Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][N:10]3[C:16](=[O:18])[CH:17]=2)=[N:3][CH:2]=1.[CH3:19][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI>O1CCCC1>[CH3:19][CH:15]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]2[C:16](=[O:18])[CH:17]=[C:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][N:3]=3)[N:8]=[C:9]12
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: O=c1cc(-c2ccncn2)nc2n1CCCCC2
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1CCCCn2c1nc(-c1ccncn1)cc2=O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 52 %

Procedure:
To a solution of 26.1 g (107.73 mmol) of 2-pyrimidin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-a]azepin-4-one in dry tetrahydrofuran (450 mL) under argon at −78° C. was added 82.5 mL (82.5 mmol) of lithium bis(trimethylsilyl)amide (1M in tetrahydrofuran). The solution was stirred at −78° C. for 10 min and 25.7 mL of methyl iodide (412.7 mmol) was added. The reaction was stirred at −78° C. for 1 h and then at 0° C. for 2 h. The mixture was quenched with the addition of a saturated solution of ammonium chloride and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated. The residue was chromatographed on silica gel eluting with a mixture of dichloromethane/methanol in the proportions 99/1 to afford 11.0 g (40%) of the desired compound as a white solid.
Reaction SMILES: [N+:1]([NH:4][C:5]1[C:9]([N+:10]([O-:12])=[O:11])=[N:8][O:7][N:6]=1)([O-:3])=[O:2].[NH2:13][C:14]([NH2:16])=[NH:15]>CO>[NH:4]([C:5]1[C:9]([N+:10]([O-:12])=[O:11])=[N:8][O:7][N:6]=1)[N+:1]([O-:3])=[O:2].[NH2:15][C:14]([NH2:16])=[NH2+:13]
Reactant: N=C(N)N
Agent: O=[N+]([O-])Nc1nonc1[N+](=O)[O-]
Solvent: CO
Product: NC(N)=[NH2+]
Reaction time: 0.17 h

Procedure:
A clean dry 3 neck round bottom flask was equipped with magnetic stirring bar, thermocouple, and nitrogen inlet is placed in an ice bath. 3-Nitroamino-4-nitrofurazan (1.75 grams; 0.1 mol) was added with 5 mls dry methanol. Guanidine (0.59 grams; 0.01 mol) was preweighed into a vial and dissolved in 5 ml dry methanol. The guanidine-containing mixture was added over 5 minutes while the temperature did not exceed 10° C. The resulting mixture was stirred cold for 10 min, and then stirred for an additional hour at ambient. After transfer to a tarred one neck flask, the solvent was removed in vacuo at 35° C. After a period of high vacuum, the yield of crystals was 100% of theoretical. DSC: exothermic peak at 90.96° C. FTIR: 3517, 3413, 3270, 3212 (m), 1660 (d), 1576 (s), 1386, 1344, 1311 (t).
Reaction SMILES: CO[CH:3](OC)[CH2:4][C:5]1[CH:38]=[CH:37][C:8]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:27])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)=[CH:7][CH:6]=1.[I-].[Na+].Cl[Si](Cl)(Cl)C.C(O)(=O)C.[NH2:52][CH2:53][C@@H:54]([C:56]1[CH:57]=[CH:58][C:59]([OH:67])=[C:60]([NH:62][S:63]([CH3:66])(=[O:65])=[O:64])[CH:61]=1)[OH:55].C([BH3-])#N.[Na+]>C(#N)C.CO.ClCCl>[OH:67][C:59]1[CH:58]=[CH:57][C:56]([C@@H:54]([OH:55])[CH2:53][NH:52][CH2:3][CH2:4][C:5]2[CH:6]=[CH:7][C:8]([NH:9][CH:10]3[CH2:15][CH2:14][N:13]([S:16]([C:19]4[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:27])=[CH:23][CH:24]=4)(=[O:18])=[O:17])[CH2:12][CH2:11]3)=[CH:37][CH:38]=2)=[CH:61][C:60]=1[NH:62][S:63]([CH3:66])(=[O:65])=[O:64]
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: CCCCCCCCNC(=O)Nc1ccc(S(=O)(=O)N2CCC(Nc3ccc(CC(OC)OC)cc3)CC2)cc1
Agent: C[Si](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [I-]
Solvent: CO
Solvent: CC(=O)O
Solvent: CC#N
Product: CCCCCCCCNC(=O)Nc1ccc(S(=O)(=O)N2CCC(Nc3ccc(CCNC[C@H](O)c4ccc(O)c(NS(C)(=O)=O)c4)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 13.9 %

