Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10](SC)[N:11]=[N:12][CH:13]=2)=[CH:4][C:3]=1[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1.[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1B(O)O>>[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[C:10]1[N:11]=[N:12][CH:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[CH:4]=2)[N:9]=1
Reactant: CSc1nncc(-c2ccc(F)c(-c3cccnc3)c2)n1
Reactant: OB(O)c1ccc(F)cc1F
Product: Fc1ccc(-c2nncc(-c3ccc(F)c(-c4cccnc4)c3)n2)c(F)c1

Procedure:
5-[4-Fluoro-3-(pyridin-3-yl)phenyl]-3-methylsulfanyl-[1,2,4]triazine was coupled to 2,4-difluorophenylboronic acid by the method of Example 2 to give 3-(2,4-difluorophenyl)-5-[4-fluoro-3-(pyridin-3-yl)phenyl]-[1,2,4]triazine as a yellow solid: δH (400 MHz, CDCl3) 7.00-7.12 (2H, m), 7.42 (2H, m), 7.96 (1H, dd, J 2.0, 7.8 Hz), 8.27-8.36 (2H, m), 8.42 (1H, dd, J 2.5, 7.2 Hz), 8.70 (1H, s), 8.89 (1H, s), 9.66 (1H, s); m/z (ES+) 365.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[C:22]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)c1ccc(-c2ccc(O)cc2)cc1
Agent: O=S(=O)(O)O
Product: CC(=O)Oc1ccc(-c2ccc(C(C)=O)cc2)cc1
Yield: 97 %

Procedure:
10.5 g of 4-hydroxy-4'-acetylbiphenyl (C) obtained in Example 1 was heated together with 20 ml of acetic anhydride in the presence of a small amount of concentrated sulfuric acid. Crude crystals thus obtained were recrystallized from carbon tetrachloride to obtain 12.5 g of 4-acetoxy-4'-acetylbiphenyl (1): ##STR51##
Reaction SMILES: [CH3:1][O:2][CH:3]([CH3:7])[CH2:4][CH2:5][OH:6].[F:8][C:9]([F:21])([F:20])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16](Cl)(=[O:18])=[O:17].C(OCC)(=O)C>C(Cl)Cl>[F:21][C:9]([F:8])([F:20])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([O:6][CH2:5][CH2:4][CH:3]([O:2][CH3:1])[CH3:7])(=[O:17])=[O:18]
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Reactant: COC(C)CCO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(C)CCOS(=O)(=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.4 %

Procedure:
To a solution of 3-methoxybutane-1-ol (0.63 g, 6.0 mmol) and TEA (0.42 g, 4.1 mmol), in CH2Cl2 (5 mL) was added o-(trifluoromethyl)benzenesulfonyl chloride (0.50 g, 2.0 mmol). The solution was stirred at rt for 2 h. The reaction mixture was diluted with CH2Cl2 (15 mL) and washed with 1 M HCl (3×15 mL), saturated aqueous NaHCO3 (1×15 mL) and saturated aqueous NaCl (1×15 mL). The organics were dried over Na2SO4 and concentrated to give a crude mixture. Silica gel chromatography with ethyl acetate in hexanes yielded the desired product (0.34 g, 50%). 1H NMR (400 MHz CDCl3) δ 8.23 (m, 1H), 7.91 (m, 1H), 7.75 (m, 2H), 4.24 (m, 2H), 3.40 (m, 1H), 3.21 (s, 3H), 1.80 (m, 2H), 1.10 (d, 3H, J=6.2 Hz). Anal. Calcd. For C12H15F3O4S: C, 46.15; H, 4.84. Found: C, 46.30; H, 4.88.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]([N+:18]([O-:20])=[O:19])=[C:7]([CH:17]=1)[O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15][CH3:16])[CH2:11][CH2:10]1.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>>[F:2][C:3]1[CH:4]=[CH:5][C:6]([N+:18]([O-:20])=[O:19])=[C:7]([CH:17]=1)[O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]([CH3:16])[S:22]([CH3:21])(=[O:24])=[O:23])[CH2:11][CH2:10]1
Reactant: CS(=O)(=O)Cl
Reactant: CN[C@H]1CC[C@@H](Oc2cc(F)ccc2[N+](=O)[O-])CC1
Agent: Cl
Product: CN([C@H]1CC[C@@H](Oc2cc(F)ccc2[N+](=O)[O-])CC1)S(C)(=O)=O

