Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(CC)CC.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[CH3:13][C:14]1[C:19]([CH2:20][OH:21])=[C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:17]=[C:16]([CH3:28])[N:15]=1>C(Cl)Cl>[CH3:8][S:9]([O:21][CH2:20][C:19]1[C:14]([CH3:13])=[N:15][C:16]([CH3:28])=[CH:17][C:18]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(-c2ccccc2)c(CO)c(C)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(-c2ccccc2)c(COS(C)(=O)=O)c(C)n1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
NEt3 (0.60 mL, 4.31 mmol) and methanesulphonyl chloride (0.20 mL, 2.59 mmol) were added to a solution of (2,6-dimethyl-4-phenylpyridin-3-yl)methanol (460 mg, 2.16 mmol) in DCM (40 mL) at 0° C. After stirring for 40 min at 0° C. the reaction mixture was diluted with DCM, washed with sat. aqueous NaHCO3 solution, water and dried (MgSO4). Removal of the solvent provided crude (2,6-dimethyl-4-phenylpyridin-3-yl)methyl methanesulfonate which was used without further purification (650 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:42])[C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:12][CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=3)[N:16]([CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:15]=2[CH2:37][CH2:38][N:39]=[N+]=[N-])[CH3:11])=[CH:6][CH:5]=1.C(Cl)Cl>CO.[Pd]>[CH3:1][O:2][C:3](=[O:42])[C:4]1[CH:5]=[CH:6][C:7]([N:10]([CH2:12][CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=3)[N:16]([CH:24]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:15]=2[CH2:37][CH2:38][NH2:39])[CH3:11])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(N(C)CCc2c(CCN=[N+]=[N-])n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc(N(C)CCc2c(CCN)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 78 %

Procedure:
A solution of 4-({2-[2-(2-azido-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethyl}-methyl-amino)-benzoic acid methyl ester (410 mg, 0.709 mmol) and 10% Pd/C (155 mg) in MeOH:CH2Cl2 (=7 mL:1 mL) was stirred under H2 atmosphere (1 atm) for 2 h 15 min. The reaction mixture was filtered through celite and rinsed with MeOH and CH2Cl2. Flash column chromatography (CH2Cl2 to 8% MeOH/CH2Cl2) of the residue gave the desired 4-({2-[2-(2-Amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethyl}-methyl-amino)-benzoic acid methyl ester in 78% yield (305 mg).
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:32]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@H:17]([F:29])[CH2:16][O:15]2)[N:6]=1.[Cl:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[C:42]=1B(O)O>>[NH2:32][C:4]1[S:3][C:2]([C:42]2[C:43]([F:47])=[CH:44][CH:45]=[CH:46][C:41]=2[Cl:40])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:30])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@H:17]([F:29])[CH2:16][O:15]1)=[O:31]
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: OB(O)c1c(F)cccc1Cl
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3Cl)sc2N)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6S)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 95), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-chloro-6-fluorophenyl)boronic acid gave 328. 1H NMR (400 MHz, DMSO-d6) δ 9.26 (s, 1H), 7.69 (s, 1H), 7.58-7.51 (m, 1H), 7.49-7.45 (m, 1H), 7.40-7.33 (m, 1H), 7.00-6.60 (m, 2H), 4.74 (dd, J=11.1, 3.6 Hz, 1H), 4.41-4.23 (m, 1H), 4.16-3.86 (m, 2H), 3.76 (s, 3H), 2.07-1.97 (m, 1H), 1.89-1.77 (m, 1H), 1.69 (d, J=9.1 Hz, 2H). LCMS (ES+) m/z 483 (M+1).
Reaction SMILES: C([O:8][C:9]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]2[C:10]=1[CH:11]=[N:12][N:13]2[CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[F:18][C:15]1[C:14]2[N:13]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:25])([CH3:24])[CH3:26])[N:12]=[CH:11][C:10]=2[C:9]([OH:8])=[CH:17][CH:16]=1
Reactant: [H][H]
Reactant: C[Si](C)(C)CCOCn1ncc2c(OCc3ccccc3)ccc(F)c21
Agent: [Pd]
Solvent: CCO
Product: C[Si](C)(C)CCOCn1ncc2c(O)ccc(F)c21
Reaction time: 8 h

Procedure:
A mixture of EXAMPLE 419C (1.25 g) and 5% palladium on carbon (0.35 g) in ethanol (20 mL) was treated with a balloon of hydrogen. The reaction mixture was stirred overnight. The solid was filtered off. The filtrate was concentrated. The residue was purified by flash chromatography on silica gel to give the title compound.
Reaction SMILES: [I:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:16]([O:18]CC)=[O:17])[CH:8]([C:12]([F:15])([F:14])[F:13])[O:9]2)=[CH:4][CH:3]=1.[OH-].[Na+]>CCO.O>[I:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:16]([OH:18])=[O:17])[CH:8]([C:12]([F:14])([F:13])[F:15])[O:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1=Cc2ccc(I)cc2OC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C1=Cc2ccc(I)cc2OC1C(F)(F)F

