Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]3[CH:19]=[C:20]([OH:23])[CH:21]=[CH:22][C:13]2=3)=[O:11])[CH:6]=[CH:7][CH:8]=1.[Cl:26][C:27]1[CH:32]=[C:31](Cl)[N:30]=[CH:29][N:28]=1>CC(C)=O.O.[OH-].[Na+].CCOC(C)=O>[F:25][C:2]([F:24])([F:1])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]3[CH:19]=[C:20]([O:23][C:31]4[CH:32]=[C:27]([Cl:26])[N:28]=[CH:29][N:30]=4)[CH:21]=[CH:22][C:13]2=3)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)N1CCCCc2cc(O)ccc21
Reactant: Clc1cc(Cl)ncn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)=O
Product: O=C(Nc1cccc(C(F)(F)F)c1)N1CCCCc2cc(Oc3cc(Cl)ncn3)ccc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 1.00 g (2.85 mMol) of 7-hydroxy-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide (Step 6.2) and 447 mg (3.0 mMol) 4,6-dichloro-pyrimidine in 8 ml acetone, 5 ml H2O and 3 ml NaOH 1 M is stirred at rt for 5 h. The reaction mixture is diluted with water and EtOAc, the aqueous phase separated off and extracted twice with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Chromatography (Combi Flash; hexane/EtOAc 19:1→7:3→1:4) gives the title compound: m.p.: 120° C.; MS: [M+1]+=463/465; Anal.: C,H,N,F,Cl.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH:9][CH:10]([C:12]1[N:17]=[N:16][C:15]([NH:18][C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)=[N:14][CH:13]=1)[CH3:11])=O.N1C=NC=N1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[N:17]2[C:12]([CH:13]=[N:14][C:15]([NH:18][C:19]3[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=3)=[N:16]2)=[C:10]([CH3:11])[N:9]=1
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3sccc3Br)nn2)cc(OC)c1OC
Agent: c1nc[nH]n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1cc(Nc2ncc3c(C)nc(-c4sccc4Br)n3n2)cc(OC)c1OC
Yield: 14.7 %

Procedure:
In a similar manner as described for Example 9, 3-bromo-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)thiophene-2-carboxamide (Intermediate 19) (0.23 g, 0.47 mmol) and 1,2,4-triazole (100 mg, 1.5 mmol) in pyridine (4 mL) and phosphorus oxychloride (0.070 mL, 0.75 mmol) gave 7-(3-bromothien-2-yl)-5-methyl-N-(3,4,5-trimethoxyphenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (0.033 g) as a yellow solid. 1H NMR (CDCl3): δ8.82 (s, 1H), 7.47 (d, J=5.3 Hz, 1H), 7.13 (s, 1H), 7.10 (d, J=5.3 Hz, 1H), 6.89 (s, 2H), 3.80 (s, 3H), 3.75 (s, 6H), 2.63 (s, 3H). MS m/z 476, 478 (M+1, M+3).
Reaction SMILES: [F:1][C:2]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)=[O:12])[O:7][N:6]=1)([CH3:4])[CH3:3].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:40][CH3:41])=[C:29]([O:32][CH2:33][CH2:34][CH2:35][S:36]([CH3:39])(=[O:38])=[O:37])[CH:30]=2)[N:25]=[CH:24][N:23]=1>>[F:1][C:2]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:22]3[C:31]4[C:26](=[CH:27][C:28]([O:40][CH3:41])=[C:29]([O:32][CH2:33][CH2:34][CH2:35][S:36]([CH3:39])(=[O:37])=[O:38])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[O:7][N:6]=1)([CH3:3])[CH3:4]
Reactant: COc1cc2ncnc(Cl)c2cc1OCCCS(C)(=O)=O
Reactant: CC(C)(F)c1cc(NC(=O)Nc2cccc(O)c2)on1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)F)no4)c3)c2cc1OCCCS(C)(=O)=O
Yield: 60.9 %