Procedure:
Prepared analogously to example IV.3 from 0.252 g [cis-4-(5-fluoro-2-nitro-phenoxy)cyclohexyl]-methyl-amine hydrochloride and methanesulfonyl chloride.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=O.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:29][O:30][C:31](=[O:46])[C:32]1[CH:37]=[CH:36][C:35]([NH:38][CH:39]2[CH2:43][CH2:42][CH2:41][CH:40]2[CH3:44])=[C:34]([NH2:45])[CH:33]=1.Cl>CN(CC1C=C(CN(C)C)C(O)=C(CN(C)C)C=1)C.C(OCC)(=O)C.O.C(Cl)CCl>[CH3:29][O:30][C:31](=[O:46])[C:32]1[CH:37]=[CH:36][C:35]([NH:38][CH:39]2[CH2:43][CH2:42][CH2:41][CH:40]2[CH3:44])=[C:34]([NH:45][C:7](=[O:9])[CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH:33]=1
Reactant: COC(=O)c1ccc(NC2CCCC2C)c(N)c1
Reactant: O=C(O)Cc1cccs1
Agent: CN(C)Cc1cc(CN(C)C)c(O)c(CN(C)C)c1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)c1ccc(NC2CCCC2C)c(NC(=O)Cc2cccs2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.3 %

Procedure:
To a solution of 3.44 g of thiophen-2-yl-acetic acid in 40 ml of dry DMF 3.62 g of HOAT, 6.48 g of EDC and 12 ml of DIPEA were added at 0° C. After 30 min 6.00 g of 3-Amino-4-(2-methyl-cyclopentylamino)-benzoic acid methyl ester were added, and the reaction was stirred at rt for 16 h. The reaction was then poured into water and the pH was adjusted to 3 by the addition of 2 m aqueous hydrochloric acid. Ethyl acetate was added and the layers were separated. The aqueous layer was extracted with ethyl acetate three times. The combined organic phases were washed with saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulphate and concentrated to obtain 9.03 g (100%) of 4-(2-Methyl-cyclopentylamino)-3-(2-thiophen-2-yl-acetylamino)-benzoic acid methyl ester, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:13]2[C:21]3[C:16](=[C:17]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)([CH2:11][CH3:12])[C:9]#[CH:10])=[CH:4][CH:3]=1>O=[Pt]=O.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:13]2[C:21]3[C:16](=[C:17]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:28])[CH3:27])[CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:4][CH:3]=1
Reactant: C#CC(CC)(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Agent: O=[Pt]=O
Solvent: CO
Product: CCC(CC)(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl 1-(3-(4-chlorophenyl)pent-1-yn-3-yl)-1H-indol-4-ylcarbamate (100 mg, 0.245 mmol), as described in Example 44 Step A, PtO2 (5.5 mg, 0.0245 mmol) and methanol (2 mL) was degassed three times and backfilled with dihydrogen. The mixture was stirred at room temperature for 2 h under dihydrogen atmosphere. The solid was filtered off and the filtrate was concentrated in vacuo to give the title compound as colorless oil. LC/MS m/z=357.0[M-tBu+H]+.
Reaction SMILES: Cl.C([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[N:12]=[CH:11][N:10]=[C:9]2[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[CH:26])[CH:20]=1)(=O)C.N>CO>[C:25]([C:21]1[CH:20]=[C:19]([NH:18][C:9]2[C:8]3[C:13](=[CH:14][C:15]([O:16][CH3:17])=[C:6]([OH:5])[CH:7]=3)[N:12]=[CH:11][N:10]=2)[CH:24]=[CH:23][CH:22]=1)#[CH:26]
Reactant: C#Cc1cccc(Nc2ncnc3cc(OC)c(OC(C)=O)cc23)c1
Agent: Cl
Agent: N
Solvent: CO
Product: C#Cc1cccc(Nc2ncnc3cc(OC)c(O)cc23)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 72 %