Procedure:
To a suspension of ethyl 7-iodo-2-(trifluoromethyl)-2H-chromene-3-carboxylate (1.50 g, 3.9 mmol) in 5 mL EtOH was added NaOH (0.46 g, 11.6 mmol) in 2.5 mL of H2O. After heating for 1.5 h, reaction solvent was removed under vacuum. The resulting sodium salt was used immediately.
Reaction SMILES: C(O)CO.[CH2:5]([O:12][CH2:13][N:14]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH:26]([F:28])[F:27])=[C:21]([O:29][CH:30]3[CH2:32][CH2:31]3)[CH:20]=2)=[C:17]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[F:40])[C:16]([C:41]([O:43]CC)=O)=[C:15]1[CH:46]=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O.[NH2:49][NH2:50]>O>[CH2:5]([O:12][CH2:13][N:14]1[C:15]2[CH:46]=[N:49][NH:50][C:41](=[O:43])[C:16]=2[C:17]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[F:40])=[C:18]1[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH:26]([F:27])[F:28])=[C:21]([O:29][CH:30]2[CH2:32][CH2:31]2)[CH:20]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1c(Cc2ccccc2F)c(-c2ccc(OC(F)F)c(OC3CC3)c2)n(COCc2ccccc2)c1C=O
Reactant: NN
Solvent: OCCO
Solvent: O
Product: O=c1[nH]ncc2c1c(Cc1ccccc1F)c(-c1ccc(OC(F)F)c(OC3CC3)c1)n2COCc1ccccc1
Temperature: 130 °C
Reaction time: 8.5 h
Yield: 90.3 %

Procedure:
To 46 ml of ethylene glycol solution containing 5.01 g (8.44 mmol) of ethyl 1-benzyloxymethyl-5-(3-cyclopropoxy-4-difluoromethoxyphenyl)-4-(2-fluorobenzyl)-2-formyl-1H-pyrrol-3-carboxylate obtained in the following Reference example 36-(f) was added 2.13 ml (42.5 mmol) of hydrazine monohydrate at 60° C., and then the mixture was stirred at 130° C. for 8.5 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer after separation was washed successively with water and then with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=1:1→1:2 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 4.28 g of the title compound as a white solid. (Yield: 90%)
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[N+:15]([O-])([OH:17])=[O:16]>S(=O)(=O)(O)O>[N+:15]([C:5]1[CH:4]=[C:3]([C:2]([F:13])([F:14])[F:1])[CH:8]=[CH:7][C:6]=1[CH2:9][C:10]([OH:12])=[O:11])([O-:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Agent: O=S(=O)(O)O
Product: O=C(O)Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a cooled (0°) solution of 4-trifluoromethylphenylacetic acid (550 g; 1.45 mol) in sulfuric acid (2.0 L) was added, over 1.5 hours, nitric acid (90%; 300 mL) at such a rate as to maintain the temperature between 0° and 5° C. The solution was stirred for 15 minutes, then poured into ice water (17 L). The solid that separated was collected on a filter, washed with water (2 times with 2.5 L, by resuspension), then dissolved in ether (3.0 L). The ethereal solution was washed with water (2 times with 1.0 L), dried, then concentrated in vacuo. The last traces of water were removed by co-distillation with ethanol (500 mL). Yield: 588.2 g (96.4%). The material was suitable for further transformation. Additional product (116.6 g) was obtained from a scouting run.
Reaction SMILES: C[O:2][C:3]1(OC)[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]([C:10](=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4]1=O.Cl.[NH2:21]O>CCO>[O:2]=[C:3]1[C:4]2=[N:21][O:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: CCOC(=O)C(=O)C1CCCCC(OC)(OC)C1=O
Reactant: NO
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1onc2c1CCCCC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
To a solution of ethyl (3,3-dimethoxy-2-oxocycloheptyl)(oxo)acetate (0.850 g, 3.12 mmol) in 15 mL of EtOH, hydroxylamine hydrochloride (0.225 g, 3.24 mmol) was added. The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the crude solid was purified by flash chromatography on silica gel (eluant: AcOEt/hexane:1/9) to afford 0.245 g (35% yield) of:
Reaction SMILES: [C:1]1([O:11][CH2:12][CH:13]([OH:23])[CH2:14][NH:15][CH:16]([CH3:22])[CH2:17][CH2:18][C:19](O)=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:24]([NH:28][C:29](=[O:37])[CH2:30]CCCC(=O)C)[CH2:25][CH2:26][CH3:27].C([BH3-])#N.[Na+]>CO>[CH2:24]([NH:28][C:29](=[O:37])[CH2:30][CH2:19][CH2:18][CH2:17][CH:16]([NH:15][CH2:14][CH:13]([OH:23])[CH2:12][O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH3:22])[CH2:25][CH2:26][CH3:27]
Reactant: CCCCNC(=O)CCCCC(C)=O
Reactant: CC(CCC(=O)O)NCC(O)COc1cccc2ccccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCCNC(=O)CCCCC(C)NCC(O)COc1cccc2ccccc12

