Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[O:10][C:3]=12.[F:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([C:33]2[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=2)=[O:32])=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:25]=[CH:26][C:27]([NH:30][C:31](=[O:32])[C:33]2[CH:34]=[CH:35][CH:36]=[C:37]([C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]5[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=5)[O:10][C:3]=34)[CH:38]=2)=[CH:28][CH:29]=1
Reactant: COc1cc(-c2cc3nccc(Cl)c3o2)cc(OC)c1OC
Reactant: O=C(Nc1ccc(F)cc1)c1cccc(B(O)O)c1
Product: COc1cc(-c2cc3nccc(-c4cccc(C(=O)Nc5ccc(F)cc5)c4)c3o2)cc(OC)c1OC

Procedure:
The title compound was prepared by procedure C using 7-chloro-2-(3,4,5-trimethoxyphenyl)furo[3,2-b]pyridine (45.00 mg; 0.14 mmol; 1.00 eq.) instead of 7-chloro-2-iodo-furo[3,2-b]pyridine, and 3-(4-fluorophenyl)aminocarbonyl-phenylboronic acid (40.10 mg; 0.15 mmol; 1.10 eq.) instead of 4-fluorophenylboronic acid and was obtained as a white solid (57 mg, 81%). (HPLC (method F): 87%, RT: 4.33 min); 1H NMR (500 MHz, DMSO-d6) δ [ppm] 10.51 (s, 1H), 8.96 (s, 1H), 8.67-8.58 (m, 1H), 8.34 (d, J=7.4, 1H), 8.15 (d, J=7.4, 1H), 7.88-7.74 (m, 5H), 7.38 (s, 2H), 7.24 (t, J=7.8, 2H), 3.87 (s, 6H), 3.77-3.68 (m, 3H); MS (m/z) 499 [M+H]+, RT: 4.3 min.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].Cl.[CH2:6]([N:8]1[C:12]2[N:13]=[CH:14][C:15]([C:24]3[O:28][N:27]=[C:26]([CH2:29][CH:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)[N:25]=3)=[C:16]([NH:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:11]=2[CH:10]=[N:9]1)[CH3:7].C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[C:1]([N:33]1[CH2:34][CH2:35][CH:30]([CH2:29][C:26]2[N:25]=[C:24]([C:15]3[CH:14]=[N:13][C:12]4[N:8]([CH2:6][CH3:7])[N:9]=[CH:10][C:11]=4[C:16]=3[NH:17][CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[O:28][N:27]=2)[CH2:31][CH2:32]1)(=[O:3])[CH3:2]
Reactant: CCn1ncc2c(NC3CCOCC3)c(-c3nc(CC4CCNCC4)no3)cnc21
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCn1ncc2c(NC3CCOCC3)c(-c3nc(CC4CCN(C(C)=O)CC4)no3)cnc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Acetyl chloride (0.04 mmol) was added to a stirred solution of Intermediate 125 (0.033 mmol) and diisopropylethylamine (0.1 mmol) in chloroform (1 ml) at room temperature. After stirring at room temperature for 1.5 h, a further quantity of acetyl chloride (0.04 mmol) and diisopropylethylamine (0.1 mmol) were added to the reaction mixture. After 3.5 h the reaction mixture was applied to a SPE cartridge (aminopropyl, 1 g) and the cartridge was eluted sequentially with chlororm, ethyl acetate and methanol. Fractions containing the desired product were combined and blown down under nitrogen. The resulting residue was further purified on a SPE cartridge (silica, 1 g) eluting with a gradient of 30-100% ethyl acetate in petroleum ether to afford Example 175 LCMS showed MH+=454, TRET=2.79 min.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:8][CH3:9])[O:6][CH3:7].[C:12]([O-:17])(=[O:16])[C:13]([CH3:15])=[CH2:14].[K+]>C(P(CCCC)CCCC)CCC.C1C2NC3C(=CC=CC=3)SC=2C=CC=1>[C:12]([O:17][CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:8][CH3:9])[O:6][CH3:7])(=[O:16])[C:13]([CH3:15])=[CH2:14]
Reactant: C=C(C)C(=O)[O-]
Reactant: CO[Si](CCCCl)(OC)OC
Agent: CCCCP(CCCC)CCCC
Agent: [K+]
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: C=C(C)C(=O)OCCC[Si](OC)(OC)OC
Reaction time: 10 h
Yield: 89 %

