Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22](O)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[N:34]1[C@H:38]([CH2:39][O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH2:37][CH2:36][C:35]1=[O:48]>>[Si:41]([O:40][CH2:39][C@H:38]1[CH2:37][CH2:36][C:35](=[O:48])[N:34]1[C:28]1[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:27]=1[CH2:26][NH:25][C:22]([C:10]1[N:11]=[C:12]2[N:17]([C:18](=[O:19])[C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:16][CH2:15][O:14][C:13]2([CH3:20])[CH3:21])=[O:23])([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42]
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1CCC(=O)N1c1cc(F)ccc1CN
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1N1C(=O)CC[C@@H]1CO[Si](C)(C)C(C)(C)C)c(OCc1ccccc1)c2=O

Procedure:
The title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid and (S)-1-(2-(aminomethyl)-5-fluorophenyl)-5-((tert-butyldimethylsilyloxy)methyl)pyrrolidin-2-one, derived from reduction of intermediate 122, (R)-2-(2-((tert-butyldimethylsilyloxy)methyl)-5-oxopyrrolidin-1-yl)-4-fluorobenzonitrile 1HNMR 400 MHz (DMSO) δ ppm: 8.82 (1H, broad s), 7.47 (2H, m), 7.35 (4H, m), 7.00 (1H, broad s), 5.09 (2H, s), 4.60-4.10 (3H, m), 4.02 (3H, m), 3.88 (2H, m), 3.53 (2H, broad s), 2.42-2.35 (2H, m), 1.94 (1H, m), 1.56 (3H, s), 1.55 (3H, s), 0.82 (9H, broad s), −0.01 (6H, s). LCMS (M+H)+ m/z 665.
Reaction SMILES: [N:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]([NH:16][C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)=[C:9]([C:14]#[N:15])[CH:10]=[N:11]2)=[CH:6][C:5]=1[N+:29]([O-])=O)=[N+]=[N-]>C1COCC1.C(O)C.[Pd]>[NH2:29][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:4]=1[NH2:1])[N:11]=[CH:10][C:9]([C:14]#[N:15])=[C:8]2[NH:16][C:17]1[CH:18]=[C:19]([O:27][CH3:28])[C:20]([O:25][CH3:26])=[C:21]([O:23][CH3:24])[CH:22]=1
Reactant: COc1cc(Nc2c(C#N)cnc3cc(N=[N+]=[N-])c([N+](=O)[O-])cc23)cc(OC)c1OC
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(Nc2c(C#N)cnc3cc(N)c(N)cc23)cc(OC)c1OC
Yield: 98.7 %

Procedure:
A solution of 493.4 mg (1.17 mmol) of 7-azido-6-nitro-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile in 15 mL of THF and 5 mL of ethanol is hydrogenated at 30 psi for 1 hour in the presence of 100.0 mg of 10% palladium-on-carbon. The catalyst is removed by filtration and the solvent removed in vacuo to give 422.1 mg (98.8%) of 6,7-diamino-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile as a deep yellow solid which is used directly in the next step.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.S([O-])([O-])(=O)=O.[Mg+2].[CH3:19][C:20]([CH3:24])=[CH:21][CH:22]=O>N1C=CC=CC=1.CO.C(Cl)(Cl)Cl>[CH3:19][C:20]1([CH3:24])[O:12][C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[NH:3][C:2](=[O:1])[C:11]=2[CH:22]=[CH:21]1
Reactant: Oc1cc(O)c2ccccc2n1
Reactant: CC(C)=CC=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: c1ccncc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC1(C)C=Cc2c(c3ccccc3[nH]c2=O)O1
Reaction time: 12 h
Yield: 63.9 %

