Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([C:27]1[N:28]=[N:29][N:30]([CH3:32])[N:31]=1)[C@H:8]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH2:16][OH:17])[C:10]2[CH:18]=[C:19]([C:23]([F:26])([F:25])[F:24])[C:20]([CH3:22])=[CH:21][C:9]1=2.N1C=CC=CC=1.[C:48](Cl)(=[O:50])[CH3:49]>ClCCl>[F:37][C:36]([F:39])([F:38])[C:34]1[CH:33]=[C:5]([CH:4]=[C:3]([C:2]([F:40])([F:1])[F:41])[CH:35]=1)[CH2:6][N:7]([C:27]1[N:28]=[N:29][N:30]([CH3:32])[N:31]=1)[C@H:8]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH2:16][O:17][C:48](=[O:50])[CH3:49])[C:10]2[CH:18]=[C:19]([C:23]([F:24])([F:25])[F:26])[C:20]([CH3:22])=[CH:21][C:9]1=2
Reactant: Cc1cc2c(cc1C(F)(F)F)N(CCO)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCCN1CCC[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2cc(C)c(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of (S)-2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-ethanol (Example 130, Step 2) (0.12 mmol) in dichloromethane (5 mL), add pyridine (0.47 mmol) followed by acetyl chloride (0.47 mmol). After stirring at room temperature for 14 h, quench the reaction with water (5 mL) and dilute with dichloromethane (5 mL). Separate the organic phase and wash the aqueous with dichloromethane (2×5 mL). Dry the combined organics over sodium sulfate, filter, and remove solvent under vacuum. Chromatograph the product over silica gel, eluting with ethyl acetate/hexane (5-40%), to afford the title compound as a colorless foam. MS (ES+): 639 (M+H).
Reaction SMILES: [C:1]1([C@@H:7]([OH:14])[CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:22]([Cl:26])[C:23](Cl)=[O:24]>O1CCCC1.CN(C1C=CN=CC=1)C>[N:9]1([CH2:8][C@H:7]([O:14][C:23](=[O:24])[CH:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[Cl:15])[Cl:26])[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C(Cl)C(Cl)c1ccccc1Cl
Reactant: O[C@@H](CN1CCCC1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: O=C(O[C@@H](CN1CCCC1)c1ccccc1)C(Cl)c1ccccc1Cl

Procedure:
A solution of 5.7 g of (R)-1-phenyl-2-(1-pyrrolidinyl)-ethanol in 25 ml of tetrahydrofurane was added to a solution of 6.5 g of 2,α-dichlorophenyl acetyl chloride in 25 ml of tetrahydrofurane containing 0.9 g of 4-dimethylamine pyridine. According to a similar procedure as in example 3, a mixture of diastereomeric esters containing 72% (R,R) and 28% (R,S) of the product in a yield of 8.4 g (74%) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]([OH:15])=[O:14])[CH:7]=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10])([O-:3])=[O:2].[CH2:16](Br)[CH:17]=[CH2:18]>>[CH2:18]([O:14][C:13]([C:6]1[CH:7]=[C:8]([CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[C:9]([OH:11])=[O:10])=[O:15])[CH:17]=[CH2:16]
Reactant: O=C(O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Reactant: C=CCBr
Product: C=CCOC(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1

Procedure:
5-Nitroisophthalic acid (5 g) was converted to the mono allyl ester using one equivalent of allyl bromide (2 ml) using a similar method to that described in example 1. The required acid (2.7 g) was extracted from the organic phase with aqueous NaHCO3. The organic layer contained the di-allyl ester (2.7 g). The mono acid, 3-allyloxycarbonyl-5-nitrobenzoic acid, was obtained as a white solid. Nmr (CDC13): 4.87 (d, 2H); 5.3-5.5 (q, 2H); 5.97-6.15 (m, 1H); 9.01 (t, 3H).
Reaction SMILES: [CH3:1][C:2](O)([C:4](=O)[CH3:5])[CH3:3].[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O)(=O)C.C1(C)C=CC=CC=1>O>[CH3:5][C:4]1[C:2]([CH3:3])([CH3:1])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1
Reactant: Nc1ccccc1
Reactant: CC(=O)C(C)(C)O
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC1=Nc2ccccc2C1(C)C
Temperature: 160 °C
Reaction time: 5 h

