Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][C:10]([CH:12]=[CH:13][C:14](=O)[CH:15]([CH3:17])[CH3:16])=[CH:11][C:6]=2[O:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.[Na+].[NH2:24][OH:25]>CO>[O:1]1[C:7]2[CH:8]=[CH:9][C:10]([CH:12]=[CH:13][C:14](=[N:24][OH:25])[CH:15]([CH3:17])[CH3:16])=[CH:11][C:6]=2[O:5][CH2:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: CC(C)C(=O)C=Cc1ccc2c(c1)OCCCO2
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)C(C=Cc1ccc2c(c1)OCCCO2)=NO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
145 mg 1-(3,4-dihydro-2H-1,5-benzodioxepine-7-yl)-4-methyl-1-penten-3-one was dissolved in methanol (20 ml), along with hydroxylamine hydrocholoride (244 mg) and sodium acetate (480 mg) and stirred in room temperature overnight. The reaction mixture was evaporated and the residue was dissolved in ethyl acetate (30 ml). After washing with 30 mL water and 30 mL Brine and drying with anhydrous sodium sulfate, the organic layer was concentrated under reduced pressure to yield crude product (M+1=262.1), that was used for next reaction.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[C:5]([CH3:19])[CH:4]=1)=O.[CH3:20][C:21]([CH3:26])([CH3:25])[CH2:22][CH2:23][NH2:24].[BH4-].[Na+]>CO>[CH3:20][C:21]([CH3:26])([CH3:25])[CH2:22][CH2:23][NH:24][CH2:1][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[C:5]([CH3:19])[CH:4]=1
Reactant: CC(C)(C)CCN
Reactant: Cc1cc(C=O)ccc1Oc1cnc(C(N)=O)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(CNCCC(C)(C)C)ccc1Oc1cnc(C(N)=O)cn1
Reaction time: 8 h
Yield: 41.3 %

Procedure:
Place 5-(4-formyl-2-methylphenoxy)pyrazine-2-carboxamide (Example 404, Part D) (0.200 g, 0.777 mmol), 3,3-dimethylbutylamine (0.100 g, 0.777 mmol) and 3 Å molecular sieves in a vial. Add methanol (3.8 mL), cap and stir overnight. Add NaBH4 (in excess over two portions) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 5 g ISCO® pre-load column. Dry the pre-loaded column in a vacuum oven at room temperature. Purify by eluting through a 10 g ISCO® column with (2.0 M NH3 in methanol), ethyl acetate and hexanes. After concentrating, take the product up in CH2Cl2 (25 mL) and wash with 1.0 N NaOH solution (2× 10 mL). Dry the organic layer over Na2SO4, filter and concentrate to give the title compound (0.110 g, 41.4%): MS ES+ 343.1 (M+H)+, base peak 242.0 (M-C6H14N)+; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95% over 19 min], tR=9.7 min, 94.3% purity.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([NH:17][CH3:18])=[O:16])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH:9]=2)=[CH:6][N:7]=1.CN(C=O)C.[Br:24][CH2:25][CH2:26]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:15]([NH:17][CH3:18])=[O:16])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:26][CH2:25][Br:24])[CH:9]=2)=[CH:6][N:7]=1
Reactant: CNC(=O)c1nc(-c2cccc(O)c2)cnc1N
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)c1nc(-c2cccc(OCCBr)c2)cnc1N
Temperature: 85 °C
Reaction time: 4 h
Yield: 34 %