Procedure:
The title compound was prepared from 1-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)-3-(3-hydroxyphenyl)urea (84 mg, 0.3 mmol) and 4-chloro-7-methoxy-6-(3-(methylsulfonyl)propoxy)quinazoline from Example 41B Step 1 (76 mg, 0.23 mmol) using the procedure described in Example 16C. The crude product was purified by chromatography on silica gel (25-100% EtOAc/hexanes) to afford 1-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)-3-(3-(7-methoxy-6-(3-(methylsulfonyl)propoxy)quinazolin-4-yloxy)phenyl)urea (81 mg, 0.14 mmol, 61%). 1H NMR (300 MHz, DMSO-d6) δ 10.42 (br s, 1H), 9.11 (s, 1H), 8.57 (s, 1H), 7.63-7.58 (m, 2H), 7.47-7.40 (m, 2H), 7.32 (d, 1H), 7.00 (d, 1H), 6.15 (s, 1H), 4.32 (t, 2H), 4.02 (s, 3H), 3.41-3.29 (m, 2H), 3.06 (s, 3H), 2.31-2.22 (m, 2H), 1.66 (d, 6H); LC-MS (ESI) m/z 574 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C@@H:7]2[CH2:8][C@H:3]1[CH2:4][CH2:5][C:6]2=O.Cl.[CH3:12][O:13][NH2:14].N1C=CC=CC=1>C(O)C>[CH3:12][O:13][N:14]=[C:6]1[CH2:5][CH2:4][C@H:3]2[CH2:8][C@@H:7]1[C:2]2([CH3:10])[CH3:1]
Reactant: CON
Reactant: CC1(C)[C@@H]2CCC(=O)[C@H]1C2
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CON=C1CC[C@H]2C[C@@H]1C2(C)C
Yield: 89.9 %

Procedure:
To a solution of (1S,5R)-6,6-dimethylnorpinan-2-one (3.09 g, 22.35 mmol) in ethanol (70 mL) was added O-methylhydroxylamine hydrochloride (2.05 g, 24.59 mmol) and pyridine (1.29 mL, 15.92 mmol). Heated reaction mixture to 80° C. for 4 hours. Removed solvent under reduced pressure. Diluted residue with 1N HCl and extracted twice with ether. The combined organic phases were washed with aqueous saturated NaHCO3, dried (MgSO4), filtered, concentrated in vacuo to afford 3.36 g of a colorless oil (mixture of oxime isomers) that was used without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1.[CH3:19][C:20]([Si:23]([CH3:33])([CH3:32])[O:24][CH2:25][C@H:26]([OH:31])[CH2:27][O:28][CH2:29][CH3:30])([CH3:22])[CH3:21].[H-].[Na+]>C1COCC1>[Cl:8][C:6]1[CH:7]=[C:2]([O:31][C@H:26]([CH2:27][O:28][CH2:29][CH3:30])[CH2:25][O:24][Si:23]([C:20]([CH3:19])([CH3:21])[CH3:22])([CH3:32])[CH3:33])[N:3]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:5]=1
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Reactant: CCOC[C@@H](O)CO[Si](C)(C)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC[C@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1

Procedure:
The subtitle compound was prepared according to the procedure outlined in example 1 step iv) using 4,6-Dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (product of example 1 step ii) (0.43 g), (2R)-1-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3-ethoxy-2-propanol (product of step iii) (0.47 g), THF (20 mL) and 60% sodium hydride (67 mg), to give the subtitle compound as a colourless oil. Yield: 0.7 g
Reaction SMILES: [C:1]1([CH:7]([N:14]2[CH2:17][CH:16]([CH2:18]OS(C)(=O)=O)[CH2:15]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[NH:26]1[CH:30]=[CH:29][N:28]=[CH:27]1>CN(C=O)C>[C:1]1([CH:7]([N:14]2[CH2:17][CH:16]([CH2:18][N:26]3[CH:30]=[CH:29][N:28]=[CH:27]3)[CH2:15]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)OCC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(C(c2ccccc2)N2CC(Cn3ccnc3)C2)cc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 99.6 %

Procedure:
A solution of the title compound from Step C (2.3 g, 6.95 mmoles) in DMF (15 mL) was added to a stirred solution of NaH (0.25 g, 10.42 mmoles) and imidazole (0.71 g, 10.44 mmoles) in DMF (10 mL) under nitrogen atmosphere. The mixture was stirred at 60° C. for 16 h. DMF was evaporated in vacuo. The resulting crude product was extracted with CH2Cl2 and the extract was successively washed with water and brine, and the CH2Cl2 was evaporated to leave the title compound (2.1 g, 100%). FABMS (M+1)=304.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=2)[CH:3]=1.[NH2:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23]>>[ClH:1].[C:14]1([CH3:18])[CH:15]=[CH:16][CH:17]=[C:12]([C:4]2[CH:3]=[C:2]([NH:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH:13]=1
Reactant: NCC(O)CO
Reactant: Cc1cccc(-c2cc(Cl)c3ccccc3n2)c1
Product: Cc1cccc(-c2cc(NCC(O)CO)c3ccccc3n2)c1
Product: Cl