Procedure:
N-[4-({4-[4-(2,2-Dimethoxyethyl)anilino]-1-piperidinyl}sulfonyl)phenyl]-N′-octylurea (0.53 g, 0.92 mmol) was added to a pre-prepared mixture of sodium iodide (0.346 g, 2.31 mmol) and trichloro(methyl)silane (0.217 mL, 1.85 mmol) in anhydrous acetonitrile (27 mL). The reaction was stirred at ambient temperature for 10 minutes. Dichloromethane was added and the reaction washed with 10% sodium thiosulfate solution, water and brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and the solvent partially removed in vacuo. The aldehyde solution was used directly and treated with methanol, acetic acid (0.066 mL, 1.1 mmol), N-{5-[(1R)-2-amino-1-hydroxyethyl]-2-hydroxyphenyl}methanesulfonamide (0.227 g, 0.92 mmol) followed by sodium cyanoborohydride (0.063 g, 0.92 mmol). The reaction was stirred at ambient temperature overnight. The reaction was taken to dryness in vacuo, adsorbed onto silica and purified by flash chromatography on silica gel Merck-60 (eluant: 5:1 chloroform-methanol containing 1% ammonium hydroxide) to yield the title compound (0.097 g, 0.128 mmol).
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C@@H:51]([CH:56]([CH3:58])[CH3:57])[C:52]([O:54][CH3:55])=[O:53])[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.[CH3:59][C:60]1[CH:68]=[C:67]([CH3:69])[CH:66]=[C:65]([CH3:70])[C:61]=1[C:62](Cl)=[O:63]>>[CH3:57][CH:56]([CH3:58])[C@H:51]([N:46]1[CH2:45][C:44]2[C:48](=[CH:49][C:41]([C:38]3[CH:37]=[CH:36][C:35]([NH:34][C:62](=[O:63])[C:61]4[C:65]([CH3:70])=[CH:66][C:67]([CH3:69])=[CH:68][C:60]=4[CH3:59])=[CH:40][CH:39]=3)=[CH:42][CH:43]=2)[C:47]1=[O:50])[C:52]([O:54][CH3:55])=[O:53]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: Cc1cc(C)c(C(=O)Cl)c(C)c1
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4c(C)cc(C)cc4C)cc3)cc2C1=O
Yield: 77 %

Procedure:
The compound of example 153 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 2,4,6-trimethyl benzoyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].C([Sn](CCCC)(CCCC)[C:36]1[CH:41]=[N:40][CH:39]=[CH:38][N:37]=1)CCC.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13]([C:36]3[CH:41]=[N:40][CH:39]=[CH:38][N:37]=3)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1nc(-c2cnccn2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 120 °C
Yield: 66.2 %

