Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(N)([O-])[O-].[CH3:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[CH2:12])=[CH:9][CH:8]=1.[C:15]1(=[O:21])[CH2:20][CH2:19][CH2:18][CH:17]=[CH:16]1.C[Si](Cl)(C)C>CCOCC.C(Cl)Cl.[Cu].C1C=CC=CC=1>[CH3:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][CH2:12][C@H:17]2[CH2:18][CH2:19][CH2:20][C:15](=[O:21])[CH2:16]2)=[CH:9][CH:8]=1
Reactant: C=Cc1ccc(OC)cc1
Reactant: O=C1C=CCCC1
Agent: [Cu]
Agent: C[Si](C)(C)Cl
Agent: NP([O-])[O-]
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: ClCCl
Product: COc1ccc(CC[C@H]2CCCC(=O)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.5 %

Procedure:
(C6H6) (10.1 mg, 0.02 mmol, 0.05 eq.) and the phosphoramidite ligand (21.6 mg, 0.040 mmol, 0.10 eq.) were dissolved in Et2O (2.0 mL) under an argon atmosphere and allowed to stir for 1 h at room temperature. In another flask, Cp2ZrHCl (206.0 mg, 0.80 mmol, 2.0 eq.) was added to a stirred, room temperature, solution of 4-methoxystyrene (0.13 mL, 1.0 mmol, 2.5 eq.) in CH2Cl2 (0.40 mL) under an argon atmosphere. After stirring for 15 min, the resulting clear red/orange solution was transferred via syringe over about 1 min to the stirred solution containing the copper and ligand under an argon atmosphere. The resulting black mixture was allowed to stir for an additional 10 minutes before cyclohexenone (39 μL, 0.40 mmol, 1.0 eq) and then TMSCl (0.26 mL, 2.0 mmol, 5.0 eq.) were added dropwise via syringe. Stirring continued at room temperature for 4 h before the reaction was quenched by the addition of Et2O (ca 3 mL) and then NH4Cl (1M aq., ca 1.5 mL). The mixture was partitioned between the aqueous and Et2O layers and the aqueous phase extracted with Et2O (3×10 mL). The combined organic phase was washed with NaHCO3 (aq. sat., ca 10 mL), dried (Na2SO4), filtered and concentrated in vacuo. Flash column chromatography of the yellow residue (1:9 EtOAc/petrol; SiO2) gave (R)-3-(4-methoxyphenethyl)cyclohexanone (45 mg, 0.19 mmol, 48%) as a colourless oil. HPLC analysis indicated an enantiomeric excess of 90% [Chiralpak® IA; flow: 1 mL/min; hexane/i-PrOH: 90:10; λ=210 nm; minor enantiomer (S)-3-(4-methoxyphenethyl)-cyclohexanone, tR=11.4 minutes; major enantiomer (R)-3-(4-methoxyphenethyl)-cyclohexanone, tR=12.2 minutes]. 1H NMR (500 MHz, CDCl3) δH/ppm 1.33-1.44 (m, 1H) 1.55-1.71 (m, 3H) 1.81 (apparent tspt, J=11.03, 3.50 Hz, 1H) 1.92-1.99 (m, 1H) 2.02-2.10 (m, 2H) 2.27 (dddd, J=13.70, 12.50, 6.50, 1.40 Hz, 1H) 2.33-2.40 (m, 1H) 2.48 (ddt, J=13.75, 4.14, 1.93, 1.93 Hz, 1H) 2.58 (t, J=8.04 Hz, 2H) 3.79 (s, 3H) 6.83 (d, J=8.83 Hz, 2H) 7.09 (d, J=8.80 Hz, 2H); 13C NMR (126 MHz, CDCl3) δC/ppm 25.2, 31.2, 32.0, 38.4, 38.6, 41.5, 48.0, 55.2, 113.8 (2C), 129.1 (2C), 134.0, 157.8, 211.8; HRMS (ESI) m/z calcd for C16H20NaO2 [M+Na]+: 255.1356 found: 255.1349; [α]24589=−20.1 (c 1.03, CHCl3); IR (vmax/cm−1): 1710, 2933.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:5])#[N:2].C(N(CC)CC)C.[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[C:21]([N+:28]([O-:30])=[O:29])[CH:20]=1.[OH-].[Na+].Cl>C1COCC1.C(Cl)Cl>[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([CH:3]([C:1]#[N:2])[C:4]([O:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:5])=[O:24])=[C:21]([N+:28]([O-:30])=[O:29])[CH:20]=1
Reactant: CCCCOC(=O)CC#N
Reactant: O=C(Cl)c1ccc(Cl)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCOC(=O)C(C#N)C(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.3 %