Procedure:
The title compound, m.p. 208-215° C., and MS: m/e=309.2 (M+H+), was prepared from 4-chloro-2-m-tolyl-quinoline and (RS)-3-amino-1,2-propandiol.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[C:15]3[S:16][C:17]([C:19]([N:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[Cl:29])[CH3:22])=[O:20])=[CH:18][C:14]=3[CH2:13][CH2:12][O:11][C:10]=2[CH:30]=1)=[O:4].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[N:21]([CH3:22])[C:19]([C:17]1[S:16][C:15]2[C:9]3[CH:8]=[CH:7][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[CH:30][C:10]=3[O:11][CH2:12][CH2:13][C:14]=2[CH:18]=1)=[O:20]
Reactant: C1COCCN1
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(NC(=O)CCl)cc1OCC2)c1ccccc1Cl
Product: CN(C(=O)c1cc2c(s1)-c1ccc(NC(=O)CN3CCOCC3)cc1OCC2)c1ccccc1Cl

Procedure:
Following the procedure in Example 147 for 237, 8-(2-chloroacetamido)-N-(2-chlorophenyl)-N-methyl-4,5-dihydro-benzo[b]thieno[2,3-d]oxepine-2-carboxamide and morpholine were reacted to give 170. MS: (ESI+) 512.2
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([OH:11])=[C:6]([O:12][CH3:13])[CH:5]=1.[CH3:15][I:16]>O1CCOCC1>[I-:16].[CH3:14][N+:2]([CH3:15])([CH3:1])[CH2:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([OH:11])=[C:6]([O:12][CH3:13])[CH:5]=1
Reactant: CI
Reactant: COc1cc(CN(C)C)cc(C)c1O
Solvent: C1COCCO1
Product: COc1cc(C[N+](C)(C)C)cc(C)c1O
Product: [I-]
Yield: 97.9 %

Procedure:
To a dioxane solution (600 ml) of dimethyl(4-hydroxy-3-methoxy-5-methylbenzyl)amine (98 g, 0.50 mol) was added methyl iodide (69 ml, 1.11 mol) and the resulting mixture was refluxed for 2 h. The solid formed was filtered and washed with dioxane to yield 165 g (98%) of the trimethyl(4-hydroxy-3-methoxy-5-methylbenzyl)ammonium iodide salt.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:18](O)[CH2:19][OH:20].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:11]([O:10][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=1[CH:7]1[O:20][CH2:19][CH2:18][O:8]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=Cc1cc(Br)ccc1OCc1ccccc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1ccc(OCc2ccccc2)c(C2OCCO2)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 5-bromo-2-benzyloxybenzaldehyde, prepared from commercial 5-bromosalicylicaldehyde by benzylation according to the method given in Reference example 22a), (25 g, 74.6 mmol) in toluene (250 ml) was treated with ethylene glycol (5 ml), and p-toluenesulfonic acid (0.24 g). The reaction was heated to reflux with azeotropic removal of water (Dean Stark trap). After 2.5 hrs, no further water was collected. The reaction was cooled to ambient temperature and washed with saturated aqueous NaHCO3, dried (MgSO4 and evaporated to give 2-(2-benzyloxy-5-bromophenyl)-1,3-dioxolane as a pale orange solid (26.8 g). This material was used without purification.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:13]([NH2:14])=[CH:12][N:11]=[C:10]3[NH:15][CH:16]=[CH:17][C:9]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:18](OCC)(OCC)OCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH:1]1([N:7]2[C:8]3=[C:9]4[CH:17]=[CH:16][NH:15][C:10]4=[N:11][CH:12]=[C:13]3[N:14]=[CH:18]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1cnc2[nH]ccc2c1NC1CCCCC1
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: c1cc2c(ncc3ncn(C4CCCCC4)c32)[nH]1
Temperature: 80 °C
Reaction time: 1 h
Yield: 2.3 %