Procedure:
A mixture of 4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yl acetate hydrochloride (10 g, 0.027 mol), methanol (250 ml) and 25% aqueous ammonia (8 ml, 0.106 mol, 3.93 equiv) was stirred at room temperature for 17 hours and then heated to reflux for 1.5 hours. The mixture was cooled and the precipitate was formed and isolated and dried to give 5.66 g product. MS (ESI) m/z: 307 (M+1).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[F:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH3:34])[C:29]([C:35](O)=[O:36])=[CH:28]2>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:35]([C:29]3[N:30]([CH3:34])[C:31]4[C:27]([CH:28]=3)=[CH:26][C:25]([F:24])=[CH:33][CH:32]=4)=[O:36])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: Cn1c(C(=O)O)cc2cc(F)ccc21
Product: Cn1c(C(=O)NC[C@@H]2C[C@@H]3C[C@@H]3N2C(=O)c2nc(N)sc2-c2cccc(F)c2)cc2cc(F)ccc21

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with 5-fluoro-1-methyl-1H-indole-2-carboxylic acid. LC-MS (basic): tR=0.88 min; [M+H]+=508.1.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[CH2:11][CH2:12][NH:13][CH:14]([C:16]1[N:17]=[CH:18][N:19]([C:22]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20]=1[CH3:21])[CH3:15].C1CCN2C(=NCCC2)CC1.[O:52]1CCC[CH2:53]1>C(OCC)(=O)C>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:53](=[O:52])[N:13]([CH:14]([C:16]3[N:17]=[CH:18][N:19]([C:22]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:20]=3[CH3:21])[CH3:15])[CH2:12][CH2:11][C:3]=12
Reactant: Cc1c(CCNC(C)c2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2C)[nH]c2ccccc12
Reactant: C1CCOC1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1c2n(c3ccccc13)C(=O)N(C(C)c1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2

Procedure:
A mixture of 3-methyl-2-[2-[[1-(5-methyl-1-trityl-1H-imidazol-4-yl)ethyl]amino]ethyl]indole (262 mg), N,N'-carbonxyldiimidazole (210 mg), 1.8-diazabicyclo[5.4.0]-7-undecene (84 mg) and molecular sieves (100 mg) in dry tetrahydrofuran (3 ml) was stirred at reflux for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was chromatographed over silica gel (eluted with 5% methanol in chloroform) to give 3,4-dihydro-5-methyl-2-[1-(5-methyl-1-trityl-1H-imidazol-4-yl)ethyl]-pyrimido[1,6-a]indol-1(2H)-one (208 mg) as glassy solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([CH:8]1[CH2:20][CH2:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([Cl:21])[CH:16]=3)[NH:11][C:10]=2[CH2:9]1)=[O:7])[CH3:4].[CH3:22]I>CN(C)C=O>[CH2:3]([O:5][C:6]([CH:8]1[CH2:20][CH2:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([Cl:21])[CH:16]=3)[N:11]([CH3:22])[C:10]=2[CH2:9]1)=[O:7])[CH3:4]
Reactant: CCOC(=O)C1CCc2c([nH]c3ccc(Cl)cc23)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCc2c(n(C)c3ccc(Cl)cc23)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 1.3 g. of 55 percent sodium hydride in mineral oil, 8 g. of 6-chloro-1,2,3,4-tetrahydrocarbazole-2-carboxylic acid ethyl ester and 50 ml. of dimethylformamide was stirred at room temperature. After 1.5 hours all the sodium hydride had reacted and a solution of 4.5 g. of methyl iodide in 15 ml. of dimethylformamide was added. The mixture was stirred for 6 hours between 60°-65° C. Upon cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure and the residue was partitioned between ether (200 ml.) and water (200 ml.). The ether phase was separated and washed by extraction with water (2 × 100 ml.). After the ether solution had dried over sodium sulfate, the desiccant was removed by filtration and the ether evaporated, yielding 7.2 g. of product. Following crystallization from methanol, 4.6 g. of 6-chloro-9-methyl-1,2,3,4-tetrahydrocarbazole-2-carboxylic acid ethyl ester was obtained, m.p. 126°-127°.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][C:12]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)=[N:13][C:14]([NH2:15])=[C:9]3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:22]Br.[OH-].[NH4+].C(O)(=O)C>O>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([C:16]4[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=4)=[N:13][C:14]([NH2:15])=[C:9]3[C:8]([Br:22])=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1nc(-c2ccncc2)nc2c1cnn2C1CCCC1
Reactant: BrBr
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Nc1nc(-c2ccncc2)nc2c1c(Br)nn2C1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
To a solution of 1-cyclopentyl-6-(4-pyridyl)-pyrazolo(3,4-d)pyrimidin-4-amine (3.0 g, 0.011 mole) in water 60 ml) at room temperature was added bromine (1.8 g, 0.011 mol). The reaction mixture was stirred at room temperature for 1 hour, then was heated on a steam bath for 2 hours. The solvent was removed in vacuo and the residue was suspended in water. Ammonium hydroxide was added followed by acetic acid until a pH of 4-5 was obtained. A solid was collected by filtration and washed with water. Water (60 ml) and bromine (0.3 ml, 0.006 mol) were added to the solid residue and the mixture was heated on a steam bath for 1 hour. The mixture was poured into ice-water and ammonium hydroxide, then acetic acid was added. A solid was collected by filtration, dissolved in ethyl acetate, dried over MgSO4 and concentrated in vacuo to afford 2.2 g (56%) of 1-cyclopentyl-3-bromo-6-(4-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-amine, m.p. 189°-191° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([OH:16])=O)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[F:52][C:53]1[CH:54]=[C:55]2[C:60](=[CH:61][C:62]=1[F:63])[N:59]=[C:58]([NH:64][CH2:65][CH2:66][NH:67][CH3:68])[CH:57]=[N:56]2>CN(C=O)C>[F:52][C:53]1[CH:54]=[C:55]2[C:60](=[CH:61][C:62]=1[F:63])[N:59]=[C:58]([NH:64][CH2:65][CH2:66][N:67]([CH3:68])[C:14]([C:9]1[N:10]=[C:11]([CH3:13])[S:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:16])[CH:57]=[N:56]2
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Reactant: CNCCNc1cnc2cc(F)c(F)cc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)N(C)CCNc2cnc3cc(F)c(F)cc3n2)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40 %

