Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29]Cl.C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CC3C=CC=CC=3OC)N=2)CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=3[O:26][CH3:25])[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: COc1ccccc1CCl
Agent: COc1ccccc1Cn1nc2c(c1-c1ccc(Cl)cc1)CCN(C(=O)OC(C)(C)C)CC2
Product: COc1ccccc1Cn1nc(-c2ccc(Cl)cc2)c2c1CCNCC2
Yield: 54.4 %

Procedure:
The title compound (0.06 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.3 mmol) using 2-methoxybenzyl chloride (0.3 mmol) in place of 2-chloromethyl-thiophene. The reaction sequence also yielded 3-(4-chloro-phenyl)-2-(2-methoxy-benzyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C21H22ClN3O, 367.15; found, m/z 368.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.45-7.43 (m, 2H), 7.30-7.27 (m, 2H), 7.18-7.17 (m, 1H), 6.80-6.77 (m, 2H), 6.61-6.59 (m, 1H), 5.26 (s, 2H), 3.80 (s, 3H), 2.92-2.86 (m, 4H), 2.74-2.69 (m, 4H).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[C:35]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][C@@H:43]1[CH3:48])([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36].C(N(CC)CC)C>O1CCOCC1>[C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:45]4[CH2:46][CH2:47][N:42]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C@@H:43]([CH3:48])[CH2:44]4)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)n3)sc2c1-c1ccc(Cl)cc1
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CCN(C(=O)OC(C)(C)C)[C@@H](C)C4)n3)sc2c1-c1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyrimidin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (80.0 mg, 0.155 mmol) and (S)-1-boc-2-methylpiperazine (93.1 mg, 0.465 mmol) in 1,4-dioxane (2 mL) was added triethylamine (156.8 mg, 0.19 mL, 1.549 mmol). The reaction mixture was stirred at 40° C. for 4 h, at room temperature overnight, then at 40° C. for an additional 7 h. The reaction mixture was filtered through Celite (ethyl acetate eluent), concentrated, and used without further purification. LCMS-ESI+ calc'd for C35H43ClN5O5S (M+H+): 680.3; Found: 680.0 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:13]2[O:14][CH:15]=[CH:16][N:17]=2)=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7]CC)=[O:6].[OH-].[Na+]>CO>[CH3:1][C:2]1[C:3]([C:13]2[O:14][CH:15]=[CH:16][N:17]=2)=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)c1cccc(C)c1-c1ncco1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cccc(C(=O)O)c1-c1ncco1
Yield: 99.1 %

Procedure:
To the title compound of step A (166 mg, 0.72 mmol) was added MeOH (7.2 mL) and 1M NaOH(aq) (7.2 mL). MeOH was evaporated and then 1 M HCl(aq) was added. To the solution was added DCM and the aqueous was extracted with DCM (3×). The combined organic layers were dried over MgSO4, filtered and evaporated to give the title compound (145 mg). MS (ESI) mass calcd. for C11H9NO3, 203.1. m/z found 204.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.20 (s, 1H), 7.79-7.68 (m, 1H), 7.65-7.49 (m, 2H), 7.35 (s, 1H), 4.34 (s, 1H), 2.20 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11]([C@H:13]2[CH2:18][CH2:17][C@H:16]([NH:19][S:20]([C:23]3[CH:24]=[N:25][C:26](Cl)=[C:27]([Br:29])[CH:28]=3)(=[O:22])=[O:21])[CH2:15][CH2:14]2)=[O:12])[CH3:9])=[CH:4][CH:3]=1.[CH3:31][OH:32]>C[O-].[Na+]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11]([C@H:13]2[CH2:18][CH2:17][C@H:16]([NH:19][S:20]([C:23]3[CH:24]=[N:25][C:26]([O:32][CH3:31])=[C:27]([Br:29])[CH:28]=3)(=[O:22])=[O:21])[CH2:15][CH2:14]2)=[O:12])[CH3:9])=[CH:4][CH:3]=1
Reactant: CO
Reactant: C[C@@H](NC(=O)[C@H]1CC[C@H](NS(=O)(=O)c2cnc(Cl)c(Br)c2)CC1)c1ccc(F)cc1
Agent: C[O-]
Agent: [Na+]
Product: COc1ncc(S(=O)(=O)N[C@H]2CC[C@H](C(=O)N[C@H](C)c3ccc(F)cc3)CC2)cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trans-4-(5-Bromo-6-chloro-pyridine-3-sulfonylamino)-cyclohexanecarboxylic acid [(R)-1-(4-fluoro-phenyl)-ethyl]-amide (Example 144, 484 mg, 0.933 mmol) was dissolved in a solution of NaOMe in MeOH (0.5M, 28 ml, 13.99 mmol). The reaction mixture was stirred overnight at room temperature. LCMS indicated that the reaction was complete and it was concentrated in vacuo then taken up in EtOAc and purified via column chromatography using a biotage SP1, 40+M column, with 50% EtOAc in heptane as calculated gradient to yield the title compound as a white solid (313 mg, 65%). [M+H]=516.0
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[C:9]([O-:11])[CH:10]=1.[K+].Br[CH:25]([CH3:38])[C:26]([O:28][CH2:29][P:30](=[O:37])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])=[O:27]>>[Cl:1][C:2]1[CH:18]=[C:17]([C:19]([F:21])([F:20])[F:22])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[C:9]([CH:10]=1)[O:11][CH:25]([CH3:38])[C:26]([O:28][CH2:29][P:30](=[O:37])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])=[O:27]
Reactant: CCOP(=O)(COC(=O)C(C)Br)OCC
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1[O-]
Agent: [K+]
Product: CCOP(=O)(COC(=O)C(C)Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])OCC

