus pentoxide (37.0 g) and toluene (160 ml) was refluxed for 90 minutes. After cooling, toluene was removed in vacuo. The residue was washed with ether to give 7-chloro-2,3-dihydro-8-nitro-4(1H)-quinolinone (yield 10.0 g).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)[N:27]2[C:31]3=[N:32][C:33]([CH3:37])=[CH:34][C:35]([CH3:36])=[C:30]3[C:29]([C:38]#[N:39])=[CH:28]2)=[CH:22][CH:21]=1.CN(C)[CH:49]=[O:50]>O1CCCC1.O>[F:46][C:43]1[CH:42]=[CH:41][C:40]([CH:26]([C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)[N:27]2[C:31]3=[N:32][C:33]([CH3:37])=[CH:34][C:35]([CH3:36])=[C:30]3[C:29]([C:38]#[N:39])=[C:28]2[CH:49]=[O:50])=[CH:45][CH:44]=1
Reactant: Cc1cc(C)c2c(C#N)cn(C(c3ccc(F)cc3)c3ccc(F)cc3)c2n1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: Cc1cc(C)c2c(C#N)c(C=O)n(C(c3ccc(F)cc3)c3ccc(F)cc3)c2n1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of diisopropylamine (5.27 ml, 40.2 mmol) in tetrahydrofuran (50 ml) was added a 1.6 N solution of butyllithium in hexane (25.1 ml, 40.2 mmol) at −78° C., which was stirred at −78° C. for 15 minutes. To the resultant solution was added dropwise 1-[bis(4-fluorophenyl)methyl]-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (11.6 g, 31.1 mmol) at −78° C., and the mixture was stirred at −78° C. for 30 minutes. Dimethylformamide (6.23 ml, 80.4 mmol) was added thereto, and the mixture was stirred at room temperature for 1.5 hours, poured into iced water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give the objective product as a solid material.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[C:6]([Cl:13])[C:3]=1[C:4]#[N:5].[Cl-].[NH4+].O>CO.[Fe]>[NH2:10][C:8]1[CH:7]=[C:6]([Cl:13])[C:3]([C:4]#[N:5])=[C:2]([Cl:1])[CH:9]=1
Reactant: N#Cc1c(Cl)cc([N+](=O)[O-])cc1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: N#Cc1c(Cl)cc(N)cc1Cl
Yield: 64.8 %

Procedure:
A solution of 2,6-dichloro-4-nitrobenzonitrile (2.46 g, 11.3 mmol, Eq: 1.00), iron (3.17 g, 56.7 mmol, Eq: 5) and ammonium chloride (6.06 g, 113 mmol, Eq: 10) in methanol (30 mL)/water (10 mL) was heated at reflux o/n. TLC shows incomplete reaction. Continued heating at 100 deg for 6 hr, then 60 deg overnight. The reaction mixture was filtered over Celite. The filtrate was suspended in ethyl acetate to give insoluble solid. The slurry was concentrated to dryness, suspended in water, filtered, and rinsed with water. The solid was transferred to a round bottom flask, suspended in benzene, and concentrated. An additional portion of benzene was added and concentrated once more to give 1.37 g (65%) of desired product as a light brown solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N+:11]([O-])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH2:14].NN>C(O)C>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([NH2:11])=[CH:10][C:5]=2[N:4]=[C:3]1[NH2:14]
Reactant: Cn1c(N)nc2cc([N+](=O)[O-])ccc21
Agent: NN
Solvent: CCO
Product: Cn1c(N)nc2cc(N)ccc21
Temperature: 80 °C

Procedure:
To a solution of 1-Methyl-5-nitro-1H-benzoimidazol-2-ylamine (0.19 g, 1 mmol) 10% Pd/C (50 mg) in ethanol (10 ml) was added hydrazine (0.5 ml) and the reaction was heated to 80° C. After TLC showed the starting material to be consumed, the reaction was cooled to rt and passed through a plug of celite. The filtrate was concentrated to give the title compound as an off-white solid. MS (ESI) m/z=163 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:27])[CH2:17][C@H:16]4[C:28]#[N:29])[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C1COCC1.CO>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C@@H:18]([OH:27])[CH2:17][C@H:16]4[C:28]#[N:29])[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]1[C@H](C#N)CC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]1[C@H](C#N)C[C@@H]2O
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A solution of 558 mg (1.45 mmol) of 45 in THF (6.6 mL) and MeOH (34 mL) was stirred at rt as 400 mg (10.6 mmol) of NaBH4 was added in small portions over 10 min. The reaction was stirred at rt under N2 for 3.5 h, the solvent was evaporated and the residue was dissolved in EtOAc (100 mL) and H2O (50 mL). The phases were separated and the aqueous phase was extracted with EtOAc (2×, 70 mL). Combined organic extracts were dried over Na2SO4 and concentrated in vacuo giving a yellow foam which was used without purification in the next step. Data for 46: TLC, T-2, Rf 0.22; 1H NMR (400 MHz, CDCl3) δ 1.07 (s, 3H, H-18), 3.75 (t, 1H, J=8.7 Hz, H-17α), 5.05 (s, 2H, benzylic-H), 6.75 (d, 1H, J=2.7 Hz, H-4), 6.80 (dd, 1H, J=8.5, 2.7 Hz, H-4), 7.21 (d, 1H, J=8.5 Hz, H-1), 7.33–7.45 (m, 5H, Ar—H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18](=[O:35])[C:19]3[CH:24]=[CH:23][C:22]([C:25]4([CH3:30])OCC[O:26]4)=[CH:21][C:20]=3[O:31]COC)=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:10])=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O>O>[C:25]([C:22]1[CH:23]=[CH:24][C:19]([C:18]([NH:17][C:16]2[C:11]([C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)=[O:10])=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:35])=[C:20]([OH:31])[CH:21]=1)(=[O:26])[CH3:30]
Reactant: COCOc1cc(C2(C)OCCO2)ccc1C(=O)Nc1cccnc1C(=O)Nc1ccc(Cl)cn1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1ccc(C(=O)Nc2cccnc2C(=O)Nc2ccc(Cl)cn2)c(O)c1
Yield: 18.6 %