Procedure:
A solution of 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid (50 mg, 0.21 mmol) in DMF (3 ml) was treated sequentially with N,N-diisopropylethylamine (0.20 ml, excess), HATU (79 mg, 0.21 mmol) then after 15 min. N-(6,7-difluoro-quinoxalin-2-yl)-N′-methyl-ethane-1,2-diamine.dihydrochloride, D2 (65 mg, 0.21 mmol). The reaction mixture was stirred at room temperature, under argon for 72 h then partitioned between diethyl ether and water. The organic phase was washed with water (3×), brine, dried (MgSO4) and the solvent removed in vacuo. The residue was triturated with pentane to afford the title compound as a pale yellow powder (38 mg, 40%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7](=[O:17])[C:8]([CH3:16])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9].[Cl:18][CH2:19][CH2:20][CH2:21][C:22](Cl)=[O:23]>>[CH3:5][O:6][C:7](=[O:17])[C:8]([C:10]1[CH:11]=[CH:12][C:13]([C:22](=[O:23])[CH2:21][CH2:20][CH2:19][Cl:18])=[CH:14][CH:15]=1)([CH3:9])[CH3:16]
Reactant: COC(=O)C(C)(C)c1ccccc1
Reactant: O=C(Cl)CCCCl
Agent: [Al+3]
Agent: [Cl-]
Product: COC(=O)C(C)(C)c1ccc(C(=O)CCCCl)cc1
Temperature: -10 °C
Reaction time: 0.75 h
Yield: 110.9 %

Procedure:
MDC (600 ml) and aluminium chloride (347 gms) were charged to a reactor and chilled to −10° C. Methyl-2-methyl-2 phenyl-propanoate (Intermediate 4) (500 gms) was dissolved in MDC (650 ml) and added slowly through a dropper at −10 to 0° C. to obtain mixture A. MDC (600 ml) and aluminium chloride (520 gms) were charged to a different reactor, and chilled to −10° C. 4-chloro butyryl chloride (550 gms) was dissolved in MDC (650 ml) and added slowly through a dropper at −10 to 0° C. to obtain mixture B. Both mixtures A and B were stirred for 45 minutes at −10 to 0° C. separately. Mixture A was added to mixture B slowly at −10 to 0° C. and the reaction monitored by GC for completion (24 hours). The mass was quenched slowly in conc. HCl (1 ltr) at 10-20° C. and stirred for 30 minutes. The MDC layer was separated and the aqueous layer extracted with MDC (500 ml). The combined MDC layer was dried over sodium sulfate and concentrated under vacuum to obtain 880 gms of the title compound as an oil.
Reaction SMILES: CC[N:3](C1C=CC=CC=1)CC.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>C1COCC1>[CH3:22][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH2:3])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCN(CC)c1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc(S(N)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 333.7 %