Procedure:
To a boiling solution of 2,4-dihydroxy quinoline (5.0 g, 31 mmol) in pyridine (300 ml) under argon was added anhydrous magnesium sulfate (20 g) followed by 3-methyl-2-butenal (2.6 g, 31.0 mmole). The reaction was heated under reflux for 16 hours. After 12 hours, more 3-methyl-2-butenal (1.3 g, 15.5 mmol) was added and the reaction was heated under reflux for 16 more hours. The reaction was diluted with 10% methanol in chloroform (200 ml) and filtered while hot. The solid was washed with hot solvent (10% methanol in chloroform) and the filtrate was concentrated in vacuo and coevaporated with toluene. The resulting solid was triturated with isopropyl ether to give the title A compound (4.5 g), m.p. 174° C.-177° C.: 1H NMR (DMSO-d6 /CDCl3) ppm: δ7.7 (d, 1H, J =8.0 Hz), 7.4 (d, 1H, J = 9.0 Hz), 7.2 (d, 1H, J =8.0 Hz), 7.1 (dd, 1H, J =7 & 8 Hz), 6.5 (d, 1H, J =8.0 Hz), 5.5 (d, 1H, J =9.0 Hz), 3.3 (s, 1H), 1.34 (2 s, 6H); 13C NMR (DMSO-d6 /CDCl3) ppm: 160.8, 158.7, 136.5, 128.9, 120.9, 120.2, 119.7, 115.0, 113.6, 113.4, 103.7, 76.7, 26.0.
Reaction SMILES: [CH2:1]([C:3]1([C:6]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)=[O:7])[CH2:5][CH2:4]1)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:19][O:18][C:12]1[CH:11]=[C:10]([CH2:9][CH2:8][CH:6]([C:3]2([CH2:1][CH3:2])[CH2:5][CH2:4]2)[OH:7])[CH:15]=[CH:14][C:13]=1[O:16][CH3:17]
Reactant: CCC1(C(=O)C=Cc2ccc(OC)c(OC)c2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCC1(C(O)CCc2ccc(OC)c(OC)c2)CC1

Procedure:
2-(3,4-Dimethoxyphenyl)ethyl 1-ethylcyclopropyl carbinol [IV; Ar is 3,4-(CH3O)2C6H3, R is C2H5 ] was prepared from 15 g. of 2-(3,4-dimethoxyphenyl)vinyl 1-ethylcyclopropyl ketone (Preparation A4) and 2.2 g. of lithium aluminum hydride according to the procedure described above in Preparation B1, affording 10 g., b.p. 148°-150° C. (0.01 mm.).
Reaction SMILES: COC1C=CC(C[N:8]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])[CH2:9]2)=CC=1.ClC(OC(Cl)C)=O.CO>ClCCCl>[CH3:24][O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[CH2:16][NH:8][CH2:9]2
Reactant: COCCOCCOc1cccc2c1CN(Cc1ccc(OC)cc1)C2
Agent: CC(Cl)OC(=O)Cl
Solvent: CO
Solvent: ClCCCl
Product: COCCOCCOc1cccc2c1CNC2
Reaction time: 17 h

Procedure:
A solution of 2-(4-methoxy-benzyl)-4-[2-(2-methoxy-ethoxy)-ethoxy]-2,3-dihydro-1H-isoindole (45 mg, 0.13 mmol) in 1,2-dichloroethane (2 mL) was treated with α-chloroethyl chloroformate (0.1 mL, 0.93 mmol). After 17 hours, methanol (5 mL) was added and the mixture stirred for 3 hours. The solvents were removed in vacuo to afford the title compound as a greenish-black solid, which was used without further purification. 1H NMR (methanol-d4) 7.36 (1H, t), 6.98 (2H, d), 4.60 (2H, s), 4.57 (2H, s), 4.23-4.21 (2H, m), 3.85-3.83 (2H, m), 3.69-3.67 (2H, m), 3.57-3.54 (2H, m), 3.36 (3H, s). MS: [M+H]+ 238.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:23][CH2:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[O:12][C:11]2=[O:31])[CH3:9])=[CH:4][CH:3]=1.[CH3:32][C:33]1[CH:38]=[C:37](B(O)O)[CH:36]=[CH:35][N:34]=1>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C@:13]2([CH2:23][CH2:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[O:12][C:11](=[O:31])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:37]4[CH:36]=[CH:35][N:34]=[C:33]([CH3:32])[CH:38]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:17][CH:18]=1
Reactant: Cc1cc(B(O)O)ccn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCNS(C)(=O)=O)(c2ccc(F)cc2)OC1=O
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CCCNS(C)(=O)=O)(c4ccc(F)cc4)OC3=O)cc2)ccn1