Procedure:
Using a method analogous to Example 1, 198.7 g (1 mol) of 3-chloropropyltrimethoxysilane are reacted in the presence of 6.1 g (0.03 mol) of tri-n-butylphosphine and 0.1 g of phenothiazine with 130.4 g (1.05 mol) of potassium methacrylate at 90° C. The reaction is complete 10 hours after all the potassium methacrylate has been introduced. Work-up gives 221.0 g (89%) of 3-methacryloxypropyltrimethoxysilane having a purity of 98.3%.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([Br:18])=[C:14]([OH:19])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].IC.[C:22]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([Br:18])=[C:14]([O:19][CH3:22])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2ccc(Br)c(O)c12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1c(Br)ccc2oc(C(=O)OC(C)(C)C)c(C)c12
Temperature: 25 °C
Yield: 100.6 %

Procedure:
To 220 mg (0.67 mmol) of 5-bromo-4-hydroxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester was added 0.42 mL (6.7 mmol) of iodomethane, 185 mg (1.34 mmol) of K2CO3 and 2 mL of DMF. The mixture was stirred at room temperature over night. The mixture was washed with brine and extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine. Removal of the solvent gave 230 mg (100% yield) of 5-bromo-4-methoxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester as a colorless oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9](=[O:33])[CH2:10][C@@:11]1([C:20]2[S:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH3:32])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[S:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[CH:39]=O.C([BH3-])#N.[Na+].C(O)(=O)C>C(O)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9](=[O:33])[CH2:10][C@@:11]1([C:20]2[S:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH3:32])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][N:14]([CH2:39][C:35]2[S:34][CH:38]=[CH:37][CH:36]=2)[CH2:13][CH2:12]1
Reactant: CCc1ccc(-c2ccc([C@@]3(CC(=O)NOC4CCCCO4)CCNCCS3(=O)=O)s2)cc1
Reactant: O=Cc1cccs1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCc1ccc(-c2ccc([C@@]3(CC(=O)NOC4CCCCO4)CCN(Cc4cccs4)CCS3(=O)=O)s2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.9 %

Procedure:
To a solution of N-(2-tetrahydropyranyloxy)-2-[(S)-7-[5-(4-ethylphenyl)-2-thienyl]-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (70.0 mg) and 2-thiophenecarbaldehyde (19.1 mg) in ethanol (1 ml) was added sodium cyanoborohydride (10.7 mg) and a drop of acetic acid at 0° C. The resulting mixture was stirred for 3 hours at room temperature. The reaction was quenched by the addition of saturated sodium bicarbonate (1 ml), and the solvent was evaporated off. The residue was dissolved in ethyl acetate (20 ml), and washed with water, brine, dried over magnesium sulfate, and evaporated. Silica gel column chromatography [eluent: acetone/chloroform (10:1)] afforded N-(2-tetrahydropyranyloxy)-2-[(S)-7-[5-(4-ethylphenyl)-2-thienyl]-1,1-dioxoperhydro-4-(2-thienylmethyl)-1,4-thiazepin-7-yl]acetamide (74.4 mg) as a colorless oil.
Reaction SMILES: [O:1]1[C@H:5]2[O:6][CH2:7][CH2:8][C@H:4]2[C@@H:3]([O:9][C:10](=[O:44])[NH:11][C@@H:12]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@H:13]([OH:36])[CH2:14][N:15]([S:24]([C:27]2[CH:35]=[CH:34][C:30]3[O:31][CH2:32][O:33][C:29]=3[CH:28]=2)(=[O:26])=[O:25])[CH2:16][C:17]([CH3:23])([CH3:22])[CH2:18][CH2:19][C:20]#[N:21])[CH2:2]1.N1C=NN=N1.C(N(C(C)C)[P:54]([O:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)(C)C.ClC1C=C(C=CC=1)C(OO)=[O:79]>C(Cl)Cl>[O:1]1[C@H:5]2[O:6][CH2:7][CH2:8][C@H:4]2[C@@H:3]([O:9][C:10](=[O:44])[NH:11][C@@H:12]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@H:13]([O:36][P:54]([O:55][CH2:56][C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)([O:63][CH2:64][C:65]2[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=2)=[O:79])[CH2:14][N:15]([S:24]([C:27]2[CH:35]=[CH:34][C:30]3[O:31][CH2:32][O:33][C:29]=3[CH:28]=2)(=[O:25])=[O:26])[CH2:16][C:17]([CH3:23])([CH3:22])[CH2:18][CH2:19][C:20]#[N:21])[CH2:2]1
Reactant: CC(C)N(C(C)C)P(OCc1ccccc1)OCc1ccccc1
Reactant: CC(C)(CCC#N)CN(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: c1nnn[nH]1
Solvent: ClCCl
Product: CC(C)(CCC#N)CN(C[C@@H](OP(=O)(OCc1ccccc1)OCc1ccccc1)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C