Procedure:
A mixture of 1-benzyl-8-bromo-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (60 mg, 0.13 mmol), 2-tributylstannanyl-pyrazine (0.061 mL, 0.19 mmol) and PdCl2(PPh3)2 (18 mg, 0.026 mmol) in 3 mL of DMF was heated at 120° C. for 2 h under nitrogen atmosphere. After the mixture was cooled to r.t., EtOAc and brine were added. 1 M HCl was added with stirring until pH was about 4. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was washed with water and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was chromatographed (5-80% EtOAc/hexanes+1% AcOH) to give 40 mg of the title compound. MS: (+) m/z 465.35 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]3[C:11]([SH:14])=[N:12][N:13]=[C:6]3[C:5]=2[CH:4]=[N:3]1.[K].[CH3:16]I>CN(C)C=O>[CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]3[C:11]([S:14][CH3:16])=[N:12][N:13]=[C:6]3[C:5]=2[CH:4]=[N:3]1
Reactant: CI
Reactant: Cn1ncc2c1ncn1c(S)nnc21
Agent: [K]
Solvent: CN(C)C=O
Product: CSc1nnc2c3cnn(C)c3ncn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 3 g. of 7-methyl-3mercapto-7H-pyrazolo[4,3-e][1,2,4]-triazolo[4,3-c]pyrimidine, potassium salt, in 25 ml. of dimethylformamide, 2.1 g. of methyl iodide are added and the mixture is stirred for 1 hour at room temperature. The reaction mixture is then poured into 200 ml. of water and the product, 7-methyl-3-methylthio-7H-pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]-pyrimidine, is filtered under suction, crystallized from dimethylformamide and obtained as yellowish crystals, m.p. 204°-206°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]#[C:12][C:13]([CH3:19])([CH3:18])[C:14]([O:16][CH3:17])=[O:15].N1C=CC=CC=1.[C:26](Cl)(=[O:30])[CH2:27][CH2:28][CH3:29]>C(Cl)Cl>[C:26]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]#[C:12][C:13]([CH3:19])([CH3:18])[C:14]([O:16][CH3:17])=[O:15])(=[O:30])[CH2:27][CH2:28][CH3:29]
Reactant: CCCC(=O)Cl
Reactant: COC(=O)C(C)(C)C#Cc1cc([N+](=O)[O-])ccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC(=O)Nc1ccc([N+](=O)[O-])cc1C#CC(C)(C)C(=O)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.1 %

Procedure:
To a solution of methyl 4-(2-amino-5-nitrophenyl)-2,2-dimethylbut-3-ynoate (260 mg, 1.0 mmol) and pyridine (160 mg, 2.0 mol) in CH2Cl2 (20 mL) was added butyryl chloride (140 mg, 1.3 mmol) at 0° C. The reaction mixture was warmed to room temperature and stirred for 3 h before the mixture was poured into ice-water. The organic layer was separated and the aqueous phase was extracted with CH2Cl2 (30 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain methyl 4-(2-butyramido-5-nitrophenyl)-2,2-dimethylbut-3-ynoate (150 mg, 45%), which was used directly in the next step. 1H NMR (400 MHz, CDCl3) δ 8.79 (brs, 1 H), 8.71 (d, J=9.2 Hz, 1 H), 8.24 (d, J =2.8 Hz, 1 H), 8.17 (dd, J=2.8, 9.2 Hz, 1 H), 3.82 (s, 3 H), 2.55 (t, J=7.2 Hz, 2 H), 1.85-1.75 (m, 2 H), 1.63 (s, 6 H), 1.06 (t, J=6.8 Hz, 3 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=1)[NH:8][CH2:7][CH2:6]2.C(N(CC)CC)C.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:35]([N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:9]1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:16][CH:15]=1)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: COc1ccc2c(c1)CCNC2Cc1ccc(OCc2ccccc2)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2c(c1)CCN(C(=O)c1ccccc1)C2Cc1ccc(OCc2ccccc2)cc1
Reaction time: 8 h
Yield: 90.1 %

Procedure:
To a solution of 6-methoxy-1-[4-(phenylmethoxy)benzyl]-1,2,3,4-tetrahydroisoquinoline (0.72 g, 2.0 mmol), 4-dimethylaminopyridine (0.2 g), and triethylamine (1.5 mL) in CH2Cl2 (8 mL) at room temperature under nitrogen was added neat benzoyl chloride (0.42 g, 3.0 mmol) dropwise. The reaction was stirred overnight, quenched with a solution of saturated sodium bicarbonate, and extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by chromatography (SiO2, 30-50% ethyl acetate/hexane) to provide the title compound (0.835 g, 90% yield): ES-MS (m/z) 464 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][C:3]=1[CH3:11].[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C.ClCCl>[CH2:12]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][C:3]=1[CH3:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClCc1ccccc1
Reactant: Cc1cc(CCO)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: ClCCl
Product: Cc1cc(CCO)ccc1OCc1ccccc1
Yield: 90.7 %