Procedure:
The title compound was prepared from N-(3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propyl)methanesulfonamide and 2-methylpyridine-4-boronic acid following procedures analogous to those described in Example 75 Step 1. LC-MS Method 2 tR=0.964 min, m/z=525.21; 1H NMR (CDCl3) 1.31-1.43 (m, 1H), 1.50 (d, 3H), 1.62 (m, 2H), 1.07-2.09 (m, 2H), 2.13-2.47 (m, 3H), 2.83 (d, 6H), 3.01 (m, 3H), 4.35 (s, 1H), 5.66 (m, 1H) 7.07 (m, 2H), 7.14 (m, 2H), 7.29 (m, 5H), 7.44 (m, 2H), 7.65 (m, 1H), 7.73 (d, 1H), 8.78 (d, 1H).
Reaction SMILES: C1(C[N:8]2[C:14](=[O:15])[C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[NH:11][C:10]3[N:20]=[CH:21][CH:22]=[CH:23][C:9]2=3)C=CC=CC=1.[H-].[Na+].Br[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>CN(C)C=O>[N:33]1([CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][N:11]2[C:12]3[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=3[C:14](=[O:15])[NH:8][C:9]3[CH:23]=[CH:22][CH:21]=[N:20][C:10]2=3)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: O=C1c2ccccc2Nc2ncccc2N1Cc1ccccc1
Reactant: BrCCCCCCN1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1Nc2cccnc2N(CCCCCCN2CCCCC2)c2ccccc21
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
24.1 g (0.08 mol) of 5,11-dihydro-5-(phenylmethyl)-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one (m.p. 152°-154° C.) were dissolved in 180 ml of anhydrous dimethylformamide, then 2.88 g (0.096 mol) of an 80% sodium hydride dispersion in mineral oil were added at ambient temperature and the resulting mixture was stirred for 45 minutes at 60° C. Then 23.8 g (0.096 mol) of 1-bromo-6-(1-piperidinyl)hexane were added dropwise and the mixture was heated to 120° C. for 30 minutes. After evaporation in vacuo, the residue was partitioned between dichloromethane and 5% aqueous hydrochloric acid, the aqueous phase was separated off and made alkaline with sodium hydroxide. The oil separated was taken up in dichloromethane, the solvent was distilled off in a water jet vacuum, the oily, highly viscous residue was carefully stirred with 250 g of 100% orthophosphoric acid and 7.5 g of phenol and the resulting mixture was heated to 120° C. for 3 hours. The mixture cooled to 70° C. was stirred into 2 kg of crushed ice, then made significantly alkaline by the addition of caustic soda and extracted exhaustively with dichloromethane. The dichloromethane extracts were dried over sodium sulphate and evaporated down, the residue remaining was digested with 10 ml of boiling ether and filtered while hot. The ether was evaporated off, the residue was purified by chromatography on silica gel (Macherey-Nagel, 0.2-0.5 mm) using dichloromethane/methanol/cyclohexane/ethyl acetate/conc. ammonia 59/7.5/7.5/25/1 (v/v/v/v/v) as eluant. By evaporating the appropriate fractions and subsequent recrystallisation from acetonitrile, colourless crystals with a melting point of 131°-132° C. were obtained in a yield of 21.8 g (72% of theory) which were found, according to their mixed melting point, thin layer chromatogram, IR, UV., 1H-NMR spectra, to be totally identical to a preparation prepared according to Example 6.
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH2:3][N:4]([CH2:11][C:12]1[S:16][C:15]([CH3:17])=[N:14][C:13]=1[CH3:18])[CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[C:20]([OH:29])(=[O:28])[C@@H:21]([C@H:23]([C:25]([OH:27])=[O:26])[OH:24])[OH:22]>CO>[C:25]([CH:23]([CH:21]([C:20]([OH:29])=[O:28])[OH:22])[OH:24])([OH:27])=[O:26].[CH3:1][CH:2]([CH3:19])[CH2:3][N:4]([CH2:11][C:12]1[S:16][C:15]([CH3:17])=[N:14][C:13]=1[CH3:18])[CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: Cc1nc(C)c(CN(CC(C)C)C2CCNCC2)s1
Solvent: CO
Product: O=C(O)C(O)C(O)C(=O)O
Reaction time: 1.5 h