Procedure:
408 parts of 2-methyl-2-hydroxy-butan-3-one, 558 parts of aniline and 20 parts of acetic acid in 650 parts of toluene are heated, with removal of water from the system, until no more water separates off. The volatile constituents are then distilled off until the internal temperature reaches 220° C. The distillate can be re-used, without further treatment, in a subsequent batch. The residue is kept for 5 hours at 220° C. and is then cooled to 160° C., and 40 parts of concentrated hydrochloric acid are added. After heating for a further three hours, during which the water formed distils off, the reaction is complete. The product is either directly processed further or distilled. 498 parts of 2,3,3-trimethyl-indolenine are obtained, corresponding to 78.5% of theory, based on 2-methyl-2-hydroxy-butan-3-one.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][CH2:9][CH2:10][OH:11].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:19][S:20]([O:11][CH2:10][CH2:9][C:8]#[C:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: OCCC#Cc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCC#Cc1ccccn1
Temperature: 4 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
To a stirred solution of 4-(pyridin-2-yl)but-3-yn-1-ol (3.60 g, 24 mmol) in dry methylene chloride (30 mL) was added triethylamine (4.40 mL, 32 mmol). The mixture was cooled at 4° C. and methanesulfonyl chloride (2.50 mL, 32 mmol) was added and the reaction was stirred at room temperature overnight. The reaction mixture was then poured over ice/water (100 mL) and stirred for 5 min. To this mixture was added saturated aqueous sodium bicarbonate solution (50 mL) chilled to 4° C., and the mixture was stirred for 30 min, then extracted with DCM. The combined organic fractions were dried over MgSO4, filtered and concentrated under pressure to afford 4.60 g of 4-(pyridin-2-yl)but-3-ynyl methanesulfonate (Yield: 83%) as a brown oil which can be used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:16][CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33].C(N(CC)CC)C>CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:16][CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])=[C:11]([C:22]3[CH:23]=[CH:24][C:25]([S:28]([NH:31][C:32](=[O:34])[CH3:33])(=[O:30])=[O:29])=[CH:26][CH:27]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(O)CCOc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2ccc(F)cc2)c1=O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: CC(=O)NS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)cc3)c(=O)c2OCCC(C)(C)O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-(4-fluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone (Example 470, 1 equivalent), acetic anhydride (3 equivalents), 4-(dimethylamino)pyridine (0.3 equivalents), and triethylamine (1.2 equivalents) is stirred at room temperature for 16 hours. The reaction mixture is partitioned between ethyl acetate and water. The organic layer is washed with brine then dried over MgSO4 and filtered. The filtrate is concentrated in vacuo to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:12]=[C:13]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[C:14]([O:17][CH3:18])=[N:15][CH:16]=2)[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[S:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:26])=[O:25].N1C=CC=CC=1.[Cl:39][CH2:40][C:41]1[N:46]=[C:45]([C:47](Cl)=[O:48])[CH:44]=[CH:43][CH:42]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:39][CH2:40][C:41]1[N:46]=[C:45]([C:47]([NH:1][C:2]2[CH:10]=[C:9]([C:11]3[CH:16]=[N:15][C:14]([O:17][CH3:18])=[C:13]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:12]=3)[CH:8]=[C:7]3[C:3]=2[CH:4]=[N:5][N:6]3[S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:26])=[O:25])=[O:48])[CH:44]=[CH:43][CH:42]=1
Reactant: O=C(Cl)c1cccc(CCl)n1
Reactant: COc1ncc(-c2cc(N)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cc1NS(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ncc(-c2cc(NC(=O)c3cccc(CCl)n3)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cc1NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 25.5 %