Procedure:
To a solution of N-cyclohexyl-1H-pyrrolo[2,3-b]pyridine-4,5-diamine (0.084 g, 0.36 mmol) in triethyl orthoformate (1 mL, 6 mmol) was added p-toluenesulfonic acid monohydrate (0.002 g, 0.011 mmol). The reaction mixture was heated at about 80° C. for about 1 h. p-Toluenesulfonic acid monohydrate (0.002 g, 0.011 mmol) was added and the reaction mixture was stirred at about 80° C. After about 1 h, p-toluenesulfonic acid monohydrate (0.002 g, 0.011 mmol) was added and the reaction mixture was stirred at about 80° C. for about 2 h. The reaction mixture was cooled to ambient temperature and concd under reduced pressure. The reaction was purified by RP-HPLC (Table 1, Method m) to give 1-cyclohexyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine (0.002 g, 2%) as a brown solid: LC/MS (Table 1, Method a) Rt=1.90 min; MS m/z 241 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:33]=[CH:32][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:20]=[C:21]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:22]=2)[C:11]([NH:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:12])=[CH:5][CH:4]=1)#[N:2].Br[CH2:35][CH:36]1[CH2:38][CH2:37]1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:20]=[C:21]([O:23][C:24]3[CH:25]=[CH:26][C:27]([C:30]#[N:31])=[CH:28][CH:29]=3)[CH:22]=2)[C:11]([NH:13][CH:14]2[CH2:15][CH2:16][N:17]([CH2:35][CH:36]3[CH2:38][CH2:37]3)[CH2:18][CH2:19]2)=[O:12])=[CH:32][CH:33]=1)#[N:2]
Reactant: BrCC1CC1
Reactant: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)NC3CCNCC3)c2)cc1
Product: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)NC3CCN(CC4CC4)CC3)c2)cc1
Yield: 71.2 %

Procedure:
Following procedure of Example 11(e) 3,5-bis-(4-cyano-phenoxy)-N-piperidin-4-yl-benzamide 0.5 g (1.14 mmol) and bromomethyl-cyclopropane (0.231 g, 1.71 mmol) were used to afford 0.4 g of the required product. Percentage purity (LCMS): 45.0%, (M+1)=492.2+1
Reaction SMILES: Br[C:2]1[C:3]([CH:16]=[O:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.C([Sn](C[CH2:43][CH2:44][CH3:45])(CCCC)/C=C/[Sn](CCCC)(CCCC)CCCC)CCC.BrC1[N:52]=[CH:51][CH:50]=[CH:49][N:48]=1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:48]1[CH:49]=[CH:50][CH:51]=[N:52][C:43]=1/[CH:44]=[CH:45]/[C:2]1[C:3]([CH:16]=[O:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1
Reactant: Brc1ncccn1
Reactant: CC1(C)CCC(C)(C)c2cc(C=O)c(Br)cc21
Reactant: CCCC[Sn](/C=C/[Sn](CCCC)(CCCC)CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC1(C)CCC(C)(C)c2cc(/C=C/c3ncccn3)c(C=O)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.8 %

Procedure:
A solution of 0.874 g (2.96 mmol) of 3-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthaldehyde, 1.886 g (3.11 mmol) of trans-1,2-bis(tri-n-butylstannyl)ethylene and 0.068 g (0.059 mmol) of tetrakis(triphenylphosphine)palladium in 20 ml toluene was heated to reflux under argon for 1.75 hour. The reaction was cooled slightly and 0.518 g (3.26 mmol) of 2-bromopyrimidine and 0.068 g (0.059 mmol) of tetrakis(triphenylphosphine)palladium was added in 3.5 ml toluene. The reaction was heated at reflux for 3 hours. The reaction was cooled to room temperature, quenched with 5% potassium fluoride and diluted with ethyl acetate. The two phases were stirred vigorously for 16 hours. The mixture was filtered through celite and the organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude material was purified by flash chromatography (gradient elution with 20% ethyl acetate/hexane-25% ethyl acetate/hexane) to afford 0.254 g (27%) of 3-((E)-2-(pyrimidin-2-yl)vinyl)-5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-naphthaldehyde (M+1=321).
Reaction SMILES: [CH:1]([CH:14]1[CH2:19][N:18]([CH2:20][C:21]2[CH:26]=[C:25]([N:27]3[C:31]([C:32]([F:35])([F:34])[F:33])=[N:30][N:29]=[N:28]3)[CH:24]=[CH:23][C:22]=2[O:36][CH3:37])[CH2:17][CH2:16][N:15]1[CH2:38][C:39]([OH:41])=O)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:44](CC)CC)C.[I-].[Cl:50]C1C=CC=C[N+]=1C.[ClH:58]>ClCCl.N.C(OCC)(=O)C>[ClH:50].[ClH:58].[CH:1]([CH:14]1[CH2:19][N:18]([CH2:20][C:21]2[CH:26]=[C:25]([N:27]3[C:31]([C:32]([F:33])([F:35])[F:34])=[N:30][N:29]=[N:28]3)[CH:24]=[CH:23][C:22]=2[O:36][CH3:37])[CH2:17][CH2:16][N:15]1[CH2:38][C:39]([NH2:44])=[O:41])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: COc1ccc(-n2nnnc2C(F)(F)F)cc1CN1CCN(CC(=O)O)C(C(c2ccccc2)c2ccccc2)C1
Reactant: C[n+]1ccccc1Cl
Agent: Cl
Agent: N
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(-n2nnnc2C(F)(F)F)cc1CN1CCN(CC(N)=O)C(C(c2ccccc2)c2ccccc2)C1
Reaction time: 0.5 h