Procedure:
Diethylaniline (0.33 μL, 2.1 μmol, 1.1 equiv) was added in one portion to a stirred solution of the amine (1.0 mg, 1.9 μmol, 1 equiv) in THF (0.1 mL) at 0° C. under an argon atmosphere and the solution was stirred for 5 min. p-Toluenesulfonyl chloride (0.73 mg, 3.8 μmol, 2.0 equiv) was then added in one portion to the above solution at 0° C. The reaction mixture was stirred at 0° C. for 1 hr and then quenched with a 1:1 mixture of saturated aqueous sodium hydrogen carbonate solution and water (4 mL). The mixture was diluted with ethyl acetate (10 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (10 mL) and the combined organic layer was dried over sodium sulfate. Concentration in vacuo left a yellow oil, which was purified by flash column chromatography (60% ethyl acetate-hexanes) to give the 4-methylphenyl sulfonamide derivative (1.2 mg, 93%) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C@H:12]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([OH:24])=[O:23])[C:15]=2[O:14][B:13]1[OH:25].[OH-:26].[Na+]>CO.O.Cl>[C:4]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=1[C:2]([NH:3][C@H:12]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([OH:24])=[O:23])[C:15]=2[O:14][B:13]1[OH:25])=[O:1])([OH:26])=[O:11]
Reactant: [OH-]
Reactant: O=C(O)c1cccc2c1OB(O)[C@@H](N1C(=O)c3ccccc3C1=O)C2
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccccc1C(=O)N[C@H]1Cc2cccc(C(=O)O)c2OB1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 20 mg of (R)-3-(1,3-dioxoisoindolin-2-yl)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid in a mixture of methanol and H2O (2 mL, 1:1) was added 1 N NaOH (0.5 mL) and the resulting reaction mixture was stirred at room temperature for 3 hr. IN HCl was added to adjust the pH of the solution to 3. The product was then purified by reverse phase HPLC and dried using lyophilization. ESI-MS m/z 356 (MH)+.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[N:21]1([CH2:27][CH2:28][NH2:29])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[CH3:20][O:19][C:5]1[CH:4]=[C:3]([CH2:1][NH:29][CH2:28][CH2:27][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=1
Reactant: COc1cc(C=O)ccc1Oc1ccc(C(N)=O)cn1
Reactant: NCCN1CCOCC1
Product: COc1cc(CNCCN2CCOCC2)ccc1Oc1ccc(C(N)=O)cn1
Yield: 48.8 %

Procedure:
Using a method similar to Example 405, a reaction of 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B) (0.050 g, 0.184 mmol) and 2-morpholin-4-ylethylamine (0.0224 g, 0.184 mmol) gives the title compound (0.0347 g, 49.0%): TOF MS ES+ 387.2 (M+H)+, HRMS calcd for C20H27N4O4 387.2032 (M+H)+, found 387.2023, time 0.41 min; 1H NMR (DMSO-d6) δ 8.51 (d. J=2.0 Hz, 1H), 8.19 (dd, J=8.8, 2.4 Hz, 1H), 7.98 (s, 2H), 7.43 (s, 1H), 7.11 (d, J=1.95 Hz, 1H), 7.06 (d, J=8.3 Hz, 1H), 6.98 (d, J=8.3 Hz, 1H) 6.91 (dd, J=8.1, 1.7 Hz, 1H) 3.72 (s, 2H), 3.66 (s, 3H), 3.55 (t, J=4.6 Hz, 4H), 2.63 (t, J=6.6 Hz, 2H), 2.41 (t, J=6.3 Hz, 2H), 2.34 (s, 4H).
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=4)=[CH:15][C:14]=3[O:25][CH2:26][CH2:27][O:28][CH3:29])[N:10]=[CH:11][C:6]=2[CH:5]=[CH:4][N:3]=1.[CH3:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1>>[CH3:29][O:28][CH2:27][CH2:26][O:25][C:14]1[CH:15]=[C:16]([C:19]2[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=2)[CH:17]=[CH:18][C:13]=1[NH:12][C:9]1[N:10]=[CH:11][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:34]3[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=3)[C:7]=2[N:8]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COCCOc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(Cl)c2n1
Product: COCCOc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(-c3cnn(C)c3)c2n1