Procedure:
N-(5-Chloropyridin-2-yl)-3-[4-(2-methyl-1,3-dioxolan-2-yl)-2-(methoxymethoxy)benzoylamino]pyridine-2-carboxamide (3.10 g) is treated with a solution of TFA (20 mL) and water (20 mL) for 2 h before the solution is evaporated. The residue is slurried with ethyl acetate to provide a solid which is collected and washed. The solid is dispersed in ethyl acetate and extracted with a mixture of aqueous potassium carbonate and 1 N NaOH. The resulting organic phase is washed with very dilute HCl, dried and evaporated to afford the product as a solid (0.476 g), which is used directly without further purification.
Reaction SMILES: [N:1]1([C:6]2[N:15]=[C:9]3[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][N:8]3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:16]([O:18][C:19]([C:21]1[CH:22]=[N:23][N:24]([CH3:29])[C:25]=1[C:26](O)=[O:27])=[O:20])[CH3:17].CCCP(=O)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH2:16]([O:18][C:19]([C:21]1[CH:22]=[N:23][N:24]([CH3:29])[C:25]=1[C:26](=[O:27])[NH:14][C:11]1[CH:12]=[CH:13][N:8]2[N:7]=[C:6]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[N:15]=[C:9]2[CH:10]=1)=[O:20])[CH3:17]
Reactant: Nc1ccn2nc(N3CCCC3)nc2c1
Reactant: CCOC(=O)c1cnn(C)c1C(=O)O
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(N3CCCC3)nc2c1
Yield: 88 %

Procedure:
A mixture of 2-(pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-amine (197 mg, 969 μmol), 4-(ethoxycarbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (231 mg, 1.16 mmol), propylphosphonic anhydride (50% in ethyl acetate, 1.43 ml, 2.42 mmol) and N,N-diisopropylethylamine (494 μl, 2.91 mmol) in tetrahydrofuran (10 ml) was refluxed for 18 hours. The solvent was evaporated, the residue was triturated with sodium hydrogencarbonate solution. The precipitated solid was filtered off, washed with water and dried affording 1-methyl-5-(2-pyrrolidin-1-yl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid ethyl ester (327 mg, 88.0%) as a light brown solid. mp: 233-234° C., MS: m/z=384.5 (M+H+).
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2=[CH:16][S:17][C:18]([CH3:19])=[C:5]12)=[O:3].[CH2:20]([N:22]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[CH2:32][CH2:33][NH2:34])[CH2:23][CH3:24])[CH3:21].Cl>C(#N)C>[CH2:20]([N:22]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[CH2:32][CH2:33][NH:34][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2=[CH:16][S:17][C:18]([CH3:19])=[C:5]12)=[O:3])[CH2:23][CH3:24])[CH3:21]
Reactant: Cc1scc2c1N(C(=O)Cl)c1ccccc1NC2=O
Reactant: CCN(CC)CC1CCCCN1CCN
Agent: Cl
Solvent: CC#N
Product: CCN(CC)CC1CCCCN1CCNC(=O)N1c2ccccc2NC(=O)c2csc(C)c21
Yield: 53 %

Procedure:
Prepared analogously to Example 1 from 4-(chlorocarbonyl)-4,9-dihydro-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and (-)-2-[2-[(diethylamino)methyl]-piperidin-l-yl]ethanamine in a yield of 53% of theory. Colourless crystals, m.p. 132°-133° C. (acetonitrile); [α]D20 =-14.00° (dilute aqueous hydrochloric acid).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:24])[CH2:15][C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2Cl)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:31]C1C=CC(F)=CC=1C[Mg]Br>>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:24])[CH2:15][C:16]2[CH:17]=[C:18]([F:31])[CH:19]=[CH:20][C:21]=2[F:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(F)c(C[Mg]Br)c1
Reactant: OC(Cc1c(F)cccc1Cl)(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Product: OC(Cc1cc(F)ccc1F)(c1ccccc1)C1CN(Cc2ccccc2)CCO1