Procedure:
3-Amino-6-(3-hydroxyphenyl)-N-methylpyrazine-2-carboxamide (1.01 g, 4.1 mmol) was taken into DMF (10 mL) followed by addition of 1,2-dibromoethane (10 mL) and cesium carbonate (2.7 g, 8.2 mmol). The mixture was warmed to 85° C. over 5 days followed by addition of another aliquot of cesium carbonate and 1,2-dibromoethane and heating was continued an additional 4 hours. The mixture was diluted with an excess of ethyl acetate and washed with water (3×) then brine and dried over anhydrous magnesium sulfate. Filtration and concentration ill vacuo followed by purification of the residue using silica gel flash chromatography using ethyl acetate:hexanes (1:1) as eluent. The pure fractions were combined and concentrated then dried in vacuo to give 3-amino-6-{3-[(2-bromoethyl)oxy]phenyl)-N-methylpyrazine-2-carboxamide (486 mg, 34% yield) was a yellow solid: MS (EI) for C14H16N4O2Br: 351, 353 (MH+).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrC[C:45]1[CH:50]=[CH:49][CH:48]=C[C:46]=1[S:51]([CH3:54])(=[O:53])=[O:52]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[CH:48]=[CH:49][CH:50]=[CH:45][C:46]=3[S:51]([CH3:54])(=[O:53])=[O:52])[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CS(=O)(=O)c1ccccc1CBr
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3ccccc3S(C)(=O)=O)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(bromomethyl)-2-(methylsulfonyl)benzene and isolated as white solid. MS (m/e): 451.3 (MH+).
Reaction SMILES: COC1C=CC(C([NH:24][C:25]2[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]3[CH:41]=[C:40](Br)[CH:39]=[CH:38][C:37]=3[F:43])([CH3:35])[N:26]=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.[NH2:44][C:45]1[CH:52]=[CH:51][C:48]([C:49]#[N:50])=[C:47]([CH3:53])[CH:46]=1>>[NH2:24][C:25]1[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:33])([CH3:34])[C@:27]([C:36]2[CH:41]=[C:40]([NH:44][C:45]3[CH:52]=[CH:51][C:48]([C:49]#[N:50])=[C:47]([CH3:53])[CH:46]=3)[CH:39]=[CH:38][C:37]=2[F:43])([CH3:35])[N:26]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(C)(C)C(=O)N2C)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: Cc1cc(N)ccc1C#N
Product: Cc1cc(Nc2ccc(F)c([C@@]3(C)N=C(N)N(C)C(=O)C3(C)C)c2)ccc1C#N

Procedure:
The coupling of (S)-2-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-6-(5-bromo-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate K) and 4-amino-2-methyl-benzonitrile according to procedure B followed by deprotection yielded the title compound as a white solid. MS (ESI): m/z=394.1 [M+H]+.
Reaction SMILES: F[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)[CH:3]=1.[NH:22]([CH3:24])[CH3:23].Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:23][N:22]([CH3:24])[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)[CH:3]=1
Reactant: CNC
Reactant: O=C(O)c1ccc(-c2cc(F)c3cc(O)ccc3n2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)c1cc(-c2ccc(C(=O)O)cc2)nc2ccc(O)cc12
Temperature: 160 °C
Yield: 32.2 %

Procedure:
30 mg of 4-(4-fluoro-6-hydroxyquinolin-2-yl)benzoic acid (Compound 26) was mixed with 1 mmol Me2NH.HCl and 0.5 ml DIEA in 3 ml DMF and heated to 160° C. for 30 minutes. The solvent was evaporated to dryness and water was added. The solid was filtered and washed with water and dried. The crude was triturated with acetone to obtain 10.5 mg of Compound 47. 1H NMR (DMSO-d6 300 MHz TMS): δ 13.2 (b, 1H), 10.28 (s, 1H), 8.22 (m, 2H), 8.11 (d, 1H), 7.99 (d, 1H), 7.50 (s, 1H), 7.39 (d, 1H), 7.26 (s, 1H), 3.24 (s, 6H), MS (ESI): m/z=309.30 [M+1]+.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:22])[NH:9]2)(=[O:3])[CH3:2].B(F)(F)F.[Br:27]Br.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Br:27][CH2:2][C:1]([C:4]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:22])[NH:9]2)=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: FB(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 30 °C