Procedure:
2-(4-Hydroxy-3-methylphenyl)ethanol (18 g), benzyl chloride (15.4 g) and anhydrous potassium carbonate (90 g) were stirred under reflux in methyl ethyl ketone (500 ml) for 20 hours. The reaction mixture was cooled and evaporated under reduced pressure to give an oily residue. This residue was dissolved in dichloromethane, washed with 2N sodium hydroxide (2×), washed with brine (2×), dried (MgSO4), and evaporated under reduced pressure to give an oil. This was triturated under petroleum ether (40°-60°) (200 ml) with cooling to afford 2-(4-benzyloxy-3-methylphenyl)ethanol as a white solid (26.0 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:32]=[CH:31][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13](/[CH:17]=[C:18]4/[C:19](=[O:30])[N:20]([CH:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[C:21](=[O:23])[S:22]/4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[C:5]([C:33]([F:36])([F:35])[F:34])[CH:4]=1.[CH2:37](I)[CH3:38]>>[CH2:37]([N:27]1[CH2:28][CH2:29][CH:24]([N:20]2[C:19](=[O:30])/[C:18](=[CH:17]/[C:13]3[CH:12]=[C:11]4[C:16](=[CH:15][CH:14]=3)[N:8]([CH2:7][C:6]3[CH:31]=[CH:32][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[C:33]([F:35])([F:36])[F:34])[N:9]=[CH:10]4)/[S:22][C:21]2=[O:23])[CH2:25][CH2:26]1)[CH3:38]
Reactant: CCI
Reactant: COc1ccc(Cn2ncc3cc(/C=C4\SC(=O)N(C5CCNCC5)C4=O)ccc32)c(C(F)(F)F)c1
Product: CCN1CCC(N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(OC)cc4C(F)(F)F)c3)C2=O)CC1

Procedure:
(5Z)-3-(1-Ethylpiperidin-4-yl)-5-({1-[4-methoxy-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-methoxy-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-piperidin-4-yl-1,3-thiazolidine-2,4-dione (Example 26) and ethyl iodide following General Procedure S.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[OH:8].[N+:12]([O-])([O-:14])=[O:13].[K+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([N+:12]([O-:14])=[O:13])[C:7]=1[OH:8]
Reactant: CC(=O)c1ccc(O)c(Cl)c1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(=O)c1cc(Cl)c(O)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.88 h

Procedure:
A 500-milliliter flask was charged with 300 milliliters of concentrated sulfuric acid, chilled to 5° to 10° C. and at this temperature 17.1 grams of 3'-chloro-4'-hydroxyacetophenone was slowly added. To the stirred clear solution 20 grams of potassium nitrate was slowly added during a period of about 30-40 minutes while the temperature was maintained between 5° and 10° C. After stirring for an additional 45-60 minutes, the solution was stirred into 1,000 grams of ice. The resulting pale yellow solid was filtered and washed with water.
Reaction SMILES: C(#N)C.[NH:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.C(N(CC)CC)C.[Br:16][C:17]1[CH:31]=[CH:30][C:20]([CH2:21][CH:22]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:23](Cl)=[O:24])=[CH:19][CH:18]=1>O>[Br:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][CH:22]([C:26]([CH3:27])([CH3:29])[CH3:28])[C:23]([N:4]2[CH:8]=[CH:7][N:6]=[CH:5]2)=[O:24])=[CH:30][CH:31]=1
Reactant: c1c[nH]cn1
Reactant: CC(C)(C)C(Cc1ccc(Br)cc1)C(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)C(Cc1ccc(Br)cc1)C(=O)n1ccnc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 72.2 %

Procedure:
To 30 ml of acetonitrile were added 0.75 g of imidazole and 1.2 g of triethylamine, and 3.0 g of α-(p-bromobenzyl)-tert-butyl-acetic acid chloride was then added dropwise at room temperature. Thereafter, the mixture was stirred at room temperature for 6 hours, poured into 300 ml of water and extracted with 300 ml of chloroform. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The oily product obtained was recrystallized from diisopropyl ether to obtain 2.39 g of N-[α-(p-bromobenzyl)-tert-butylacetyl]imidazole (compound No. 4). m.p. 101°-102° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]1=[O:14].Cl.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:31])[CH2:24][CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:31])[CH2:24][CH:25]2[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[NH:7][C:6]3=[O:14])[CH2:27][CH2:26]2)=[CH:19][CH:18]=1
Reactant: O=C(CC1CCNCC1)c1ccc(F)cc1
Reactant: O=c1[nH]c2ccccc2n1CCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(CC1CCN(CCCn2c(=O)[nH]c3ccccc32)CC1)c1ccc(F)cc1
Reaction time: 4 h
Yield: 35 %