Procedure:
N-[5-[4-Amino-1-(phenylsulfonyl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide (750 mg, 1.584 mmol) was dissolved in DCM (20 ml), cooled to 0° C. before pyridine (0.192 mL, 2.376 mmol) was added. 6-(chloromethyl)-2-pyridinecarbonyl chloride (354 mg, 1.584 mmol) in DCM (10 ml) was then added dropwise over 15 mins and the reaction was stirred at 0° C. for 2 hr; ice was allowed to melt over this time. Saturated aqueous sodium bicarbonate solution (20 ml) was added to the mixture and it was stirred vigourously for 10 mins. The organic layer was separated using a hydrophobic frit, washed with water (20 ml) and concentrated in vacuo to give an orange oil. The oil was triturated with ether and the resulting solid was filtered off then pre-adsorbed onto silica. The silica was added to the top of a 50 g silica SPE cartridge that was subsequently eluted with 0-100% EtOAc/cyclohexane over 60 mins to afford the title compound as a pale yellow solid (253 mg).
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[C:10]([F:46])=[C:11]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:44][CH3:45])=[C:23]([O:26][C@H:27]4[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[C@H:29]([C:40]([NH:42][CH3:43])=[O:41])[CH2:28]4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:13][CH:14]=1>C(Cl)Cl>[Cl:8][C:9]1[C:10]([F:46])=[C:11]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:44][CH3:45])=[C:23]([O:26][C@H:27]4[CH2:32][CH2:31][NH:30][C@H:29]([C:40]([NH:42][CH3:43])=[O:41])[CH2:28]4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: CNC(=O)[C@@H]1C[C@@H](Oc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)[C@@H]1C[C@@H](Oc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
TFA (15 ml) was added over a period of 5 minutes to a stirred solution of tert-butyl (2S,4S)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-2-[(methylamino)carbonyl]piperidine-1-carboxylate (4.1 g, 7.31 mmol) in DCM (15 ml) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour after which time, the reaction was complete. The reaction mixture was concentrated to dryness, azeotroped twice with toluene to give (2S,4S)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-N-methylpiperidine-2-carboxamide (3.0 g, 89%) the crude residue was used without further purification; Mass Spectrum: (M+H)+ 460.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[C:5](=[O:15])[CH:4]=1.[Cl-].[Li+].[CH:18](NC(C)C)(C)C.C([Li])CCC.CI.Cl>O.O1CCCC1>[CH3:1][O:2][C:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[C:5](=[O:15])[C:4]=1[CH3:18]
Reactant: CC(C)NC(C)C
Reactant: COc1cc(=O)c2ccccc2[nH]c1=O
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: COc1c(C)c(=O)c2ccccc2[nH]c1=O
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
3-Methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (0.5 g) and anhydrous lithium chloride (0.63 g) were added to dry tetrahydrofuran (10 mL), and the mixture was cooled to -70° C. To this was added diisopropylamine (380 mL), followed by butyllithium (2.2 mL, 2.5M in hexanes); and the mixture was warmed to -20° C. After 30 minutes, methyl iodide (307 mL) was added and the mixture cooled to -10° C. for 10 minutes. The mixture was diluted with water, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried and evaporated. The solid was purified by chromatography, with ethyl acetate:toluene (1:1) as the eluent, and recrystallized from hot toluene to give the methylated product as a white solid (0.367 g); NMR: 2.03 (s,3); MS(EI): m/z=217(M).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.C[Si](Cl)(C)C.CC1(C)[O:19][C:18](=O)[CH2:17][C:16](=[O:21])[O:15]1>C(Cl)Cl>[O:19]=[C:18]([NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:17][C:16]([OH:21])=[O:15]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: Nc1cccnc1
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Product: O=C(O)CC(=O)Nc1cccnc1
Reaction time: 0.5 h
Yield: 26.2 %

Procedure:
To a suspension of pyridine-3-amine (1 g, 10.6 mmol) in DCM (100 mL) was added TMSCl (1.3 mL, 10.6 mmol) at room temperature. The reaction mixture was stirred for 30 min. 2,2-Dimethyl-1,3-dioxane-4,6-dione (1.44 g, 10.6 mmol) was added and the combined mixture stirred overnight and concentrated under reduced pressure. The residue was dissolved in dilute NaHCO3 solution and washed with EtOAc. The aqueous phase was collected and acidified with cone. HCl to pH˜3 and extracted with EtOAc. The extract was dried over anhydrous Na2SO4, filtered and concentrated. The remaining solid was purified by flash chromatography (eluent CHCl3/MeOH/AcOH 8:1:0.1) to afford the title compound 39 as a white solid (0.5 g, 26% yield). 1H NMR (DMSO-d6) δ (ppm): 12.04 (bs, 1H), 9.67 (s, 1H), 8.18 (d, 1H), 8.01 (d, 1H), 7.29 (m, 1H), 2.97 (s, 2H). MS (m/z): 181.1 (M+H).
Reaction SMILES: [ClH:1].O1CCOCC1.C(OC([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[S:22][CH:23]=[C:24]([C:26]([O:28][CH3:29])=[O:27])[N:25]=2)[CH:17]([CH2:30][O:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[CH2:16]1)=O)(C)(C)C>CO>[ClH:1].[ClH:1].[N:34]1[CH:35]=[CH:36][CH:37]=[C:32]([O:31][CH2:30][CH:17]2[CH2:16][NH:15][CH2:20][CH2:19][N:18]2[C:21]2[S:22][CH:23]=[C:24]([C:26]([O:28][CH3:29])=[O:27])[N:25]=2)[CH:33]=1
Reactant: COC(=O)c1csc(N2CCN(C(=O)OC(C)(C)C)CC2COc2cccnc2)n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1csc(N2CCNCC2COc2cccnc2)n1
Reaction time: 8 h
Yield: 17 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of methyl 2-(4-(tert-butoxycarbonyl)-2-((pyridin-3-yloxy)methyl)piperazin-1-yl)thiazole-4-carboxylate (32 mg, 0.074 mmol) in MeOH (1 mL). After stirring overnight, the reaction mixture was concentrated under reduced pressure. The material was dissolved in H2O (20 mL), and the pH was adjusted to −2 with concentrated HCl. This was washed with Et2O (3×5 mL, discarded). The aqueous layer was adjusted to pH ˜12 with 1 N NaOH and was extracted with EtOAc (3×20 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure, yielding 5.0 mg (17%) of the title compound. LC-MS: RT=3.41 min, (M+H)+=335.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13](C)[C:14](=O)C(F)(F)F)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]>[OH-].[Na+].CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][CH3:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCN(C)C(=O)C(F)(F)F)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CNCCc1ccc(OC)c(OC)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Dissolve 16.5 g (57 mmol) of N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methyltrifluoroacetamide in a solution of 100 mL of 4N sodium hydroxide and 100 mL of methanol. Heat mixture at 60° C. for 1 h. After 1 h, cool reaction mixture to room temperature and extract with 2×200 mL of methylene chloride. Wash the combined organic extracts with saturated sodium chloride solution and dry over anhydrous sodium sulfate. Filter the drying agent and remove the solvent in vacuo to provide the crude title compound. Distill this material in vacuo to provide the title compound.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]#[CH:6].C([Li])CCC.B(F)(F)F.CCOCC.[CH:21]([C:23]([CH3:25])=[O:24])=[CH2:22]>C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]#[C:6][CH2:22][CH2:21][C:23](=[O:24])[CH3:25]
Reactant: C#CCCCCl
Reactant: C=CC(C)=O
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(=O)CCC#CCCCCl
Reaction time: 0.25 h