Procedure:
N-(2-Methylpropyl)-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]piperidin-4-amine (0.70 g, 2.49 mmol) and L-tartaric acid (0.37 g, 2.49 mmol) are dissolved in methanol (25 ml). The solution is stirred for 1.5 h and concentrated. The solid is dried in a vacuum oven overnight to yield (1.05 g, 98%) N-(2-methylpropyl)-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]piperidin-4-amine tartrate: mass spectrum (ion spray): m/z=282.2 (M+1); 1H NMR (CD3OD): δ=4.45 (2H, s), 3.77 (2H, s), 3.47 (2H, brd), 3.00-2.91 (2H, m), 2.88-2.79 (1H, m), 2.62 (3H, s), 2.34-2.30 (5H, m), 1.99 (2H, brd), 1.85-1.70 (3H, m), 0.93 (6H, d).
Reaction SMILES: [CH3:1][C:2]1([CH3:58])[C:10]2[C:5](=[C:6]([CH2:11][O:12][CH:13]3[CH:18]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=5[O:37][CH3:38])=[CH:21][CH:20]=4)[CH2:17][CH2:16][N:15]([C:39]([O:41][CH2:42][C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)=[O:40])[CH2:14]3)[CH:7]=[CH:8][CH:9]=2)[N:4](COCC[Si](C)(C)C)[C:3]1=[O:57].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][C:2]1([CH3:58])[C:10]2[C:5](=[C:6]([CH2:11][O:12][CH:13]3[CH:18]([C:19]4[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=5[O:37][CH3:38])=[CH:23][CH:24]=4)[CH2:17][CH2:16][N:15]([C:39]([O:41][CH2:42][C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)=[O:40])[CH2:14]3)[CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:57]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2cccc3c2N(COCC[Si](C)(C)C)C(=O)C3(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2cccc3c2NC(=O)C3(C)C)cc1

Procedure:
The solution of 0.690 g of benzyl 3-[3,3-dimethyl-2-oxo-1-(2-trimethylsilanylethoxymethyl)-2,3-dihydro-1H-indol-7-ylmethoxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 7.2 ml of tetrahydrofuran is admixed with 17.9 ml of tetrabutylammonium fluoride solution (1M in tetrahydrofuran) and stirred at reflux over 26 hours. The reaction mixture is cooled, poured onto water (100 ml) and extracted with tert-butyl methyl ether (2×100 ml). The organic phases are washed with brine (1×100 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as an orange oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.22 (1:1 EtOAc-heptane); Rt=5.89.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[OH:7][CH:8]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:9][CH2:10][CH:11]1[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[C:14](=[O:25])[CH2:13][S:12]1.C(Cl)(Cl)Cl>CO.O>[OH:7][CH:8]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:9][CH2:10][CH:11]1[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[C:14](=[O:25])[CH2:13][S:12]1=[O:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCCCCC(O)CCC1SCC(=O)N1CCCCCCC(=O)O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCCCC(O)CCC1N(CCCCCCC(=O)O)C(=O)CS1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.1 %

Procedure:
Sodium metaperiodate (749 mg., 3.5 millimole) is added to a turbid solution of 7-[2-(3-hydroxyoctyl)-4-oxo-3-thiazolidinyl]heptanoic acid (1.24 g., 3.44 millimole) in methanol-water (5:4; v:v; 18 ml.) cooled in an ice bath (0° to 5° C.). After removing the cooling bath, the reaction mixture is stirred at ambient temperature for 16 hours. Precipitated solid is removed by filtration. The filtrate is diluted with cold water and extracted twice with chloroform. The combined organic extract is washed with saturated aqueous brine, dried over magnesium sulfate, and filtered. Evaporation of the filtrate in vacuo leaves an oily residue which is applied to a silica gel column (20 g.) with chloroform. Elution with chloroform-acetic acid (25:1; v:v; 310 ml.) gives an impure forerun which is discarded. Continued elution with the same eluant (330 ml.) provides the title compound as a plae yellow oil (750 mg., 58%); pmr (CDCl3) δ 0.88 (3H, t), 4.47 (H, m) and 7.76 (2H, s, D2O exchangeable). Anal. Calcd. for C18H33NO5S: N, 3.73. Found: N, 3.37.
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[N:10]=[C:6]2[N:5]=[C:4]([CH2:12][OH:13])[CH:3]=1.CN(C=O)C.[C:19](O)(=[O:21])[CH3:20].C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC.C(O)(C)C>[C:19]([O:13][CH2:12][C:4]1[CH:3]=[C:2]([OH:1])[N:7]2[N:8]=[C:9]([CH3:11])[N:10]=[C:6]2[N:5]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)O
Reactant: Cc1nc2nc(CO)cc(O)n2n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CC(C)O
Product: CC(=O)OCc1cc(O)n2nc(C)nc2n1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
A mixture of 33.06 g of 7-hydroxy-5-hydroxymethyl-2-methyl-s-triazolo[1,5-a]pyrimidine, 500 ml of DMF, 86 ml of anhydrous acetic acid and 1.5 g of p-toluenesulfonic acid was stirred in a bath at 50 ° C. for 6 hours. To an oily isopropanol to dissolve therein, and the solution was dropwise in 4 liters of ether. Precipitates were collected by filtration and dried to obtain 38.08 g of the compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([NH2:7])=O.S(Cl)(Cl)=O>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]#[N:7]
Reactant: NC(=O)c1ccc(F)c(Br)c1
Solvent: O=S(Cl)Cl
Product: N#Cc1ccc(F)c(Br)c1
Yield: 90 %