Procedure:
A solution of {(1S,2R)-3-[(Benzo[1,3]dioxole-5-sulfonyl)-(4-cyano-2,2-dimethyl-butyl)-amino]-1-benzyl-2-hydroxy-propyl}-carbamic acid (3R,3aS,6aR)hexahydro-furo[2,3-b]furan-3-yl ester (0.077 g, 0.12 mmol) and 1H-tetrazole (0.012 g, 0.17 mmol) in CH2Cl2 was treated with dibenzyl diisopropylphosphoramidite (0.050 ml, 0.015 mmol) and stirred at ambient temperature under argon. After 2 h 3-chloroperoxybenzoic acid (0.072 g, 0.30 mmol) was added and the reaction mixture stirred an additional 1 h. Solvent was removed in vacuo, the residue taken up in EtOAc, washed with sat. aq. NaHCO3, and brine. The organic phase was dried over MgSO4, filtered and solvent removed in vacuo to give desired product, which was used directly in the next step.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][C:9](=[CH2:11])[CH3:10]>>[C:9]([C:4]1[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=1)([CH3:11])([CH3:10])[CH3:8].[C:9]([C:2]1[CH:3]=[C:4]([C:9]([CH3:11])([CH3:10])[CH3:8])[CH:5]=[CH:6][C:1]=1[OH:7])([CH3:10])([CH3:8])[CH3:11]
Reactant: Oc1ccccc1
Reactant: C=C(C)C
Product: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Product: CC(C)(C)c1ccc(O)cc1
Reaction time: 20 h
Yield: 88 %

Procedure:
A suspension of 20 parts of phenol and 0.6 part of ion exchange resin is prepared in a stirred reactor at 85° C. and 1 bar pressure, whilst stirring at 500 rpm, and 7 parts of isobutylene are passed in. The ion exchange resin is a sulfonated styrene/divinylbenzene copolymer resin, which has been dehydrated under reduced pressure for 20 hours at 100° C. before being used; it has a gel structure and its particle size is from 20 to 150 micrometers. The suspension is then stirred constantly in the reactor at 500 rpm. After 6 hours, 2.5 parts of phenol and 380 parts by volume of isobutylene are introduced per hour at 115° C. and 1 bar pressure and correspondingly 3.5 parts per hour of suspension are filtered through a suction line equipped with a metal filter (pore diameter 10 micrometers) and subjected to fractional distillation. After 200 hours' operation, 316 parts (88% of theory, based on starting material II) of 4-tert.-butylphenol of boiling point 143°-145° C./50 millibars are obtained, accompanied by 19.8 parts (5.5% of theory, based on starting material II) of 2-tert.-butylphenol and 9.9 parts (6.5% of theory, based on starting material II) of 2,4-di-tert.-butylphenol. The conversion is 60% of theory, based on phenol employed. The starting material II is consumed practically quantitatively.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:25])([F:24])[CH:21]([F:23])[F:22])[CH:14]=1)[CH:3]([C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)[OH:4].[C:26]1([C:37](O)=[O:38])[CH:27]=[CH:28][CH:29]=[C:30]2[CH2:36][CH2:35][CH2:34][CH:33]=[CH:32][C:31]=12.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[OH:4][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1)[CH:2]([NH:1][C:37]([C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[CH2:36][CH2:35][CH2:34][CH:33]=[CH:32][C:31]=12)=[O:38])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:24])([F:25])[CH:21]([F:22])[F:23])[CH:14]=1
Reactant: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(O)c1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(O)c1)c1cccc2c1C=CCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-{(1RS,2SR)-2-amino-1-hydroxy-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propyl}phenol (2.89 g, 8.04 mmol) in acetonitrile (50 ml) were added 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (1.51 g, 8.04 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.31 g, 12.06 mmol) and 1-hydroxybenzotriazole hydrate (1.23 g, 8.04 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (200 ml) and extracted with ethyl acetate (200 ml×2). The extract was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1-1:1) to give the objective substance (2.75 g, 65%) as an amorphous compound.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=1[CH2:27][C:28](O)=[O:29]>>[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=1[CH2:27][C:28]([NH:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18])=[O:29]
Reactant: Cc1ccc(C)c(CC(=O)O)c1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Product: Cc1ccc(C)c(CC(=O)Nn2nc(N3CCOCC3)c3ccccc3c2=O)c1