Procedure:
Butyl cyanoacetate (6.35 g; 0.05 mol) and triethylamine (20.9 ml; 0.15 mol) were dissolved in dry THF (100 ml) under dry nitrogen, and 4-chloro-2-nitrobenzoyl chloride (11.0 g; 0.05 mol) in dry THF (100 ml) added dropwise over 45 min. The mixture was stirred at room temperature under dry nitrogen for 18 hours, during which time a precipitate was formed. The solution was filtered and evaporated, giving a residue which was treated with 2M sodium hydroxide solution (200 ml) and CH2Cl2 (100 ml). This formed three layers. The middle layer was treated with 2M hydrochloric acid (50 ml) and extracted into CH2Cl2 (3×50 ml). The extracts were combined, dried (Na2SO4), filtered and evaporated, giving butyl 2-(4-chloro-2-nitrobenzoyl)-2-cyanoacetate (10.27 g; 63%) as a yellow solid, m.p. 56°-58° C., (Found, C: 52.01; H: 4.05; N: 8.70; Cl: 10.97. C14H13ClN2O5 requires C: 51.77; H: 4.01; N: 8.63; Cl: 10.94%), d (CDCl3 ; 60 MHz) 0.8-2.1 (7H, m), 4.4 (2H, t, J=6 Hz), 7.65 (2H, m), 8.15 (1H, d, J=2 Hz) and 13.0 (1H, br, s), vmax (nujol) 2230, 1660, 1610, 1590 and 1540.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]=1[NH2:18])=[O:5])[CH3:2].Cl[CH:20]([C:26]([O-])=[O:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]=1[NH:18][C:26](=[O:27])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:5])[CH3:2]
Reactant: CCOC(=O)C(Cl)C(=O)[O-]
Reactant: CCOC(=O)c1c(-c2ccc(Br)cc2)csc1N
Solvent: ClCCl
Product: CCOC(=O)CC(=O)Nc1scc(-c2ccc(Br)cc2)c1C(=O)OCC
Yield: 98.4 %

Procedure:
To a solution of 2-amino-4-(4-bromophenyl)-thiophene-3-carboxylic acid ethyl ester (4.00 g, 11.5 mmol) in CH2Cl2 (40 mL) was added ethyl chloromalonate (2.15 g, 14.2 mmol) slowly. The mixture was then heated to reflux for 30 min. The mixture was concentrated under reduced pressure and separated by flash chromatography on silica gel (5–30% ethyl acetate in hexanes) giving the titled compound (4.98 g, 98.5%).
Reaction SMILES: [NH:1]([C:5]1[S:6][C:7]([C:11]([OH:13])=O)=[C:8]([CH3:10])[N:9]=1)[C:2]([NH2:4])=[NH:3].Cl.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:18][CH:17]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH:1]([C:5]1[S:6][C:7]([C:11]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:20][CH:21]=2)=[O:13])=[C:8]([CH3:10])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: Cc1nc(NC(=N)N)sc1C(=O)O
Reactant: CCOC(=O)COc1ccc(N)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(NC(=O)c2sc(NC(=N)N)nc2C)cc1
Yield: 48.8 %

Procedure:
400 mg of 2-guanidino-4-methyl-thiazole-5-carboxylic acid, 463 mg of ethyl 4-amino-phenyloxyacetate hydrochloride, 6 ml of DMF, 0.67 ml of N-MM and 759 mg of HBTU are stirred at RT for 22 hrs. The working up and purification are effected as described in Example 1. Crystallization from acetonitrile (MeCN) gives 368 mg of ethyl {4-[(2-guanidino-4-methyl-thiazole-5-carbonyl)-amino]-phenoxy}-acetate, m.p. 223° C.;, MS: 378 (M+H)+.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH:10]([NH:17][C:18]1[C:27]2[C:22](=[C:23]([C:30](=[O:32])[NH2:31])[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C)(C)(C)C.C1COCC1.Cl>O1CCOCC1>[CH3:29][O:28][C:25]1[CH:26]=[C:27]2[C:22](=[C:23]([C:30]([NH2:31])=[O:32])[CH:24]=1)[N:21]=[CH:20][N:19]=[C:18]2[NH:17][CH:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:9][NH:7][CH3:6]
Reactant: COc1cc(C(N)=O)c2ncnc(NC(CN(C)C(=O)OC(C)(C)C)c3ccccc3)c2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CNCC(Nc1ncnc2c(C(N)=O)cc(OC)cc12)c1ccccc1
Reaction time: 8 h
Yield: 100 %