Procedure:
The title compound was prepared according to the method described for Example 95 using 8-chloro-N-(2-(2-methoxyethoxy)-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine (Preparation 116) and 1-methylpyrazole-4-boronic acid pinacol ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]([CH3:14])[C:11](=[O:13])[CH3:12])[CH:5]=[N:6][C:7]=1Cl.[CH3:15][C@@H:16]1[CH2:21][NH:20][CH2:19][CH2:18][NH:17]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]([CH3:14])[C:11](=[O:13])[CH3:12])[CH:5]=[N:6][C:7]=1[N:20]1[CH2:19][CH2:18][NH:17][C@H:16]([CH3:15])[CH2:21]1
Reactant: CC(=O)N(C)Cc1cnc(Cl)c(Cl)c1
Reactant: C[C@@H]1CNCCN1
Product: CC(=O)N(C)Cc1cnc(N2CCN[C@H](C)C2)c(Cl)c1

Procedure:
A mixture of N-(5,6-dichloro-pyridin-3-ylmethyl)-N-methyl-acetamide from step (a) above (233 mg, 1.0 mmol) and (R)-(−)-2-methyl-piperazine (110 mg, 1.1 mmol, Aldrich) reacted under the conditions of Example 3a to give the title compound. MS (ESI, pos. ion) m/z: 297 (M+1).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[O:3][CH2:4][CH2:5][CH2:6][C:7]([NH2:9])=[O:8].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl[C:23]([O:25][C:26]([CH3:28])=[CH2:27])=[O:24]>C1COCC1>[F:1][C:2]([F:10])([F:11])[O:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:23](=[O:24])[O:25][C:26]([CH3:28])=[CH2:27])=[O:8]
Reactant: C=C(C)OC(=O)Cl
Reactant: NC(=O)CCCOC(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(C)OC(=O)NC(=O)CCCOC(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A −78° C. mixture of 4-(trifluoromethoxy)butanamide (175 mg, 1.023 mmol) in THF (5 mL) was treated drop wise with LiHMDS (1.0M in THF, 1.33 mL, 1.33 mmol), stirred for 0.5 h, then treated drop wise with a solution of isopropenyl chloroformate (0.129 mL, 1.176 mmol) in THF (1 mL). The mixture was allowed to warm to RT, treated with satd. NaHCO3 and extracted with EtOAc (3×). The combined organics were dried over Na2SO4 and concentrated to afford prop-1-en-2-yl (4-(trifluoromethoxy)butanoyl)carbamate (100% yield assumed).
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][CH:5]=[C:6]([CH3:17])[C:7]=1[C:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15].[C:18](=O)([O:20]CC)[NH2:19]>[Cl-].[Zn+2].[Cl-]>[CH3:1][N:2]1[C:3]2[S:4][CH:5]=[C:6]([CH3:17])[C:7]=2[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])=[N:19][C:18]1=[O:20]
Reactant: CCOC(N)=O
Reactant: CNc1scc(C)c1C(=O)c1ccccc1Cl
Agent: [Cl-]
Agent: [Zn+2]
Product: Cc1csc2c1c(-c1ccccc1Cl)nc(=O)n2C
Temperature: 200 °C

Procedure:
A mixture of 16.0 g of 2-methylamino-3-(o-chlorobenzoyl)-4-methylthiophene, 16.1 g of ethyl carbamate and 1.22 g of zinc chloride is heated at 200°C for 1 hour. After cooling, the reaction mixture is extracted with chloroform. The extracts are combined, washed with water, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue is chromatographed on silica gel using chloroform as an eluent to give 1-methyl-4-(o-chlorophenyl)-5-methyl-1,2-dihydrothieno[2,3-d]pyrimidin-2-one as crystals having a melting point of 267.5° - 268.5°C (after recrystallization from chloroformethanol).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[CH3:18])[NH2:14]>>[NH2:14][C:13]1[CH:12]=[C:11]([CH3:10])[C:17]([CH3:18])=[CH:16][C:15]=1[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[Cl:1])=[O:5]
Reactant: O=Cc1ccccc1Cl
Reactant: Cc1ccc(N)cc1C
Product: Cc1cc(N)c(C(=O)c2ccccc2Cl)cc1C

Procedure:
(2-amino-4,5-dimethylphenyl)-(2-chlorophenyl)-methanone (Xw) was prepared by reacting 2-chlorobenzaldehyde with 0.123 moles of 3,4-dimethyl aniline in a manner analogous to Example 1.