Procedure:
A mixture of 2.3 parts of 1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one, 2.57 parts of 1-(4-fluorophenyl)-2-(4-piperidinyl)ethanone hydrochloride, 2.65 parts of sodium carbonate and 22.5 parts of N,N-dimethylformamide is stirred for 4 hours at 70°-80° C. The reaction mixture is poured onto water and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and recrystallized from 2-propanol, yielding 1.4 parts (35%) of 1-[3-[4-[2-(4-fluorophenyl)-2-oxoethyl]-1-piperidinyl]propyl]-1,3-dihydro-2H-benzimidazol-2-one; mp. 208° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:19])[C:9]2[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[C:11]([F:17])[C:10]=2[F:18])=[CH:6][N:5]=[C:4]([NH:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([NH:27][S:28]([CH2:31][CH2:32][CH2:33]Cl)(=[O:30])=[O:29])[CH2:23][CH2:22]2)[N:3]=1.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>O1CCCC1>[NH2:1][C:2]1[C:7]([C:8](=[O:19])[C:9]2[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[C:11]([F:17])[C:10]=2[F:18])=[CH:6][N:5]=[C:4]([NH:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([NH:27][S:28]([CH2:31][CH2:32][CH2:33][N:39]3[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]3)(=[O:30])=[O:29])[CH2:23][CH2:22]2)[N:3]=1
Reactant: CN1CCNCC1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(N[C@H]2CC[C@H](NS(=O)(=O)CCCCl)CC2)nc1N
Solvent: C1CCOC1
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(N[C@H]2CC[C@H](NS(=O)(=O)CCCN3CCN(C)CC3)CC2)nc1N

Procedure:
To a stirred solution of 3-chloro-propane-1-sulfonic acid [4-[4-amino-5-(2,3-difluoro-6-methoxy-benzoyl)-pyrimidin-2-ylamino]-cyclohexyl]-amide (104 mg, 0.20 mmol, Example 293) in tetrahydrofuran (5 mL), N-methylpiperizine (100 mg, 1 mmol, Aldrich,) was added and the mixture was heated at reflux for 24 hours. The reaction was quenched with water and the mixture was extracted with ethyl acetate (3×5 mL). The extracts were combined and dried with sodium sulfate and concentrated. The residue was chromatographed (8% 9N ammonia in methanol/dichloromethane) to give a pale yellow solid. 85 mg, 73%. MS (ES) MH+=582.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH3:11])[CH:5]=[CH:4][C:3]=1[C@H:12]1[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][CH:20]2OCCC[O:21]2)[CH2:14][CH2:13]1.C(O)=O>C1(C)C=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH3:11])[CH:5]=[CH:4][C:3]=1[C@H:12]1[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][CH:20]=[O:21])[CH2:14][CH2:13]1
Reactant: CCOc1ccc([C@H]2CC[C@H](CCC3OCCCO3)CC2)c(F)c1F
Solvent: Cc1ccccc1
Solvent: O=CO
Product: CCOc1ccc([C@H]2CC[C@H](CCC=O)CC2)c(F)c1F

Procedure:
The 2-(2-(trans-4-(2,3-difluoro-4-ethoxyphenyl)-cyclohexyl)-ethyl)-1,3-dioxane (19.8 mmol) obtained by the reaction of Step 4 was dissolved in 100 ml of toluene, 87% formic acid (198 mmol) was added, and the solution was heated to reflux for 4 hours. The reaction solution was twice washed with 50 ml of a saturated aqueous solution of sodium hydrogen carbonate, then three times with 50 ml of water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, to form crude 3-(trans-4-(2,3-difluoro-4-ethoxyphenyl)-cyclohexyl)-propanal (19.8 mmol).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:45])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[C:35]([CH2:36][O:37]C3CCCCO3)=[N:34][CH:33]=[N:32]2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:20][C:11]1[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])=[CH:13][C:8]2[N:7]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N:31]4[C:35]([CH2:36][OH:37])=[N:34][CH:33]=[N:32]4)[CH:26]=3)[CH2:23][C:22](=[O:45])[NH:21][C:9]=2[CH:10]=1
Reactant: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ncnc3COC3CCCCO3)c2)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3ncnc3CO)c1)=N2