Procedure:
The product of Example 1B and 2-(2,5-dimethylphenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.31 (dd, J=7.9, 1.3 Hz, 1H), 8.02-8.04 (m, 1H), 7.97-8.00 (m, 1H), 7.91 (td, J=7.5, 1.3 Hz, 1H), 7.13 (s, 1H), 7.07 (d, J=7.6 Hz, 1H), 6.99 (d, J=7.7 Hz, 1H), 3.81-3.84 (m, 4H), 3.62 (s, 2H), 3.05-3.11 (m, 4H), 2.29 (s, 3H), 2.26 (s, 3H); MS (ESI+) M/Z 393 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([N:12]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[C:5]([CH3:27])[CH:4]=1)#[N:2].S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+].CO>C1COCC1.O>[NH2:9][C:7]1[CH:8]=[C:3]([C:1]#[N:2])[CH:4]=[C:5]([CH3:27])[C:6]=1[N:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:20]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21]
Reactant: Cc1cc(C#N)cc([N+](=O)[O-])c1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C#N)cc(N)c1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Di-t-butyl (4-cyano-2-methyl-6-nitrophenyl)imidodicarbonate obtained in Step 1 (3.77 g, 10 mmol) was dissolved in THF (0.2 M, 50 mL), and a solution prepared by dissolving sodium hydrosulfite (15.7 g, 9 eq, 90 mmol) and sodium bicarbonate (7.56 g, 90 mmol) in H2O (0.1 M, 100 mL) was added thereto. Subsequently, MeOH (17 mL) was added to the mixture, which was then stirred at room temperature for 1 hour. Upon completion of the reaction, THF and MeOH were removed under reduced pressure, and the residue was added with brine and extracted with ethyl acetate. The organic layer thus obtained was dried over MgSO4 and concentrated under reduced pressure. Then, the residue was purified by silica gel column chromatography (EA:Hex=1:2) to obtain the title compound in a white solid (2.90 g, yield: 83%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(O)C.[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([N:35]=[C:36]=[S:37])=[O:34])=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:36]([NH:35][C:33](=[O:34])[C:30]2[CH:31]=[CH:32][C:27]([CH3:26])=[CH:28][CH:29]=2)=[S:37])=[CH:18][CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: Cc1ccc(C(=O)N=C=S)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)c4ccc(C)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 4-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (73 mg, yield 92%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=O.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][N:14]=1>C(#N)C>[Br:19][C:16]1[CH:17]=[CH:18][C:13]2[N:14]([CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=3)[N:12]=2)[CH:15]=1
Reactant: O=C(CBr)c1ccc(O)cc1
Reactant: Nc1ccc(Br)cn1
Solvent: CC#N
Product: Oc1ccc(-c2cn3cc(Br)ccc3n2)cc1
Temperature: 105 °C
Yield: 83.2 %