Procedure:
To a suspension of 2-[2-benzhydryl-4-[2-methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]benzyl]-1-piperazinyl]acetic acid (70 mg) and triethylamine (20 mg) in dichloromethane (5 ml) was added 2-chloro-1-methylpyridinium iodide (70 mg) at room temperature. After being stirred for 30 minutes, 28% aqueous ammonia (1 drop) was added to the solution. After being stirred for 1.5 hours, the mixture was washed with water. The organic layer was separated, dried over magnesium sulfate, and evaporated under reduced pressure. The syrup was purified by column chromatography on silica gel using a mixed solvent of dichloromethane and methanol (20:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give a syrup. The syrup was treated with 4N hydrogen chloride in ethyl acetate (1 ml) to give 2-[2-benzhydryl-4-[2-methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]benzyl]-1-piperazinyl]acetamide dihydrochloride (81 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].C1C(=O)N([Br:22])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>>[Br:22][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: O=[N+]([O-])c1ccc(CBr)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 12 h
Yield: 98.1 %

Procedure:
1-Methyl-4-nitro-2-(trifluoromethyl)benzene (25 g, 122 mmol) was stirred in a solvent of dichloethane (300 mL). The reaction solution was added with NBS (21.7 g, 122 mmol) and AIBN (2.0 g, 12.2 mmol), followed by stirring for about 12 hours at 80° C. The solid thus obtained was filtered under reduced pressure and dried with warm wind in an oven (40° C.) for 3 hours or more to obtain the title compound (34 g, 98%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:10])=[N:4][N:5]([CH3:9])[C:6]=1[S:7][CH3:8].Cl[C:12]1[N:13]=[N:14][CH:15]=[C:16]([O:18][CH3:19])[CH:17]=1.N1C(C)=CC=CC=1C.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([O:10][C:12]2[N:13]=[N:14][CH:15]=[C:16]([O:18][CH3:19])[CH:17]=2)=[N:4][N:5]([CH3:9])[C:6]=1[S:7][CH3:8]
Reactant: CSc1c(Cl)c(O)nn1C
Reactant: COc1cnnc(Cl)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: Cc1cccc(C)n1
Product: COc1cnnc(Oc2nn(C)c(SC)c2Cl)c1
Yield: 26 %