Procedure:
A scintillation vial equipped with a stir bar was charged with [2-(8-carbamoyl-6-methoxy-quinazolin-4-ylamino)-2-phenyl-ethyl]-methyl-carbamic acid tert-butyl ester (150 mg, 0.33 mmol) and THF, (5 mL). Then, 4 M HCl in dioxane, (5 mL) was added at RT and the mixture was stirred overnight. After 18 h, a white precipitate had formed and LCMS indicated consumption of SM. The mixture was diluted with Et2O (30 mL) and the precipitate was filtered through a filter paper and washed with Et2O, (30 mL). The solid was dried under vacuum. Amount obtained: 114 mg, 0.32 mmol, 100% yield. LCMS (ESI) 352 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:38][C:39]2[CH:44]=[CH:43][C:42]([S:45]([CH3:48])(=[O:47])=[O:46])=[CH:41][CH:40]=2)=[N:4][C:5]2[N:6]([N:25]=[CH:26][C:27]=2[C:28]2[CH:29]=[N:30][C:31]3[C:36]([CH:37]=2)=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:7]=1[N:8](COCC[Si](C)(C)C)COCC[Si](C)(C)C.C(O)(C(F)(F)F)=O.O>>[Br:1][C:2]1[C:3]([O:38][C:39]2[CH:40]=[CH:41][C:42]([S:45]([CH3:48])(=[O:47])=[O:46])=[CH:43][CH:44]=2)=[N:4][C:5]2[N:6]([N:25]=[CH:26][C:27]=2[C:28]2[CH:29]=[N:30][C:31]3[C:36]([CH:37]=2)=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:7]=1[NH2:8]
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1c(Br)c(Oc2ccc(S(C)(=O)=O)cc2)nc2c(-c3cnc4ccccc4c3)cnn12
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CS(=O)(=O)c1ccc(Oc2nc3c(-c4cnc5ccccc5c4)cnn3c(N)c2Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The crude, 6-bromo-5-(4-(methylsulfonyl)phenoxy)-3-(quinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine from above step E was treated with 50% TFA/H2O (3 mL) and stirred at room temperature for 1 h. Solvent was removed to yield thick oil which was purified by prep HPLC to give the final product. 6-bromo-5-(4-(methylsulfonyl)phenoxy)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-7-amine. HPLC-MS tR=1.37 min (UV254 nm); mass calculated for formula C22H16BrN5O3S2 509.0, observed LCMS m/z 510.0 (M+H).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]([O:11][CH2:12][CH3:13])=[O:10].CN(C1C=CC=CN=1)C.[CH2:23]([NH:27][C:28]1[N:36]=[C:35]2[C:31]([N:32]=[C:33]([OH:46])[N:34]2[CH2:37][C:38]2[CH:39]=[N:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=2)=[C:30]([NH2:47])[N:29]=1)[CH2:24][CH2:25][CH3:26]>C(Cl)Cl.O>[CH2:23]([NH:27][C:28]1[N:36]=[C:35]2[C:31]([N:32]=[C:33]([O:46][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:34]2[CH2:37][C:38]2[CH:39]=[N:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=2)=[C:30]([NH2:47])[N:29]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCNc1nc(N)c2nc(O)n(Cc3ccc(OC)nc3)c2n1
Reactant: CCOC(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCNc1nc(N)c2nc(OC(=O)OCC)n(Cc3ccc(OC)nc3)c2n1
Yield: 70.6 %