Procedure:
765 g (3.5 moles) of 3-bromo-4-fluoro-benzoic acid amide was added, at 25° C., to 1,150 g (9.7 moles) of thionyl chloride and the mixture was heated under reflux at 85° to 90° C., while stirring, until virtually no further evolution of gas took place. The excess thionyl chloride was then distilled off and the residue was fractionated in a short column. 630 g (91% of theory) of 3-bromo-4-fluoro-benzonitrile with a boiling point of 115°-116° C./20 mm Hg were obtained.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH:12]1[CH2:18][CH2:17][NH:16][CH2:15][C:14]2[CH:19]=[C:20]([C:23]3[N:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[CH:21]=[CH:22][C:13]1=2.[C:29]([OH:38])(=[O:37])[C@@H:30]([C@H:32]([C:34]([OH:36])=[O:35])[OH:33])[OH:31].O>CO>[C:34]([CH:32]([CH:30]([C:29]([OH:38])=[O:37])[OH:31])[OH:33])([OH:36])=[O:35].[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH:12]1[CH2:18][CH2:17][NH:16][CH2:15][C:14]2[CH:19]=[C:20]([C:23]3[N:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[CH:21]=[CH:22][C:13]1=2
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: c1cnnc(-c2ccc3c(c2)CNCCC3Oc2ccc3ccccc3c2)c1
Solvent: O
Solvent: CO
Product: O=C(O)C(O)C(O)C(=O)O

Procedure:
To a solution of the product (45 mg, 0.12 mmol) from Step J above in methanol (1 mL) was added L-tartaric acid (17 mg, 0.12 mmol) followed by slow addition of water (5 mL). The resultant solution was lyophilized overnight to give (+)-5-(naphthalen-2-yloxy)-8-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine, tartrate salt (58 mg, 94%, AUC HPLC>99%) as white solid: mp 122-124° C.; 1H NMR (CD3OD, 500 MHz) δ 9.18 (d, J=5.0 Hz, 1H), 8.21 (s, 1H), 8.19 (d, J=8.7 Hz, 1H), 8.09 (d, J=8.0 Hz, 1H), 7.81-7.76 (m, 4H), 7.70 (d, J=8.2 Hz, 1H), 7.40 (t, J=8.2 Hz, 1H), 7.37 (s, 1H), 7.34-7.31 (m, 2H), 5.94 (d, J=8.2 Hz, 1H), 4.88-4.81 (m, 1H), 4.60-4.56 (m, 1H), 4.40 (s, 2H), 3.98-3.90 (m, 1H), 3.70-3.60 (m, 1H), 2.92 (s, 3H), 2.54-2.48 (m, 2H); ESI MS m/z 382 [M+H].
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[CH:5][CH:4]=1)=O.[CH:19]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)([CH3:21])[CH3:20].[BH4-].[Na+]>CO>[CH:19]([N:22]1[CH2:27][CH2:26][N:25]([CH2:1][C:3]2[CH:18]=[CH:17][C:6]([O:7][C:8]3[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=3)=[CH:5][CH:4]=2)[CH2:24][CH2:23]1)([CH3:21])[CH3:20]
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Reactant: CC(C)N1CCNCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)N1CCN(Cc2ccc(Oc3ccc(C(N)=O)cn3)cc2)CC1
Yield: 35.4 %

Procedure:
Using a method similar to Example 334, using 6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1) (0.304 g, 1.26 mmol), 1-isopropyl-piperazine (0.161 g, 1.26 mmol), and sodium borohydride (0.108 g, 2.85 mmol) in methanol (12 mL) provides 0.158 g (32%) of the title compound as a white solid (chromatography solvent: ethyl acetate→7:3 ethyl acetate:methanol): high resolution mass spectrum (electrospray): m/z calc for C20H27N4O2 355.2134, found 355.2140; 1H NMR (methanol-d4): 8.67 (d, 1H, J=2.0 Hz), 8.30 (dd, 1H, J=2.4, 8.8 Hz), 7.48-7.43 (m, 2H), 7.18-7.13 (m, 2H), 7.04 (d, 1H, J=8.3 Hz), 3.56 (s, 2H), 2.79-2.52 (m, 9H), 1.13 (d, 6H, J=6.8 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:9]2[C:10]([Cl:15])=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[S:7][CH:6]=1.[CH3:17][C:18]1[C:23]([CH2:24]O)=[CH:22][CH:21]=[C:20]([C:26]([F:29])([F:28])[F:27])[N:19]=1.C(P(CCCC)CCCC)CCC.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:9]2[C:10]([Cl:15])=[CH:11][C:12]([O:14][CH2:24][C:23]3[C:18]([CH3:17])=[N:19][C:20]([C:26]([F:29])([F:27])[F:28])=[CH:21][CH:22]=3)=[CH:13][C:8]=2[S:7][CH:6]=1
Reactant: COC(=O)Cc1csc2cc(O)cc(Cl)c12
Reactant: Cc1nc(C(F)(F)F)ccc1CO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)Cc1csc2cc(OCc3ccc(C(F)(F)F)nc3C)cc(Cl)c12
Temperature: 25 °C
Reaction time: 12 h
Yield: 89 %