Procedure:
2.15 g (corresponding to 10.0 mmol) of 2-bromo-4′-hydroxyacetophenone and 1.74 g (corresponding to 10.0 mmol) of 2-amino-5-bromopyridine were dissolved in 50 mL of acetonitrile. The resulting solution was refluxed in an oil bath at 105° C. for 6 hours. After the completion of the reaction, the reaction solution was cooled down to room temperature, and precipitates were filtered and recovered. The precipitates were washed with acetonitrile and dried under reduced pressure. The resulting crude crystals were suspended in a mixed solution of 20 mL of water and 20 mL of methanol. Then, about 25 mL of a saturated sodium hydrogencarbonate solution was added thereto, and the mixture was sonicated for 5 minutes using an ultrasonic washing machine. Precipitates were filtered and recovered from the resulting mixture, sufficiently washed with water, and dried under reduced pressure, to obtain 2.41 g (corresponding to 8.32 mmol) of 6-bromo-2-(4′-hydroxyphenyl)imidazo[1,2-a]pyridine (FIG. 1-3, Step 2).
Reaction SMILES: C[NH+]([CH2:4][C:5]([CH2:10]N(C)C)=[CH:6][NH+](C)C)C.Cl.[NH2:15][C:16]([NH2:18])=[NH:17].[OH-:19].[Na+]>C(#N)C.O>[NH2:17][C:16]1[N:18]=[CH:6][C:5]([CH:10]=[O:19])=[CH:4][N:15]=1
Reactant: [OH-]
Reactant: CN(C)CC(=C[NH+](C)C)C[NH+](C)C
Reactant: N=C(N)N
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Nc1ncc(C=O)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.9 %

Procedure:
Vinamidinium salt (68, 158 g, 413 mmol) and guanidine hydrochloride (69, 63.3 g, 455 mmol) were dissolved in 527 mL of acetonitrile and cooled on an ice/water bath. Sodium hydroxide (66.1 mL, 50% w/w, 827 mmol) was added dropwise, keeping the temperature below 25° C. The reaction was allowed to warm to 25° C. and stirred for 4 hours, then diluted with water and filtered, stripped from ethanol/heptane, then triturated with heptane. The resulting solid was dried under vacuum to provide the desired compound (70, 37 g, 301 mmol, 72.7% yield).
Reaction SMILES: Cl.[F:2][C:3]1([C:9]([OH:11])=[O:10])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[CH3:12][CH2:13]N(C(C)C)C(C)C.[Br:21][C:22]1[CH:23]=[N:24][C:25](Cl)=[N:26][CH:27]=1.CCCCCC>CCO>[Br:21][C:22]1[CH:23]=[N:24][C:25]([N:6]2[CH2:7][CH2:8][C:3]([F:2])([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4][CH2:5]2)=[N:26][CH:27]=1
Reactant: O=C(O)C1(F)CCNCC1
Reactant: CCN(C(C)C)C(C)C
Reactant: Clc1ncc(Br)cn1
Agent: Cl
Solvent: CCCCCC
Solvent: CCO
Product: CCOC(=O)C1(F)CCN(c2ncc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 41.6 %

Procedure:
To a solution of 4-fluoropiperidine-4-carboxylate hydrochloride (0.70 g, 4.34 mmol) in EtOH (10.0 mL) was added DIPEA (1.92 mL, 10.86 mmol) at rt and the mixture stirred at rt for 10 min followed by addition of 5-bromo-2-chloropyrimidine (0.70 g, 3.62 mmol). The reaction was then heated up to 70° C. for 1 h. After completion of reaction (by TLC), solvent was evaporated and the crude residue purified over 100-200 M silica-gel using 3.0% EtOAc:hexane to obtain the desired product as a yellow solid (0.50 g, 42% yield). MS: 332.12 [M+H]+.
Reaction SMILES: [CH2:1]1[CH:9]([CH2:10][C:11]([OH:13])=O)[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.C(N(CC)CC)C.Cl.Cl.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1.C(OP(C#N)(=O)OCC)C>C(Cl)Cl>[CH:9]1([CH2:10][C:11]([N:34]2[CH2:33][CH2:32][N:31]([C:28]3[CH:27]=[CH:26][C:25]([O:24][CH3:23])=[CH:30][CH:29]=3)[CH2:36][CH2:35]2)=[O:13])[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2][CH2:1]1
Reactant: O=C(O)CC1CCc2ccccc21
Reactant: COc1ccc(N2CCNCC2)cc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(N2CCN(C(=O)CC3CCc4ccccc43)CC2)cc1
Reaction time: 3 h