Procedure:
Triethylamine (100 μL, 0.75 mmol), ethyl chloroformate (67 μL, 0.70 mmol), and dimethylaminopyridine (20 mg, 0.17 mmol) were added to a solution (15 ml) of the compound (200 mg, 0.58 mmol) obtained in Example 19 in methylene chloride in that order, and the resultant was allowed to react at room temperature for 15 hours. Water was added to the reaction solution to extract an organic layer. The organic layer was washed with an aqueous solution of 5% citric acid and 10% saline solution and dried over anhydrous sodium sulfate. The solvent was then removed by distillation. Hexane was added to the residue, and the solid was precipitated, followed by collection by filtration. Thus, 170 mg of the title compound was obtained as a white powdery solid (yield: 71%).
Reaction SMILES: C(O[C:6]([N:8]([CH2:10][C:11]1[N:12]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]([C:38]([OH:40])=[O:39])=[O:37])=[CH:26][CH:25]=2)[C:13]([C:20]([OH:22])=[O:21])=[C:14]([C:16]([OH:19])([CH3:18])[CH3:17])[N:15]=1)C)=O)(C)(C)C.[ClH:41]>O1CCOCC1>[ClH:41].[OH:19][C:16]([C:14]1[N:15]=[C:11]([CH2:10][NH:8][CH3:6])[N:12]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]([C:38]([OH:40])=[O:39])=[O:37])=[CH:28][CH:29]=2)[C:13]=1[C:20]([OH:22])=[O:21])([CH3:17])[CH3:18]
Reactant: CN(Cc1nc(C(C)(C)O)c(C(=O)O)n1Cc1ccc(-c2ccccc2C(=O)C(=O)O)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CNCc1nc(C(C)(C)O)c(C(=O)O)n1Cc1ccc(-c2ccccc2C(=O)C(=O)O)cc1

Procedure:
339 mg of 2-(N-t-Butoxycarbonyl-N-methylaminomethyl)-4-(1-hydroxy-1-methylethyl)-1-[(2'-oxalobiphenyl-4-yl) methyl]imidazole-5-carboxylic acid [prepared as described in step (b) above] were subjected to de-t-butoxycarbonylation using 3 ml of a 4N solution of hydrogen chloride in dioxane in the same manner as described in Example 3(b), to give 260 mg of the title compound, melting at 172°-175° C. (with decomposition).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:12][CH2:11]1)[CH:5]=O.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24]C1>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:12][CH2:11]1)[CH2:5][N:22]1[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: C1CCNCC1
Reactant: Cc1cc(C=O)ccc1N1CCC(CN2CCCC2)CC1
Product: Cc1cc(CN2CCCC2)ccc1N1CCC(CN2CCCC2)CC1

Procedure:
Prepared from the product of Example 66 and piperidine.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([S:13]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)(=[O:15])=[O:14])=[CH:9][CH:8]=1.[B:21](OC(C)C)([O:26]C(C)C)[O:22]C(C)C>O1CCCC1>[N:16]1([S:13]([C:10]2[CH:11]=[CH:12][C:7]([B:21]([OH:26])[OH:22])=[CH:8][CH:9]=2)(=[O:15])=[O:14])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=S(=O)(c1ccc(Br)cc1)N1CCCC1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(B(O)O)cc1)N1CCCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 70.4 %

Procedure:
n-Butyllithium (20 mL, 31 mmol) was added dropwise over 30 min to a cooled (−78° C.) solution of 1-[(4-bromobenzenesulfonyl)pyrrolidine (3.0 g, 10.3 mmol) and triisopropyl borate (7.2 mL, 30.9 mol) in anhydrous tetrahydrofuran (10 mL) under a nitrogen atmosphere. The reaction mixture was stirred for 1 h at −78° C. whereafter the temperature was allowed to reach room temperature over 3 h. Silica gel was added and the solvent was evaporated. Chromatography on a silica gel column using a gradient methylene chloride (100%) to methylene chloride/ethanol, (1:1), gave 1.85 g (70% yield) of the title compound as a white solid: 1H NMR (CD3OD, 400 MHz) δ 7.90 (d, J=7 Hz, 2H), 7.75 (d, J=8 Hz, 2H), 3.21 (m, 4H), 1.72 (m, 4H); 13C NMR (CDCl3/CD3OD (1:1), 100 MHz) δ 136.79, 133.50, 125.48, 47.19, 24.30; MS (ES) m/z 256 (M++1).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1([CH:18]([O:20]C(=O)C)[CH3:19])[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7]1)=[O:5]>CO>[CH3:2][O:3][C:4]([C:6]1([CH:18]([OH:20])[CH3:19])[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7]1)=[O:5]
Reactant: COC(=O)C1(C(C)OC(C)=O)CCN(Cc2ccccc2)C1
Agent: Cl
Solvent: CO
Product: COC(=O)C1(C(C)O)CCN(Cc2ccccc2)C1