Procedure:
A dry 3 liter, 4-necked round bottom flask equipped with a mechanical stirrer, thermometer, addition funnel and refluxing condenser was charged with of 5-Acetyl-8-benzyloxycarbostyril (50 gms/0.17 moles) and dry dichloromethane (1 liter) under argon. To this solution was added boron trifluoride etharate (25.7 ml/0.204 moles). The reaction mass was heated to reflux. To this reaction mass was added slowly solution of bromine (8.4 ml/0.17 moles) in dichloromethane (100 ml) at reflux in 4 hours. The mixture was refluxed for additional 30 minutes. The mass was cooled to 30° C. and adjusted to pH 8-9 using 10% aqueous potassium carbonate solution (470 ml).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[CH3:18][OH:19]>>[CH3:18][O:19][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1
Reactant: CO
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Product: COc1nc(Nc2cc[nH]n2)cc2ccccc12

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and methanol to give (1-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine. LC-MS m/e 241(MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:9]=1)[C:7]#[N:8].[Br-].[CH2:12]([Zn+])[CH:13]([CH3:15])[CH3:14]>>[CH3:12][CH:13]([CH3:15])[CH2:14][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: CC(C)C[Zn+]
Reactant: N#Cc1cc(Br)ccc1I
Agent: [Br-]
Product: CC(C)Cc1ccc(Br)cc1C#N
Temperature: 25 °C
Reaction time: 48 h

Procedure:
5-Bromo-2-iodobenzonitrile (3.25 mmol) was combined with 6.5 mL of 0.5 M solution of iso-butylzinc bromide, the solution was degassed with argon, 100 mg of tetrakis(triphenylphosphine) palladium was added in one portion and the solution was stirred at rt under argon for 48 h. The solvents were removed under reduced pressure and the residual mixture was purified by column chromatography using Biotage 40L cartridge to obtain the title compound: 1H NMR (500 MHZ, CDCl3) δ 0.97 (d, J=8.5, 6H), 2.00 (m, 1H), 2.71 (d, J=7.5, 2H), 7.19 (d, J=8.5, 1H), 7.65 (dd, J=8.5, 2.0, 1H), 7.76 (d, J=2.0, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:6][CH:7]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:24][C:25]1[CH:26]=[C:27]([O:35][CH3:36])[C:28]([O:33][CH3:34])=[CH:29][C:30]=1[CH2:31]Cl>O>[CH3:36][O:35][C:27]1[CH:26]=[C:25]2[C:30](=[CH:29][C:28]=1[O:33][CH3:34])[CH2:31][N:11]([S:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)(=[O:10])=[O:9])[CH2:24]2
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: COc1cc(CCl)c(CCl)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(cc1OC)CN(S(=O)(=O)c1ccc(C)cc1)C2
Temperature: 25 °C
Yield: 95.2 %