Procedure:
by using potassium 5-(o-chloro-p-trifluoromethyl-phenoxy)-2-nitrophenolate and diethyl (2-bromopropionyloxy)-methylphosphonate there is obtained diethyl [2-[5-(o-chloro-p-trifluoromethyl-phenoxy)-2-nitrophenoxy]-propionyloxy]methylphosphonate, 1H-NMR (CDCl3 ; 400 MHz) 7.93 ppm (d, 1H), 7.79 ppm (d, 1H), 7.58 ppm (q, 1H), 7.21 ppm (d, 1H), 6.63 ppm (d, 1H), 6.49 ppm (q, 1H), 4.89 ppm (q, 1H), 4.45 ppm (m, 2H), 4.14 ppm (m, 4H), 1.74 ppm (d, 3H), 1.32 ppm (tt, 6H).
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([F:16])[CH:8]=1.[Cl:18][C:19]1[C:20]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:21][CH:22]=[C:23]([Cl:25])[CH:24]=1>>[Cl:18][C:19]1[C:20]([N:26]2[CH2:31][CH2:30][N:29]([C:11]([C:10]3[CH:14]=[CH:15][C:7]([N:3]4[CH2:4][CH2:5][CH2:6][S:2]4(=[O:1])=[O:17])=[CH:8][C:9]=3[F:16])=[O:13])[CH2:28][CH2:27]2)=[N:21][CH:22]=[C:23]([Cl:25])[CH:24]=1
Reactant: Clc1cnc(N2CCNCC2)c(Cl)c1
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1F
Product: O=C(c1ccc(N2CCCS2(=O)=O)cc1F)N1CCN(c2ncc(Cl)cc2Cl)CC1
Yield: 102.3 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-fluorobenzoic acid (272 mg) described in Preparation Example 23 and 1-(3,5-dichloropyridin-2-yl)piperazine (244 mg) and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (508 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@H:10]2[CH2:11][CH:12]=[C:13]([CH2:14][OH:15])[C@H:9]2[C@H:8]([O:16][C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[O:7][CH:6]=1)=[O:4].C(Cl)(Cl)Cl.CO.S(=O)(=O)(O)O>O>[CH3:1][O:2][C:3]([C:5]1[C@H:10]2[CH2:11][CH:12]=[C:13]([CH2:14][OH:15])[C@H:9]2[C@H:8]([OH:16])[O:7][CH:6]=1)=[O:4]
Reactant: COC(=O)C1=CO[C@@H](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H]2C(CO)=CC[C@H]12
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CO
Product: COC(=O)C1=CO[C@@H](O)[C@@H]2C(CO)=CC[C@H]12
Reaction time: 4.5 h
Yield: 67.3 %