Procedure:
2M HCl (25 ml) was added to a solution of 3-(1-Acetoxy-ethyl)-1-benzyl-pyrrolidine-3-carboxylic acid methyl ester (2N) (5 g, 16.39 mmol) in MeOH (50 ml) at room temperature, then refluxed for 2 hours. The solvent was evaporated yielding the product (4.39, 100%) ESMS (MH, 264).
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([NH:25][C:26]([NH:28][C:29](=[O:37])[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[S:27])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]2)=[O:13])[CH:6]=1.Cl.[CH3:39][NH:40][CH3:41].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:39][N:40]([CH3:41])[CH:17]1[CH2:18][CH2:19][N:14]([C:12]([NH:11][C:7]2[CH:6]=[C:5]([O:4][C:3]3[CH:21]=[CH:22][C:23]([NH:25][C:26]([NH:28][C:29](=[O:37])[CH2:30][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)=[S:27])=[CH:24][C:2]=3[F:1])[CH:10]=[CH:9][N:8]=2)=[O:13])[CH2:15][CH2:16]1
Reactant: O=C1CCN(C(=O)Nc2cc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)ccn2)CC1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)C1CCN(C(=O)Nc2cc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)ccn2)CC1
Reaction time: 8 h
Yield: 56.8 %

Procedure:
To a solution of 4-{2-fluoro-4-[3-(2-phenylacetyl)thioureido]phenoxy}-2-[(4-oxopiperidin-1-yl)carbonylamino]pyridine (38 mg) in dichloromethane (2.0 ml) were added dimethylamine HCl (15 mg) and sodium triacetoxyborohydride (40 mg) at room temperature, followed by stirring overnight. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under a reduced pressure to give a residue, which was dried in vacuum to provide the titled compound (22.8 mg, 57%) as white powder.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH2:23][CH2:22][C:21]([C:30](O)=[O:31])=[CH:20][C:19]=3[CH:33]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].S(Cl)(Cl)=O.[CH3:38][N:39]([CH:41]=O)[CH3:40]>C1COCC1>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH2:23][CH2:22][C:21]([C:30]([NH:24][C:18]4[CH:19]=[CH:33][C:15]([CH2:41][N:39]([CH3:38])[CH:40]5[CH2:7][CH2:6][O:5][CH2:1][CH2:2]5)=[CH:16][CH:17]=4)=[O:31])=[CH:20][C:19]=3[CH:33]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CN(C)C=O
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CCCOC)cc1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3CCCOC)cc1
Reaction time: 1 h

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-(3-methoxypropyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (200 mg) in THF (10 ml) were added thionyl chloride (0.064 ml) and DMF (one droplet) at room temperature, and the mixture was stirred for 1 hour. The solvent was evaporated under reduced pressure, and the resulting residue was dissolved in THF (15 ml), which was added dropwise to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (107 mg) and triethylamine (0.37 ml) in THF (5 ml) at 0° C. The mixture was stirred at room temperature for 18 hours, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried with magnesium sulfate. After concentration under reduced pressure, the residue was purified with column chromatography (ethanol:ethyl acetate=1:3), and the resulting crystals were purified by recrystallization (hexane-ethyl acetate) to give 7-[4-(2-butoxyethoxy)phenyl]-1-(3-methoxypropyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 104) (264.2 mg) as yellow crystals.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]#[C:10][C:11]1[CH:12]=[C:13]([C:23]([N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:24])[N:14](C(OC(C)(C)C)=O)[CH:15]=1.C[Si]([N:34]=[N+:35]=[N-:36])(C)C>>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[NH:36][N:35]=[N:34][C:10]=1[C:11]1[CH:12]=[C:13]([C:23]([N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:24])[NH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)n1cc(C#Cc2cccc(F)c2F)cc1C(=O)N1CCCC1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Product: O=C(c1cc(-c2nn[nH]c2-c2cccc(F)c2F)c[nH]1)N1CCCC1
Temperature: 150 °C
Yield: 11 %