Procedure:
1.89 g (11 mmol) of p-toluenesulfonamide was added to 20 ml of N,N-dimethylformamide, and 3.3 g (24 mmol) of pulverised potassium carbonate and 2.0 g (8.5 mmol) of 4,5-bischloromethyl veratrol were added thereto at room temperature under stirring. The mixture was stirred at room temperature for 20 hours, and after an addition of 40 ml of water, extracted with methylene chloride. The extract was washed with water, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the crystalline residue was washed with diisopropyl ether to obtain 2.7 g (yield: 95.2%) of the above identified compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=[O:11].C1N=CN(C(N2C=NC=C2)=O)C=1.[C:25](O)([CH3:28])([CH3:27])[CH3:26]>C1COCC1>[C:25]([O:11][C:10]([C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:12])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)O
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.00 g (6.21 mmol) indole-2-carboxylic acid is dissolved in 15 ml absolute THF, mixed with 1.01 g (6.23 mmol) N,N-carbonyldiimidazole and stirred at room temperature for 1 hour. Thereafter, 0.77 g (6.86 mmol) potassium-tert-butylate and 9.12 g (123 mmol) tert-butanol are added. Following heating under reflux for 6 hours, quenching using 5 ml water, filtrating off, rinsing with THF, drying on sodium sulfate and concentration on the rotary evaporator, a brown solid is obtained as the crude product. Preliminary purification by means of column chromatography on silica gel using a short column with petroleum ether/ethyl acetate 95:5 leaves a white solid which is purified on silica gel by means of column chromatography (flow agent: petroleum ether/ethyl acetate 98:2) and yields the product as a white solid.
Reaction SMILES: [CH2:1]([NH:13][C:14](=[O:35])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:22][CH:23]([C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=[CH:27][CH:26]=2)[CH3:24])=[CH:17][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CCN(C(C)C)C(C)C.[CH2:45]([O:47][C:48](=[O:52])[C:49](Cl)=[O:50])[CH3:46]>C(Cl)Cl>[CH2:45]([O:47][C:48](=[O:52])[C:49]([N:22]([CH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]([NH:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:35])=[CH:20][CH:19]=1)[CH:23]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)[CH3:24])=[O:50])[CH3:46]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CCCCCCCCCCCCNC(=O)c1ccc(CNC(C)c2cccc3ccccc23)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCCNC(=O)c1ccc(CN(C(=O)C(=O)OCC)C(C)c2cccc3ccccc23)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
The resin-bound N-dodecyl-4-({[1-(1-naphthyl)ethyl]amino}methyl)benzamide (described in step c, 0.0426 mmol) was swelled in DCM (1.0 mL) for 15 min at 0° C. DIEA (28 mg, 0.213 mmol) and chloro-oxo-acetic acid ethyl ester (29 mg, 0.213 mmol) were added and the reaction mixture was shaken 3 h at 0° C. then 14 h at rt. The resin was washed successively with THF (1×15 min), MeOH (1×15 min), THF (1×15 min), MeOH (3×10 min), DMF (3×10 min), MeOH (1×5 min), THF (3×10 min), MeOH (1×5 min), DCM (3×10 min) and with Et2O (1×10 min). The resin was then dried under vacuum to afford the resin-bound ethyl{{4-[(dodecylamino)carbonyl]benzyl}[1-(1-naphthyl)ethyl]amino}-(oxo)acetate which was used directly in the next step.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].Cl.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]([CH:21]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[C:22]([NH:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:23])[C:19]3[CH:37]=[CH:38][CH:39]=[CH:40][C:18]=3[N:17]=2)=[CH:12][CH:11]=1.N1C=CC=CC=1.Cl>ClCCl>[C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]([CH:21]([CH:31]3[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]3)[C:22]([NH:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:23])[C:19]3[CH:37]=[CH:38][CH:39]=[CH:40][C:18]=3[N:17]=2)=[CH:12][CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(-c2nc3ccccc3n2C(C(=O)NC2CCCCC2)C2CCCCC2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc(-c2nc3ccccc3n2C(C(=O)NC2CCCCC2)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Acetic anhydride (175 mg, 1.71 mmol, 1.0 equiv.) was added to a solution of 2-[2-(4-amino-phenyl)-benzoimidazol-1-yl]-2,N-dicyclohexyl-acetamide hydrogen chloride (example 34) (74 mg, 1.71 mmol, 1.0 equiv.) and pyridine (13 mg, 1.71 mmol, 1.0 equiv.) in dichloromethane (2 mL). The reaction was stirred at room temperature for 16 hours then retreated with pyridine (13 mg, 1.71 mmol, 1.0 equiv.) and acetic anhydride (17 mg, 0.17 mmol, 0.1 equiv.) and stirred at room temperature for a further 24 hours. The reaction mixture was added to 1 N HCl (2 mL) and the resultant precipitate was filtered and washed with dichloromethane. The solid was dissolved in hot ethyl acetate (3 mL) and filtered, the filtrate was concentrated in vacuo to afford 2-[2-(4-acetylamino-phenyl)-benzoimidazol-1-yl]-2,N-dicyclohexyl-acetamide as a cream solid, 26 mg (32%), MS (ES+): 473 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH3:24])[CH:18]([C:19]([O:21][CH3:22])=[O:20])[C:17](=[O:23])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[O:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[BH4-].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH3:24])[CH:18]([C:19]([O:21][CH3:22])=[O:20])[CH:17]([OH:23])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[O:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)C1C(=O)c2ccccc2OC1(C)c1ccc(Cl)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)C1C(O)c2ccccc2OC1(C)c1ccc(Cl)c(Cl)c1
Yield: 98.6 %