Procedure:
14.85 Parts of 5-chloropent-1-yne is dissolved in 250 parts by volume of toluene and the resulting solution is cooled to approximately -40°. To that solution is then added 62.8 parts by volume of 2.31 M ethereal butyl lithium and stirring is continued for approximately 15 minutes. 6.87 Parts of boron trifluoride etherate is added and the reaction mixture is stirred for about two hours, then is allowed to stand for about 16 hours at -5° to -10°. At the end of that time, 10.14 parts of methyl vinyl ketone is added at -40° and the reaction mixture is stirred for about 4 hours, then is quenched with water. 50 Parts by volume of 3 N hydrochloric acid is added and the mixture is kept at room temperature for about 16 hours, at the end of which time the aqueous and organic layers are separated. The aqueous layer is extracted with toluene and the organic layer with water. The organic solutions are combined, washed successively with aqueous sodium hydroxide and water, then dried over anhydrous sodium sulfate and stripped to dryness under reduced pressure, thus affording the crude product. This material is purified by distillation under reduced pressure to afford 9-chloro-5-nonyn-2-one, boiling at about 80°-92° at a pressure of 0.11-0.06 mm.
Reaction SMILES: B([O-])([O-])O[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:5][CH:4]=1.Br[C:20]1[CH:21]=[CH:22][C:23]2[N:29]([CH2:30][CH2:31][CH3:32])[CH2:28][CH2:27][C:26]([C:33]([NH:35][C:36]3[CH:41]=[CH:40][C:39]([CH2:42][N:43]([CH3:50])[CH:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)=[CH:38][CH:37]=3)=[O:34])=[CH:25][C:24]=2[CH:51]=1.C(=O)([O-])[O-].[K+].[K+]>O.C(O)C.C1(C)C=CC=CC=1.C(OCC)(=O)C.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>[CH2:13]([O:12][CH2:11][CH2:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][CH2:31][CH3:32])[CH2:28][CH2:27][C:26]([C:33]([NH:35][C:36]4[CH:37]=[CH:38][C:39]([CH2:42][N:43]([CH3:50])[CH:44]5[CH2:45][CH2:46][O:47][CH2:48][CH2:49]5)=[CH:40][CH:41]=4)=[O:34])=[CH:25][C:24]=3[CH:51]=2)=[CH:4][CH:5]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCN1CCC(C(=O)Nc2ccc(CN(C)C3CCOCC3)cc2)=Cc2cc(Br)ccc21
Reactant: CCCCOCCOc1ccc(OB([O-])[O-])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3CCC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.8 %