Procedure:
4-Chloro-1-methyl-5-(methylthio)-1H-pyrazol-3-ol which is a known compound (2.7 g, 0.015 mole), 3-chloro-5-methoxypyridazine (1.45 g, 0.01 mole), and 2,6-lutidine (1.4 mL, 0.012 moles) were heated to reflux in toluene (40 mL) under N2 for 18 h. The mixture was then poured into aqueous ammonium chloride and extracted 3×100 mL with ethyl acetate. The organic layers were washed with water and brine, dried (MgSO4), filtered and evaporated in vacuo. The crude solid was purified by flash chromatography to give 3-[[4-chloro-1-methyl-5-(methylthio)-1H-pyrazol-3-yl]oxy]-5-methoxypyridazine (1.1 g, 26% yield) as a white solid.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:21]([O:25][C:26](Cl)=[O:27])[CH2:22][CH2:23][CH3:24]>ClCCl>[C:10]([O:9][C:7]([N:1]1[CH2:6][CH2:5][N:4]([C:26]([O:25][CH2:21][CH2:22][CH2:23][CH3:24])=[O:27])[CH2:3][CH2:2]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCCCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCOC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 10.9 g tert-butyl 1-piperazinecarboxylate in 145 ml dichloromethane were added 17.8 ml triethylamine. The solution was cooled to 0° C. and 8.3 ml butylchloro-formate added dropwise at this temperature. After stirring for 1 h the reaction mixture was diluted with dichloromethane and washed with 0.1 M HCl and saturated NaHCO3. The crude product obtained after evaporation of the solvent was directly used in the next reaction step. Yield: 18.0 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[Cl-].C([N:14]([CH2:17][CH3:18])[CH2:15]C)C.N1CCC1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:7]([N:14]2[CH2:15][CH2:18][CH2:17]2)=[O:9])[CH:10]=1
Reactant: O=C(O)c1cncc(Br)c1
Reactant: CCN(CC)CC
Agent: C1CNC1
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1cncc(Br)c1)N1CCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
To a stirred suspension of 5-bromonicotinic acid (1.0 g, 4.95 mmol) in 15 mL of anhydrous methylene chloride at 0° C. under nitrogen was added oxaylic chloride (817 mg, 6.44 mmol). The reaction mixture was stirred at 0° C. for 30 minutes. Then triethylamine (1.25 g, 12.38 mmol) was added slowly, and followed by the addition of azetidine (565 mg, 9.90 mmol) at 0° C. The reaction was warmed to ambient temperature, and stirred for another hour. The reaction mixture was diluted with methylene chloride, quenched with water, washed with 10% potassium carbonate aqueous solution twice, dried through magnesium sulfate, and the solvent was evaporated to dry. The residue was purified by flash chromatography using a gradient of methanol in methylene chloride to give a yellow liquid as 3-bromo-5-(azetidin-1-ylcarbonyl)-pyridine (846 mg, 70.9% yield). Following, to a stirred solution of 3-bromo-5-(azetidin-1-ylcarbonyl)-pyridine (600 mg, 2.50 mmol) and tetrakis(triphenylphosphine)palladium(0) (240 mg, 0.21 mmol) in 40 mL of xylene at ambient temperature under nitrogen was added hexamethylditin (1.58 g, 4.50 mmol). The reaction was heated to 150° C. overnight. The reaction mixture was filtrated through Celite, and the filtrate was vacuumed to dry. The residual was dissolved in methylene chloride, washed with water twice, dried through MgSO4, and then the solvent was evaporated. The precipitate was purified by flash chromatography using a gradient of ethyl acetate in hexane to give a yellow solid as 3-trimethylstannyl-5-(azetidin-1-ylcarbonyl)-pyridine (846 mg, 83.0% yield). 1H NMR (300 MHz, CDCl3) δ 8.65-8.70 (m, 2H), 8.04 (t, J=1.9 Hz, 1H), 4.31 (t, J=7.63 Hz, 2H), 4.00-4.10(m, overlapped with H2O), 2.27 (m, J=6.2 Hz, 2H MS APCI, m/z=323/325/327 (M+H) HPLC 1.61 min.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:30]3[CH:31]=[C:32]4[O:37][CH2:36][O:35][C:33]4=[CH:34][C:29]=3[CH2:28][C:27]([CH3:38])=[N:26][N:25]=2)=[CH:20][CH:19]=1.C(O)C>ClCCl>[C:1]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:30]3[CH:31]=[C:32]4[O:37][CH2:36][O:35][C:33]4=[CH:34][C:29]=3[CH2:28][C:27]([CH3:38])=[N:26][N:25]=2)=[CH:20][CH:19]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC1=NN=C(c2ccc(N)cc2)c2cc3c(cc2C1)OCO3
Solvent: ClCCl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC1=NN=C(c2ccc(NC(=O)c3ccccc3)cc2)c2cc3c(cc2C1)OCO3
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.2 %

Procedure:
1.0 ml (15 mmol) of benzoyl chloride and 2.1 ml (15 mmol) of triethylamine were added to a solution of 4 g (13.6 mmol) of 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine in dichloromethane and the reaction mixture was stirred at 25° C. for 24 hours. The solution was extracted with 3×30 ml of water, 3×20 ml of a 4% aqueous sodium hydroxide solution and finally with 2×30 ml of distilled water. The organic layer was dried, evaporated under reduced pressure, then the crystalline residue was treated with 20 ml of hot ethanol to obtain 3.97 g of raw product, m.p. 242°-243° C. This raw product was repeatedly treated with 20 ml of hot ethanol, next day it was filtered at 0-5° C., washed with 3×3 ml of ethanol and dried at 100° C. to yield 3.85 g (71.3%) of the pure aimed product, m.p. 246°-247° C. (decomp.).