Procedure:
To a solution of geniposide (6.5 g) dissolved in distilled water (65 ml), was added β-glucosidase (No.G-0395, β-D-glucoside glucohydrase EC 3.2.1.21) (316.55 mg, 1677.72 units) the mixture was incubated at 37° C. for 4.5 hours. The progress of the reaction was monitored by TLC (chloroform:methanol=8:2, visualized with 50%-sulfuric acid). After the reaction was complete, the reaction solution was extracted several times with ethyl acetate, and subsequently the ethyl acetate layer was concentrated to give genipin as white needles (2.55 g, yield 67.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:21])[CH:5]=[C:6]([Cl:20])[C:7]=1[O:8][C:9]1[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][N:10]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:28][C:29]([Cl:33])=[CH:30][CH2:31]Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:21][CH2:31][CH:30]=[C:29]([Cl:33])[Cl:28])[CH:5]=[C:6]([Cl:20])[C:7]=1[O:8][C:9]1[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:17])[F:18])=[CH:11][N:10]=1
Reactant: Oc1cc(Cl)c(Oc2ncc(C(F)(F)F)cc2Cl)c(Cl)c1
Reactant: ClCC=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1cnc(Oc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)c(Cl)c1
Temperature: 0 °C
Yield: 79.2 %

Procedure:
To a mixture of 93 mg of 3,5-dichloro-4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenol, 40 mg of potassium carbonate and 10 ml of N,N-dimethylformamide, a solution prepared by dissolving 42 mg of 1,1,3-trichloro-1-propene in 3 ml of N,N-dimethylformamide was added dropwise at room temperature with stirring. After stirring at room temperature for 5 hours, the reaction solution was poured into ice-water, and extracted twice with 40 ml of diethyl ether. Then, the ether layers were combined, washed with water, dried over anhydrous magnesium sulfate and concentrated to give a crude product. This crude product was subjected to silica gel chromatography to give 96 mg of 3,5-dichloro-4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene, yield 79%; m.p., 97.8° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[CH3:9].Cl[C:11]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]>>[Br:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:11]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:12]=2[C:13]([OH:15])=[O:14])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(N)cnc1Br
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Product: Cc1cc(Nc2ccc(Cl)cc2C(=O)O)cnc1Br
Yield: 24 %

Procedure:
Obtained (0.51 g, yield 24%) following the procedure described in Intermediate 13 starting with 6-bromo-5-methylpyridin-3-amine (5.35 mmol, 1.0 g) and 2,5-dichlorobenzoic acid (10.68 mmol, 2.04 g).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:11][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[CH2:9]1)=[O:7])(C)(C)C.[C:21](O)([C:23](F)(F)F)=O.C(Cl)(=O)CC.C(N(CC)CC)C>C(Cl)Cl.C1COCC1>[N+:18]([C:15]1[CH:14]=[CH:13][C:12]([CH:10]2[CH2:9][N:8]([C:6](=[O:7])[CH2:21][CH3:23])[CH2:11]2)=[CH:17][CH:16]=1)([O-:20])=[O:19]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc([N+](=O)[O-])cc2)C1
Agent: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(=O)N1CC(c2ccc([N+](=O)[O-])cc2)C1
Yield: 87 %