Procedure:
In a mixture of water:ethanol:toluene (1:1:10, v/v, 24.0 ml) were dissolved 4-(2-butoxyethoxy)phenyl borate (519 mg) and 7-bromo-1-propyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (745 mg). To the solution was added potassium carbonate (482 mg), and the mixture was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (67 mg), and the mixture was refluxed under argon atmosphere for 10 hours. The mixture was diluted with ethyl acetate, and washed with water and saturated brine, and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (35 g, ethyl acetate→ethyl acetate:ethanol=10:1) and recrystallized from ethyl acetate-IPE to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 27) (453 mg, 50%) as yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:10][C:11]([CH3:17])([CH3:16])[CH2:12][C:13](Cl)=[O:14])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl[Sn](Cl)(Cl)Cl>C(Cl)Cl>[CH3:9][O:8][C:7]1[CH:6]=[C:5]2[C:4](=[CH:3][C:2]=1[F:1])[S:10][C:11]([CH3:17])([CH3:16])[CH2:12][C:13]2=[O:14]
Reactant: COc1ccc(SC(C)(C)CC(=O)Cl)cc1F
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc2c(cc1F)SC(C)(C)CC2=O
Yield: 78 %

Procedure:
To a solution of the acyl chloride (Compound 202, 2.80 g, 10.1 mmol) in 35 mL of CH2Cl2 at 0° C. was added dropwise a solution of SnCl4 (2.64 g, 10.1 mmol) in 5 mL of CH2Cl2. After 2.5 hours the reaction was quenched by the slow addition of 20 mL H2O. The organic layer was washed with 1M aqueous HCl, 5% aqueous NaOH, H2O, and finally saturated aqueous NaCl before being dried over MgSO4. Concentration under reduced pressure afforded 1.90 g (78%) the title compound as a tan solid. 1H NMR (300 MHz, CDCl3)δ: 7.72 (1H, d, J=8.9 Hz), 6.95 (1H, d, J=11.0 Hz), 3.91 (3H, s), 2.85 (2H, s), 1.47 (6H,s).
Reaction SMILES: [C-:1]#[N:2].[K+].[F:4][CH:5]([F:21])[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13]O)=[CH:9][C:8]=1[O:15][CH:16]1[CH2:20][CH2:19][O:18][CH2:17]1>O.CN(C=O)C>[F:4][CH:5]([F:21])[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:1]#[N:2])=[CH:9][C:8]=1[O:15][CH:16]1[CH2:20][CH2:19][O:18][CH2:17]1
Reactant: [C-]#N
Reactant: OCc1ccc(OC(F)F)c(OC2CCOC2)c1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1ccc(OC(F)F)c(OC2CCOC2)c1
Temperature: 80 °C
Yield: 80.4 %

Procedure:
A mixture of KCN (0.076 mol) in H2O (4 ml), heated to 80° C., was added dropwise to a mixture of intermediate 3 (0.038 mol) in DMF (82.4 ml), stirred at 60° C. The resulting reaction mixture was stirred for 30 minutes at 60° C. The reaction mixture was cooled, washed with water, extracted with DIPE. The extract was dried, filtered, and the filtrate was evaporated, yielding 8.23 g (80%) of (±)-4-(difluoromethoxy)-3-[(tetrahydro-3-furanyl)oxy]benzeneacetonitrile (intermediate 4).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.Br[C:17]1[N:21]2[CH:22]=[CH:23][C:24]([C:26]([OH:29])([CH3:28])[CH3:27])=[N:25][C:20]2=[N:19][CH:18]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:17]2[N:21]3[CH:22]=[CH:23][C:24]([C:26]([OH:29])([CH3:27])[CH3:28])=[N:25][C:20]3=[N:19][CH:18]=2)=[CH:4][C:3]=1[N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: OB(O)c1ccc(F)c(-n2cncn2)c1
Reactant: CC(C)(O)c1ccn2c(Br)cnc2n1
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-n4cncn4)c3)cnc2n1

Procedure:
4-Fluoro-3-([1,2,4]triazol-1-yl)phenylboronic acid (100 mg, 0.48 mmol) was coupled to 2-(3-bromoimidazo[1,2-α]pyrimidin-7-yl)propan-2-ol (113 mg, 0.44 mmol) using the method in Example 1. Purification by chromatography on silica gel eluting with dichloromethane containing 5% methanol then trituration with diethyl ether gave 2-[3-(4-fluoro-3-([1,2,4]triazol-1-yl)phenyl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol as a pink solid: δH (400 MHz, CDCl3) 1.63 (6H, s), 4.31 (1H, s), 7.12 (1H, d, J 7), 7.47-7.57 (2H, m), 7.91 (1H, s), 8.14-8.18 (2H, m), 8.61 (1H, d, J 7), 8.79 (1H, d, J 3); m/z (ES+) 339 (M++H).