Procedure:
A solution of methyl 2-(3,4-dichlorophenyl)-2-methyl-4-oxochroman-3-carboxylate (490 mg, 1.34 mmol) in THF (2.0 mL) was diluted with methanol (4.0 mL) and treated at rt with sodium borohydride (51 mg, 1.34 mmol). Additional sodium borohydride was added after 4 h. After 2.5 h more the solution was concentrated under vacuum. The residue was partitioned between water (containing a few drops of 1.0 M aqueous sodium hydroxide) and ethyl acetate. The organic phase was dried over sodium sulfate and concentrated under vacuum to provide crude methyl 2-(3,4-dichlorophenyl)-4-hydroxy-2-methylchroman-3-carboxylate as a white solid (485 mg, 98%), which was used without further purification. Mass spectrum m/z 389, 391 (M+Na)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[S:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH:11]=[C:10]1B(O)O.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:10]2[S:9][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH:11]=2)=[N:3][CH:4]=1
Reactant: Clc1ccc(Cl)nc1
Reactant: OB(O)c1cc2ccccc2s1
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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Clc1ccc(-c2cc3ccccc3s2)nc1
Reaction time: 8 h
Yield: 56.4 %

Procedure:
In a 500 ml-three-necked flask, 12.6 g (85.2 mM) of 2,5-dichloropyridine, 15.2 g (85.4 mM) of benzothiophene-2-boronic acid, 75 ml of toluene, 37.5 ml of ethanol and 75 ml of 2M-sodium carbonate aqueous solution were placed and stirred at room temperature under nitrogen stream, and 3.06 g (2.64 mM) of tetrakis(triphenylphosphine)palladium (0) was added thereto, followed by refluxing under stirring for 8 hours under nitrogen stream. After the reaction, the reaction mixture was cooled on an ice bath to precipitate a crystal, which was then filtered out and washed with water. To the crystal, 100 ml of methanol was added and washed under stirring at room temperature, followed by filtration to recover the crystal. The crystal was purified by silica gel column chromatography (eluent: chloroform) and recrystallized from a mixture solvent of chloroform-methanol to obtain 11.8 g (Yield: 56.4%) of 5-chloro-2-(benzo[b]thienyl)pyridine (colorless crystal).
Reaction SMILES: [C:1](=[NH:25])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([O:20][C:21]([F:24])([F:23])[F:22])[CH:14]=2)=[CH:8][CH:7]=1)[NH2:2].[OH:26]/[CH:27]=[C:28](/[CH2:33][C:34]1[CH:35]=[N:36][C:37]([O:40][CH3:41])=[N:38][CH:39]=1)\[C:29](OC)=O.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][O:3][C:1]3[NH:2][CH:29]=[C:28]([CH2:33][C:34]4[CH:35]=[N:36][C:37]([O:40][CH3:41])=[N:38][CH:39]=4)[C:27](=[O:26])[N:25]=3)=[CH:11][CH:10]=2)=[CH:14][C:15]=1[O:20][C:21]([F:24])([F:22])[F:23]
Reactant: N=C(N)OCCc1ccc(Oc2ccc(Cl)c(OC(F)(F)F)c2)cc1
Reactant: COC(=O)/C(=C\O)Cc1cnc(OC)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COc1ncc(Cc2c[nH]c(OCCc3ccc(Oc4ccc(Cl)c(OC(F)(F)F)c4)cc3)nc2=O)cn1
Reaction time: 4 h
Yield: 15.7 %