Procedure:
The procedure for the synthesis of example 18a, 1-(4-Benzyl-morpholin-2-yl)-2-(2-chloro-6-fluoro-phenyl)-1-phenyl-ethanol, using 2,5-difluorobenzyl magnesium bromide as starting material (available from Rieke Metals) was followed making non-critical variations, to yield the title compound. This material was used in step b) without further purification. LCMS (6 minutes method) [M+H]+=410 @ Rt 3.11 min. major peak.
Reaction SMILES: [OH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12](=[O:26])[CH2:13][C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[CH:10]=2)[O:5][C:4]([CH3:28])([CH3:27])[CH2:3]1.[S:29](Cl)([C:32]1[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=1)(=[O:31])=[O:30]>ClCCl.CN(C1C=CN=CC=1)C.O>[CH3:27][C:4]1([CH3:28])[CH2:3][CH:2]([O:1][S:29]([C:32]2[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12](=[O:26])[CH2:13][C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[CH:10]=2)[O:5]1
Reactant: COc1cc(CC(=O)c2ccc3c(c2)C(O)CC(C)(C)O3)cc(OC)c1OC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: COc1cc(CC(=O)c2ccc3c(c2)C(OS(=O)(=O)c2ccc(C)cc2)CC(C)(C)O3)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution 1-(4-hydroxy-2,2-dimethyl-chroman-6-yl)-2-(3,4,5-trimethoxy-phenyl)-ethanone (3.5 mg, 0.009 mmol) dissolved in anhydrous dichloromethane (1.0 mL) is added TsCl (1.94 mg, 0.011 mmol), DMAP (1.24 mg, 0.011 mmol) and TEA (21.3 μL, 0.015 mmole). The reaction mixture continues stirring at room temperature overnight. The next day, the reaction mixture is diluted with water. The aqueous layer is separated and extracted with ethyl acetate (3×). All combined organic layers are dried over Na2SO4, filtered, and concentrated to yield an oil. The crude material is purified using silica gel chromatography to yield the desired product.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:3]=1.[CH2:20]([O:27][C:28]([N:30]1[CH2:35][CH2:34][NH:33][CH:32]([CH2:36][OH:37])[CH2:31]1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>C(Cl)Cl.O>[CH2:20]([O:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=3)[N:5]=[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[OH:19])[N:3]=2)[CH:32]([CH2:36][OH:37])[CH2:31]1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(OCc1ccccc1)N1CCNC(CO)C1
Reactant: Cc1ccc2c(Cl)nc(-c3ccccc3O)nc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc2c(N3CCN(C(=O)OCc4ccccc4)CC3CO)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 76.9 %

Procedure:
To 2-(4-chloro-7-methyl-quinazolin-2-yl)-phenol (245 mg, 0.91 mmol) in 3.0 mL of CH2Cl2 was added 3-hydroxymethyl-piperazine-1-carboxylic acid benzyl ester (226 mg, 0.58 mmol) and triethylamine (190 μL, 1.37 mmol). The reaction mixture was stirred for 12 hours at room temperature, and additional 3-hydroxymethyl-piperazine-1-carboxylic acid benzyl ester (100 mg, 0.4 mmol) and triethylamine (200 μL, 1.4 mmol) was added, and the reaction mixture was heated at 40° C. for 6 h. The reaction mixture was cooled, and diluted with 5 mL of CH2Cl2 and 5 mL of water, and the organic layer was separated and dried over Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by silica gel chromatography eluting with 20-85% EtOAc/hexanes to give 3-hydroxymethyl-4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazine-1-carboxylic acid benzyl ester (216 mg, 65%). LCMS: m/z 485 (M+H)+ at 3.03 min (10%-99% CH3CN/H2O)
Reaction SMILES: C(N1CC=C(C2C3C(=CC(C(N4CCN(C(C)C)CC4)=O)=CC=3)NC=2)CC1)C(C)C.Cl.[NH:32]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([C:41]([OH:43])=[O:42])[CH:39]=2)[CH:34]=[CH:33]1.[CH2:44]([N:51]1[CH2:56][CH2:55][C:54](=O)[CH2:53][CH2:52]1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[CH2:44]([N:51]1[CH2:52][CH:53]=[C:54]([C:34]2[C:35]3[C:40](=[CH:39][C:38]([C:41]([OH:43])=[O:42])=[CH:37][CH:36]=3)[NH:32][CH:33]=2)[CH2:55][CH2:56]1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: CC(C)CN1CC=C(c2c[nH]c3cc(C(=O)N4CCN(C(C)C)CC4)ccc23)CC1
Agent: Cl
Product: O=C(O)c1ccc2c(C3=CCN(Cc4ccccc4)CC3)c[nH]c2c1

Procedure:
According to the procedure described for the synthesis of [3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone; hydrochloride (Example 1; step 2) the title compound was prepared from indole-6-carboxylic acid (commercially available) and 1-benzyl-4-piperidone (commercially available). MS (m/e): 333.2 (MH+).