Procedure:
(4-(2-(2,3-difluorophenyl)ethynyl)-1-BOC-pyrrol-2-yl)(pyrrolidin-1-yl)methanone (0.2 g, 0.5 mmol) was dissolved in trimethylsilylazide (3 mL) and heated at 150° C. for 18 hr. The solvent was evaporated and the crude product was purified by Biotage HPFC system (100% EtOAC) to afford title compound as a brown foam (0.019 g, 11%).; Mass Spec FIA MS 344; 1H NMR(CDCl3, 500 MHz) 10.05(s,1H), 7.06-7.25(m, 3H), 6.98(s,1H), 6.71(s,1H),3.55-3.60(m,4H), 1.79-1.95(m,4H).
Reaction SMILES: [Na].[Br:2][C:3]1[C:4](=[O:18])[N:5]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=2)[N:6]=[CH:7][C:8]=1Br.[CH3:19][OH:20]>>[Br:2][C:3]1[C:4](=[O:18])[N:5]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=2)[N:6]=[CH:7][C:8]=1[O:20][CH3:19]
Reactant: CO
Reactant: O=c1c(Br)c(Br)cnn1-c1cc(Cl)cc(Cl)c1
Agent: [Na]
Product: COc1cnn(-c2cc(Cl)cc(Cl)c2)c(=O)c1Br

Procedure:
Sodium (0.28 g, 0.012 moles) was dissolved in methanol (100 ml) and a suspension of 4,5-Dibromo-2-(3,5-dichlorophenyl)pyridazin-3-one (4.0 g, 0.01 moles) in methanol (60 ml) was added. Refluxed overnight. Evaporated to dryness and added water. Filtered off the solid and dried in a dessicator. Triturated with ether and dried in a dessicator. (3.1 g, 89%)
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN.[CH2:19]([N:21]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C([O-])(O)=O.[Na+]>C1COCC1.CN(C=O)C>[CH3:19][NH:21][C:14]([CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][CH2:10]1)=[O:16]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)C1CCN(Cc2ccccc2)CC1
Agent: CN
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNC(=O)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1-benzylpiperidine-4-carboxylic acid (1 g, 4.56 mmol), methylamine (9.12 ml of a 2N solution in THF, 18.2 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.75 g, 9.1 mmol) and 1-hydroxybenzotriazole (0.7 g, 4.56 mmol) in 10 ml DMF was stirred at rt for 3 h. The reaction mixture was poured on saturated aqueous NaHCO3 and extracted with ethyl acetate. The organic layer was washed with NaHCO3 solution and brine, dried (Na2 SO4) and evaporated. Drying in vacuo gave a colorless solid which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([CH2:14][C:15]2[C:20]([Cl:21])=[CH:19][N:18]=[CH:17][C:16]=2[Cl:22])=[N:4][N:3]=1>C(N)CC>[Cl:22][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([Cl:21])[C:15]=1[CH2:14][C:5]1[C:6]2[C:11](=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=2)[C:2]([NH:3][CH2:2][CH2:11][CH3:10])=[N:3][N:4]=1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(Cl)c2c1
Solvent: CCCN
Product: CCCNc1nnc(Cc2c(Cl)cncc2Cl)c2ccc(OC)cc12
Yield: 157.1 %

Procedure:
4-Chloro-1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-phthalazine (3.9 g, 11 mmoles), prepared as described in example 45, and n-propylamine (40 ml) were put in autoclave at external 120° C. (internal 100° C., 4 atm) for 2 hours. The solution was concentrated to residue, taken up in CH2Cl2 and 5% HCl and extracted more times. The aqueous phase was alkalinised with K2CO3 and extracted with CH2Cl2. The resultant solid was crystallised from acetonitrile (110 ml), then filtered to give 3.26 g of the title compound (yield: 82%). m.p.: 222-223° C.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6](=O)[C:7]3[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:20].C[Si](C)(C)O[Si](C)(C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6](=[S:20])[C:7]3[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: O=C1c2ccc(Cl)cc2CCc2cc(Cl)ccc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: Cc1ccccc1
Solvent: C[Si](C)(C)O[Si](C)(C)C
Product: S=C1c2ccc(Cl)cc2CCc2cc(Cl)ccc21
Temperature: 25 °C
Yield: 191.9 %

Procedure:
To a stirred solution of 2,8-dichloro-10,11-dihydro-dibenzo[a,d]cycloheptene-5-one (0.70 g, 2.53 mMol) in toluene (20 ml) were added phosphorus pentasulfide (1 eq, 561 mg) and hexamethyldisiloxane (1 eq, 0.54 ml). The mixture was heated 3 h at reflux and allowed to cool to room temperature. The mixture was filtered through a pad of silica gel (70 g) and washed through with 8:1 heptane/ethyl acetate. Evaporation of the solvent under reduced pressure afforded 2,8-dichloro-10,11-dihydro-dibenzo[a,d]cycloheptene-5-thione as a blue solid (710 mg, 95%) that was used without further purification.