Procedure:
Using the same procedure as described in 46.4, 3-(4-nitro-phenyl)-azetidine-1-carboxylic acid tert-butyl ester was deprotected with TFA (15 ml) in CH2Cl2 (100 ml) and the resulting amine treated with propionyl chloride (2900, 3.31 mmol) and triethylamine (470 μl, 3.37 mmol) in THF (80 ml). Purification of the crude product by flash column chromatography (heptane:ethyl acetate, 1:1) provides the title compound (570 mg, 87% for two steps) as a brown oil.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:15][CH2:14][O:13][C:12]3[N:16]=[CH:17][C:18]([C:20]([OH:22])=O)=[CH:19][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:25])=O>ClCCCl>[C:1]1([S:7]([N:10]2[CH2:15][CH2:14][O:13][C:12]3[N:16]=[CH:17][C:18]([C:20]([Cl:25])=[O:22])=[CH:19][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cnc2c(c1)N(S(=O)(=O)c1ccccc1)CCO2
Solvent: ClCCCl
Product: O=C(Cl)c1cnc2c(c1)N(S(=O)(=O)c1ccccc1)CCO2
Temperature: 70 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 1-(phenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxylic acid (230 mg, 0.718 mmol) in DCE (20 mL) was added thionyl chloride (0.5 mL, 6.85 mmol). The solution turned cloudy white. The reaction was heated to 70° C. and stirred at that temperature for 2 hours, after which time the solution was clear. LCMS analysis of the reaction mixture indicated consumption of starting material. The reaction mixture was concentrated in vacuo. 1-(phenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carbonyl chloride (243 mg, 0.718 mmol, 100% yield) was used without purification. LCMS (methanol adduct, i.e. the methyl ester; +ESI) m/z=335.0 [M+H]+.
Reaction SMILES: [OH:1][CH:2]([CH:14]=[CH2:15])[CH2:3][CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[Cl:16][C:17]1[C:24]([F:25])=[CH:23][C:20]([C:21]#[N:22])=[C:19](F)[CH:18]=1>CN(C)C=O>[Cl:16][C:17]1[C:24]([F:25])=[CH:23][C:20]([C:21]#[N:22])=[C:19]([CH:18]=1)[O:1][CH:2]([CH:14]=[CH2:15])[CH2:3][CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:9])[CH3:10]
Reactant: C=CC(O)CCN(C)C(=O)OC(C)(C)C
Reactant: N#Cc1cc(F)c(Cl)cc1F
Solvent: CN(C)C=O
Product: C=CC(CCN(C)C(=O)OC(C)(C)C)Oc1cc(Cl)c(F)cc1C#N

Procedure:
The subtitle compound was prepared according to the method of Example 3 step (b) using (3-hydroxy-4-pentenyl)methylcarbamic acid, 1,1-dimethylethyl ester and 4-chloro-2,5-difluorobenzonitrile in N,N-dimethylformamide.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:26])=[C:11]2[C:16](=[C:17]([CH3:20])[C:18]=1[CH3:19])[O:15][C@@:14]([CH2:22][C:23](O)=[O:24])([CH3:21])[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C(Cl)(=O)C([Cl:31])=O>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:10]([CH3:26])=[C:11]2[C:16](=[C:17]([CH3:20])[C:18]=1[CH3:19])[O:15][C@@:14]([CH2:22][C:23]([Cl:31])=[O:24])([CH3:21])[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CC[C@@](C)(CC(=O)O)O2
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CC[C@@](C)(CC(=O)Cl)O2
Temperature: 50 °C
Reaction time: 1 h
Yield: 101.2 %

Procedure:
201.0 g (0.57 mole) of (S)-(6-benzyloxy-2,5,7,8-tetramethlchroman-2-yl)acetic acid was dissolved in 1.0 L toluene and transferred to a 3 L three necked flask equipped with a Dean-Stark trap and condenser, magnetic stirrer and a thermometer connected to a heating mantle. The solution was refluxed 1 hour with no appreciable amount of water collecting in the Dean-Stark trap. This was removed, and the solution was cooled to 50° C. Then a pressure equalizing addition funnel was placed on top and the oxalyl chloride 58.5 mL (0.68 mole, 1.2 equiv.) was added dropwise at about one drop per second. The color became orange, and the temperature increased to about 60° C. as gas evolution began smoothly. The rate of addition was monitored so that gas evolution was not too vigorous. The gas evolved was bubbled through two aqueous sodium hydroxide traps. The slow addition was continued over about 1 hour and then heating was applied with a thermowatch keeping the heat at 60° C. The solution was then condensed on the rotovap, and after pumping off any residual solvent for 2 hours, 215.2 g (>100%) of (S)-(6-benzyloxy-2,5,7,8-tetramethyl chroman-2-yl)acetic acid chloride was obtained (211.45 g theoretical).
Reaction SMILES: [N:1]1([C:7]2[C:8](=[O:25])[N:9]([CH2:13][CH2:14][O:15][C:16]3[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=3[F:24])[CH:10]=[CH:11][N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[ClH:26].N1(C2C(=O)N([CH2:39][CH2:40][O:41][C:42]3[CH:47]=[C:46](F)[C:45](F)=[CH:44][C:43]=3F)C=CN=2)CCNCC1.C1(OCCBr)C=CC=CC=1>>[ClH:26].[O:41]([CH2:40][CH2:39][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[C:8](=[O:25])[N:9]([CH2:13][CH2:14][O:15][C:16]3[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=3[F:24])[CH:10]=[CH:11][N:12]=2)[CH2:2][CH2:3]1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: O=c1c(N2CCNCC2)nccn1CCOc1cc(F)c(F)cc1F
Agent: BrCCOc1ccccc1
Agent: Cl
Product: O=c1c(N2CCN(CCOc3ccccc3)CC2)nccn1CCOc1cc(F)c(F)cc1F