Procedure:
The title compound was prepared from (RS)-[4-chloro-5-(isobutyl-methyl-amino)-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,4]triazol-1-yl]-phenyl}-propionylamino)-phenyl]-carbamic acid tert-butyl ester (Example M115) (0.61 g, 0.93 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (290 mg, 69%).
Reaction SMILES: C[O:2][C:3]1[C:4](=[O:33])[C:5](=O)[C:6]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[NH:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:9]=1.[NH3:34]>C(O)C>[NH2:34][C:5]1[C:4](=[O:33])[C:3](=[O:2])[C:6]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)[NH:15][CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:9]=1
Reactant: COc1ccc(C(NCCc2ccccc2)c2cccc(Nc3c(OC)c(=O)c3=O)c2)cc1
Reactant: N
Solvent: CCO
Product: COc1ccc(C(NCCc2ccccc2)c2cccc(Nc3c(N)c(=O)c3=O)c2)cc1

Procedure:
In a similar manner to that described in Example (1d), 3-methoxy-4-{3-[(4-methoxyphenyl)-(2-phenylethylamino)methyl]phenylamino}-3-cyclobutene-1,2-dione (1.88 g) [prepared as described in step (c) above] and a solution of ammonia in ethanol (2N, 8.4 ml) were reacted, to give the title compound (1.66 g) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:18])=[CH:5][C:6]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][O:15][CH3:16])[CH2:9][CH2:8][C:7]=2[CH:17]=1.Cl[C:20]1[N:25]=[C:24]([NH:26][C@@H:27]2[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]2[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:23]([Cl:38])=[CH:22][N:21]=1.Cl.C(O)(C)C.CC[NH+](CC)CC.CC[NH+](CC)CC.C([O-])([O-])=O>O1CCOCC1>[Cl:38][C:23]1[C:24]([NH:26][C@@H:27]2[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]2[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])=[N:25][C:20]([NH:18][C:4]2[C:3]([O:2][CH3:1])=[CH:17][C:7]3[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][O:15][CH3:16])[CH2:11][CH2:12][C:6]=3[CH:5]=2)=[N:21][CH:22]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1CCc2cc(N)c(OC)cc2CC1
Agent: CC[NH+](CC)CC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Solvent: C1COCCO1
Product: COCCN1CCc2cc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)c(OC)cc2CC1
Temperature: 130 °C
Reaction time: 0.33 h

Procedure:
8-Methoxy-3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (165 mg, 0.000659 mol), N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (220 mg, 0.00066 mol), 4 M of Hydrogen chloride in 1,4-Dioxane (200 uL) and Isopropyl alcohol (6.6 mL, 0.086 mol;) were combined in a microwave vessel. Heat at 130° C. for 20 min. The mixture was treated with 500 mgs of MP-carbonate resin and stirred for 20 min. The mixture was filtered and concentrated and put on high vac overnight. The crude solid was dissolved in DCM and purified on an ISCO column (40 g, SiO2, 100% DCM to MeOH/DCM gradient) to afford N-((1R,2R)-2-{5-Chloro-2-[8-methoxy-3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-methanesulfonam (99 mg, 48%). MP: 92-94° C. 1H-NMR (CDCl3, 400 MHz): 1H-NMR (CDCL3) δ 7.96 (s, 1H), 7.32 (s, 1H), 6.67 (s, 1H), 5.37-5.31 (m, 2H), 3.99-3.95 (broad m, 1H), 3.88 (s, 1H), 3.56 (br s, 2H), 3.38 (s, 1H), 3.28-3.24 (m, 1H), 2.99-2.70 (complex series of m, 11H), 2.26-2.20 (m, 2H), 1.88-1.80 (m, 2H), 1.41-1.28 (m, 6H), 0.92-0.85 (m, 2H); LC/MS: 552.92 (M+H).