Procedure:
To a mixture of methyl(4-chloro-6-hydroxy-1-benzothiophen-3-yl)acetate (110 mg) and THF (dry) (5 mL) were added (2-methyl-6-(trifluoromethyl)pyridin-3-yl)methanol (82 mg), tri-n-butylphosphine (0.159 mL), and ADDP (130 mg) at room temperature. The mixture was stirred at room temperature for 12 h. The insoluble material was removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (164 mg). The compound was crystallized from IPE-hexane.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12](=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([Cl:21])=[C:7]([F:20])[CH:8]=2)[N:3]=1.CO[CH:24](OC)[N:25]([CH3:27])[CH3:26]>C(OCC)(=O)C>[Cl:1][C:2]1[C:11]([C:12]([C:13](=[CH:24][N:25]([CH3:27])[CH3:26])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:19])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([Cl:21])=[C:7]([F:20])[CH:8]=2)[N:3]=1
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)CC(=O)c1cc2cc(F)c(Cl)cc2nc1Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(Cl)cc2nc1Cl
Reaction time: 2 h

Procedure:
A suspension of 16.5 g of ethyl 3-(2,7-dichloro-6-fluoro-3-quinolyl)-3-oxopropionate in 160 cm3 of ethyl acetate and 19 cm3 of N,N-dimethylformamide dimethyl acetal is heated at a temperature close to 75° C., with stirring, for 2 hours. The reaction mixture is concentrated to dryness under reduced pressure (20 kPa) at 50° C. The dry extract is taken up in 50 cm3 of diisopropyl ether, drained and washed with twice 10 cm3 of diisopropyl ether. 16.57 g of ethyl 2-(2,7-dichloro-6-fluoro-quinoline-3-carbonyl)-3-dimethylaminoacrylate are obtained in the form of an orange solid melting at 122° C. This product is used for the subsequent steps without further purification.
Reaction SMILES: N(CCC1C=CC(F)=CC=1)=[N+]=[N-].[N:13]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[N+:14]=[N-:15].[CH2:24]([NH:31][C:32]([C:34]1[S:38][C:37]([C:39]#[CH:40])=[N:36][C:35]=1[CH3:41])=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([NH:31][C:32]([C:34]1[S:38][C:37]([C:39]2[N:15]=[N:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH:40]=2)=[N:36][C:35]=1[CH3:41])=[O:33])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: [N-]=[N+]=NCc1ccc(F)cc1
Reactant: C#Cc1nc(C)c(C(=O)NCc2ccccc2)s1
Agent: [N-]=[N+]=NCCc1ccc(F)cc1
Product: Cc1nc(-c2cn(Cc3ccc(F)cc3)nn2)sc1C(=O)NCc1ccccc1
Yield: 59 %

Procedure:
Following the procedure as described in Example 1, making variations as necessary to replace 1-(2-azidoethyl)-4-fluorobenzene with 1-(azidomethyl)-4-fluorobenzene to react with N-benzyl-2-ethynyl-4-methylthiazole-5-carboxamide, the title compound was obtained as a white solid in 59% yield: mp 114-115° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.96 (s, 1H), 7.45-7.19 (m, 7H), 7.12-6.99 (m, 2H), 6.19 (t, J=5.6 Hz, 1H), 5.51 (s, 2H), 4.58 (d, J=5.6 Hz, 2H), 2.66 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.9, 161.7, 157.8, 155.5, 142.9, 137.9, 130.3, 129.6, 128.7, 127.8, 127.6, 125.0, 121.9, 115.3, 53.8, 44.1, 17.2; MS (ES+) m/z 408.3 (M+1).