Procedure:
The title compound was prepared according to the procedure of Example 60 starting from 3-(1-piperazinyl)-1-[2-(2,4,5-trifluorophenoxy)ethyl]-2(1H)-pyrazinone (0.35 g, 1.0 mmol; from the free base of Example 3) and 2-bromoethyl phenyl ether (0.22 g, 1.1 mmol). Yield 0.14 g (27%). HPLC purity: 99%. HRMS calc for C24H25F3N4O3 (M)+ 474.1879, found 474.1887.
Reaction SMILES: COC1C=CC(C2C(C)(C)CC3C(=CC=C(OC)C=3)C2)=C(N)C=1.Cl.[N:25]1([CH2:32][CH2:33][O:34][C:35]2[CH:43]=[CH:42][C:38]([C:39](O)=O)=[CH:37][CH:36]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.N1(CCOC2C=C[C:57]([CH2:58][NH:59][C:60]3[CH:65]=[C:64]([O:66][CH3:67])[CH:63]=[CH:62][C:61]=3[CH:68]3[C:77]([CH3:79])([CH3:78])[CH2:76][C:75]4[C:70](=[CH:71][CH:72]=[C:73]([O:80][CH3:81])[CH:74]=4)[CH2:69]3)=CC=2)CCCCCC1>>[N:25]1([CH2:32][CH2:33][O:34][C:35]2[CH:43]=[CH:42][C:38]([CH2:39][N:59]([CH2:58][CH3:57])[C:60]3[CH:65]=[C:64]([O:66][CH3:67])[CH:63]=[CH:62][C:61]=3[CH:68]3[C:77]([CH3:79])([CH3:78])[CH2:76][C:75]4[C:70](=[CH:71][CH:72]=[C:73]([O:80][CH3:81])[CH:74]=4)[CH2:69]3)=[CH:37][CH:36]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: O=C(O)c1ccc(OCCN2CCCCCC2)cc1
Reactant: COc1ccc2c(c1)CC(C)(C)C(c1ccc(OC)cc1NCc1ccc(OCCN3CCCCCC3)cc1)C2
Agent: COc1ccc(C2Cc3ccc(OC)cc3CC2(C)C)c(N)c1
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCCC2)cc1)c1cc(OC)ccc1C1Cc2ccc(OC)cc2CC1(C)C

Procedure:
Synthesized from 5-methoxy-2-(6-methoxy-3,3-dimethyl-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine and 4-(2-azepan-1-ylethoxy)benzoic acid hydrochloride according to an analogous synthetic method to Example 152, [4-(2-azepan-1-ylethoxy)benzyl][5-methoxy-2-(6-methoxy-3,3-dimethyl-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (522 mg) was used according to an analogous synthetic method to Example 36 to provide [4-(2-azepan-1-ylethoxy)benzyl]ethyl[5-methoxy-2-(6-methoxy-3,3-dimethyl-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (521 mg). This compound (519 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (365 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[CH2:16])[CH:10]=2)[O:3]1.[CH2:18]([Zn]CC)C.ICI.[NH4+].[Cl-]>C1(C)C=CC=CC=1>[CH:15]1([C:11]2[CH:10]=[C:9]([B:4]3[O:3][C:2]([CH3:17])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]3)[CH:14]=[CH:13][CH:12]=2)[CH2:18][CH2:16]1
Reactant: C=Cc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CC[Zn]CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: ICI
Product: CC1(C)OB(c2cccc(C3CC3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
To a solution of 4,4,5,5-tetramethyl-2-(3-vinyl-phenyl)-[1,3,2]dioxaborolane (300 mg, 1.3 mmol) in toluene (10 ml) were added diethylzinc solution (1.1 N in toluene, 5.22 ml, 5.74 mmol) and diiodomethane (8.7 ml, 33 mmol). The reaction mixture was stirred for 1 hour at room temperature and then refluxed for 3 hours. The reaction mixture was poured on sat. NH4Cl solution (20 ml) and was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to provide 2-(3-cyclopropyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (69% yield), 1H-NMR (300 MHz, CDCl3): δ=7.12-7.82 (m, 4H), 1.35 (s, 12H), 1.28 (t, 1H), 0.90-0.96 (m, 2H), 0.72-0.78 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3].C(N(C(C)C)CC)(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Br[C:42]1[CH:58]=[N:57][C:45]2[NH:46][C:47](=[O:56])[N:48]([CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH2:49][C:44]=2[CH:43]=1>C(#N)CC.CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:54]([O:53][C:51](=[O:52])[CH2:50][N:48]1[CH2:49][C:44]2[CH:43]=[C:42](/[CH:3]=[CH:2]/[C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH:58]=[N:57][C:45]=2[NH:46][C:47]1=[O:56])[CH3:55]
Reactant: CCOC(=O)CN1Cc2cc(Br)cnc2NC1=O
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CN1Cc2cc(/C=C/C(=O)OC(C)(C)C)cnc2NC1=O
Yield: 59.8 %