Procedure:
The same procedure as E177 from 4-(4-chloro-3-(trifluoromethoxy)phenoxy)phenethyl carbamimidate (100 mg, 0.267 mmol), (Z)-methyl 3-hydroxy-2-((2-methoxypyrimidin-5-yl)methyl)acrylate (180 mg, 0.803 mmol) and Cs2CO3 (260 mg, 0.798 mmol) in 1,4-dioxane (2 mL), except that the reaction temperature was 120° C. and the time was 4 h, to afford the title compound (28 mg, 0.042 mmol, 15.83% yield). LCMS: rt=3.63 min, [M+H+]=549
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8]CC2C=CC(OC)=CC=2)[CH:5]=[C:4]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[CH:24][CH:25]=3)[N:20]([S:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)(=[O:29])=[O:28])[CH:19]=2)[CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[CH:24][CH:25]=3)[N:20]([S:27]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)(=[O:28])=[O:29])[CH:19]=2)[CH:3]=1
Reactant: COc1ccc(CNc2cc(-c3cn(S(=O)(=O)c4ccccc4)c4ncccc34)cc(Cl)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cc(-c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)cc(Cl)n1
Temperature: 35 °C
Yield: 58.3 %

Procedure:
To a solution of Example 150a (0.500 g, 0.990 mmol) in CH2Cl2 (9 mL) was added trifluoroacetic acid (4 mL, 51.9 mmol). The mixture was heated at 35° C. for 6 hours and concentrated. The residue was treated with saturated NaHCO3 and extracted with EtOAc. The organic layer was concentrated. The crude was triturated with EtOAc/diethyl ether to give 222 mg of the title compound. The filtrate was concentrated and purified on a 12 g column using the ISCO Companion flash system eluting with CH2Cl2/EtOAc (95:5 to 90:10) to give more title compound (84 mg).
Reaction SMILES: [C:1]([C:3]1([OH:9])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)#[CH:2].[C:10]([C:13]1[CH:14]=[C:15](/[CH:18]=[C:19]2\[C:20](=[O:30])[NH:21][C:22]3[C:27]\2=[C:26](I)[C:25]([F:29])=[CH:24][CH:23]=3)[NH:16][CH:17]=1)(=[O:12])[CH3:11]>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.CN(C=O)C.CCN(CC)CC>[C:10]([C:13]1[CH:14]=[C:15](/[CH:18]=[C:19]2\[C:20](=[O:30])[NH:21][C:22]3[C:27]\2=[C:26]([C:2]#[C:1][C:3]2([OH:9])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)[C:25]([F:29])=[CH:24][CH:23]=3)[NH:16][CH:17]=1)(=[O:12])[CH3:11]
Reactant: C#CC1(O)CCOCC1
Reactant: CC(=O)c1c[nH]c(/C=C2\C(=O)Nc3ccc(F)c(I)c32)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)c1c[nH]c(/C=C2\C(=O)Nc3ccc(F)c(C#CC4(O)CCOCC4)c32)c1

Procedure:
Using Method C above, 4-Ethynyl-tetrahydro-pyran-4-ol (0.16 g1 1.26 mmol) (Example 85A) was coupled with (Z)-3-[(4-acetyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-5-fluoro-4-iodo-2H-indol-2-one (0.2 g, 0.50 mmol) (Example 90B above) using (Ph3P)4Pd (58.4 mg) and Cul (9.6 mg) as catalyst in DMF (15 mL) and Et3N (15 mL) as solvent at 85° C. for 18 h. (Yield 102 mg, 52%).