Procedure:
A mixture of 1-indanylacetic acid (CIX, EXAMPLE 66, 7.4 g, 42 mmol) and triethylamine (29.3 ml, 210 mmol), and 1-(4-methoxyphenyl)piperazine dihydrochloride (LXV, 13.3 g, 50.4 mmol) in methylene chloride (420 ml) is stirred at 20°-25° under a nitrogen atmosphere. Diethylcyanophosphonate (12.7 ml, 84 mmol) is added over a period of 10 min at 20°-25°. After the stirring for 3 hr, the reaction is quenched with sodium hydroxide (20%) and extracted with methylene chloride (2×500 ml). The organic phase is washed with saline, dried (magnesium sulfate), filtered and concentrated under reduced pressure. The crude product is purified by crystallization from ethyl acetate/methanol. The mother liquor is purified by liquid chromatography on silica gel 60 (230-400 mesh, 400 g), eluting with hexane/ethyl acetate (1/2). The appropriate fractions homogeneous by TLC are combined and concentrated under reduced pressure to give a solid. Both solids are combined to give the title compound, mp=111°-112°; NMR (CDCl3, TMS) 7.26-6.83, 3.77 and 3.85-1.54 δ.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH2:16])=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.[CH3:17][C:18]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.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>[CH3:15][C:14]1[N:13]=[C:12]([NH2:16])[CH:11]=[CH:10][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:22]2[CH:21]=[CH:20][N:19]=[C:18]([CH3:17])[CH:23]=2)[CH:7]=1
Reactant: Cc1nc(N)ccc1Oc1ccnc(Cl)c1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
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: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(-c2cc(Oc3ccc(N)nc3C)ccn2)ccn1
Temperature: 85 °C
Reaction time: 3 h
Yield: 71.8 %

Procedure:
A mixture of Example A7 (905 mg, 3.84 mmol), 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.010 g, 4.61 mmol), potassium carbonate (1.592 g, 11.52 mmol) and tetrakis(triphenylphosphine)palladium(0) (222 mg, 0.192 mmol) in dioxane (16 mL) and water (4 mL) was degassed with Ar, sealed and warmed to 85° C. overnight. The mixture was cooled to RT, diluted with EtOAc (40 mL) and water (50 mL), and filtered through diatomaceous earth. The organic phase was separated and washed with brine (50 mL). The organic phase was diluted with methanol (5 mL), treated with SiliaMetS Thiol, (1.42 mmol/g, 4 g, 5.68 mmol), and gently stirred for 3 h. The mixture was filtered, washing the slica gel plug with 3% MeOH/EtOAc (2×10 mL). The filtrates were evaporated at reduced pressure and the residue was purified by silica gel chromatography (0-10% MeOH/EtOAc) to give 6-methyl-5-((2′-methyl-[2,4′-bipyridin]-4-yl)oxy)pyridin-2-amine as a tan solid (806 mg, 71%). 1H NMR (400 MHz, DMSO-d6): δ 9.07 (d, J=2.3 Hz, 1 H), 8.48 (d, J=5.7 Hz, 1 H), 8.25 (dd, J=8.1, 2.4 Hz, 1 H), 7.50 (d, J=2.4 Hz, 1 H), 7.33 (d, J=8.2 Hz, 1 H), 7.21 (d, J=8.7 Hz, 1 H), 6.67 (dd, J=5.7, 2.4 Hz, 1 H), 6.35 (d, J=8.7 Hz, 1 H), 5.96 (s, 2 H), 2.50 (s, 3 H), 2.08 (s, 3 H). MS (ESI) m/z: 293.2 (M+H+).