Procedure:
tert-Butyl acrylate (1.25 mL, 8.53 mmol), diisopropylethylamine (730 μL, 4.26 mmol) and P(o-tolyl)3 (130 mg, 0.43 mmol) were successively added to a suspension of ethyl 2-(6-bromo-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)acetate (670 mg, 2.13 mmol) in propionitrile (11 mL) and dimethylformamide (2.5 mL). The resulting mixture was purged with argon prior to the addition of palladium acetate (48 mg, 0.213 mmol). The mixture was purged with argon a second time and refluxed overnight. The reaction mixture was then filtered on Celite® and washed with ethyl acetate (75 mL) and dichloromethane (75 mL). The filtrate was concentrated to dryness and the residue was partitioned between dichloromethane (50 mL) and water (50 mL). The aqueous phase was separated and extracted with dichloromethane (2×100 mL). The combined organic phases were washed with a saturated solution of sodium chloride (3×100 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was precipitated from a mixture dichloromethane/diethylether to afford the title product as a white solid (460 mg, 60%).
Reaction SMILES: [NH2:1][CH:2]([CH2:38][CH3:39])[C:3]([N:5]1[CH2:10][CH2:9][C:8]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=2)([CH2:11][CH2:12][N:13]2[CH:18]3[CH2:19][CH2:20][CH:14]2[CH2:15][CH:16]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH3:30])[CH2:17]3)[CH2:7][CH2:6]1)=[O:4].[Cl:40][CH2:41][C:42](Cl)=[O:43].CCN(C(C)C)C(C)C>>[Cl:40][CH2:41][C:42]([NH:1][CH:2]([C:3]([N:5]1[CH2:10][CH2:9][C:8]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=2)([CH2:11][CH2:12][N:13]2[CH:18]3[CH2:19][CH2:20][CH:14]2[CH2:15][CH:16]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH3:30])[CH2:17]3)[CH2:7][CH2:6]1)=[O:4])[CH2:38][CH3:39])=[O:43]
Reactant: O=C(Cl)CCl
Reactant: CCC(N)C(=O)N1CCC(CCN2C3CCC2CC(n2c(C)nc4ccccc42)C3)(c2cccc(F)c2)CC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(NC(=O)CCl)C(=O)N1CCC(CCN2C3CCC2CC(n2c(C)nc4ccccc42)C3)(c2cccc(F)c2)CC1
Yield: 44 %

Procedure:
2-Chloro-N-[1-(4-(3-fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidine-1-carbonyl)-propyl]-acetamide was obtained from treating[1-(4-(3-Fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidine-1-carbonyl)-propyl]-carbamic acid tert-butyl ester (0.580 g, 0.92 mmol) with HCl as outlined in the procedure for example 890 to form 2-Amino-1-(4-(3-fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidin-1-yl)-butan-1-one (0.488 g, 99%). 2-Amino-1-(4-(3-fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl)piperidin-1-yl)-butan-1-one (0.049 g, 0.09 mmol, Chloro-acetyl chloride (0.010 g, 0.09 mmol) and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in example 890 to give the title compound, 2-Chloro-N-[1-(4-(3-fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidine-1-carbonyl)-propyl]-acetamide (0.024 g, 44%) as an oil. ES-LCMS m/z 608 (M+1).