Procedure:
The title compound was synthesized by the method given for Compound 7 using the following quantities: Compound V (R=1-naphthyl) (0.177 g, 0.5 mmol), 6-oxoheptanoic acid n-butylamide (0.100 g, 0.5 mmol), sodium cyanoborohydride (0.32 g, 0.5 mmol), methanol (2 ml). Purification of a portion of the product after extraction was achieved by semipreparative high pressure liquid chromatography using a C18 column, 1.3 ml/min flow rate with 64% methanol/0.01N hydrochloric acid as eluant. The appropriate fractions were combined, the solvent evaporated under reduced pressure and the residue lyophilized from methanol/water to give 13.8 mg of the hydrochloride salt of the desired compound. The purity of the product was verified by HPLC (1.2 ml/min, 64% methanol/0.01N hydrochloric acid, ret. time=20 min).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[F:15][C:16]1([F:30])[CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19][NH:18][CH2:17]1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[F:15][C:16]1([F:30])[CH2:22][N:21]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=3)[N:7]=2)[CH2:20][CH2:19][NH:18][CH2:17]1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: CC(C)(C)OC(=O)N1CCNCC(F)(F)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: FC1(F)CNCCN(c2ccc3nnc(C(F)(F)F)n3n2)C1
Temperature: 135 °C
Reaction time: 6 h
Yield: 56.7 %

Procedure:
A mixture of 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (1 g, 4.49 mmol), tert-butyl 6,6-difluoro-1,4-diazepane-1-carboxylate (1.06 g, 4.49 mmol) and DIPEA (1.56 ml, 8.99 mmol) in DMA (15 mL) was stirred at 135° C. for 6 hours. The reaction mixture was concentrated to dryness and DCM (30 mL) was added. The solution was cooled in an ice bath and TFA (15 mL) was added. The resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated to dryness, diluted with water, basified with 6M aqueous sodium hydroxide and extracted with DCM. The organic phase was washed with water and brine, dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with 0 to 4% methanol in DCM to give 6-(6,6-difluoro-1,4-diazepan-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (0.820 g, 56.6%) as a beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](N(OC)C)=[O:10].[Li][CH2:16][CH2:17][CH2:18][CH3:19]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:10])[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: [Li]CCCC
Reactant: CON(C)C(=O)c1ccc(Cl)cc1Cl
Solvent: C1CCOC1
Product: CCCCC(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirring hazy solution of 2,4-dichloro-N-methoxy-N-methylbenzenecarboxamide (1 g, 4.27 mmol), in THF (20 ml) is added BuLi (2.051 ml, 5.13 mmol) in portions. The reaction is stirred for 4 hours at RT and the partitioned between 1M HCl (100 ml) and EtOAc (140 ml). The organic portion is washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude product is purified by ISCO combiflash chromatography eluting with 0 to 100% EtOAc/iso-hexane on a 40 g silica-column to yield 1-(2,4-dichloro-phenyl)-pentan-1-one as a brown oil; 1H NMR (400 MHz, CDCl3) δ 7.45 (1H, d, J 2.0), 7.43 (1H, d, J 7.3), 7.32 (1H, dd, J 7.3, 2.0), 2.94 (2H, t, J 7.4), 1.70 (2H, m), 1.40 (2H, m), 0.95 (3H, t, J 7.3).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:17][CH2:18][O:19][CH2:20][CH2:21]Br.C(N(CC)CC)C>CN(C)C=O>[O:19]1[CH2:20][CH2:21][N:14]([C@H:11]2[CH2:10][CH2:9][C@H:8]([NH:7][C:6](=[O:15])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:13][CH2:12]2)[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Reactant: BrCCOCCBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N2CCOCC2)CC1
Temperature: 25 °C

Procedure:
A solution of tert-butyl-4-aminocyclohexylcarbamate (20.32 g, 95 mmol), bis(2-bromoethyl)ether (14.30 ml, 114 mmol) and triethylamine (33.0 ml, 237 mmol) in N,N-dimethylformamide (200 ml) was stirred for 16 hours at 70° C. The reaction mixture was cooled down to room temperature, concentrated and the product was extracted with ethyl acetate. The organic layer was washed with sodium carbonate solution (15% aq.), dried and concentrated. The product was used in next step without purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:20])[C:15]([CH3:19])([CH3:18])[CH:16]=[CH2:17])=[CH:4][CH:3]=1.[CH2:21]([O:23][C:24]([C:26]1([C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=2)[CH2:28][CH2:27]1)=[O:25])[CH3:22]>>[CH2:21]([O:23][C:24]([C:26]1([C:29]2[CH:34]=[CH:33][C:32]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:20])[C:15]([CH3:19])([CH3:18])[CH:16]=[CH2:17])=[CH:4][CH:3]=3)=[CH:31][CH:30]=2)[CH2:27][CH2:28]1)=[O:25])[CH3:22]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: C=CC(C)(C)C(O)c1c(C)noc1-c1ccc(Br)cc1
Product: C=CC(C)(C)C(O)c1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2,2-dimethyl-but-3-en-1-ol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:12](O)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(Cl)(=O)C([Cl:29])=O>C(Cl)Cl.CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:12]([Cl:29])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCCCOc1ccc(C(=O)O)cc1OCCCCCCC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCOc1ccc(C(=O)Cl)cc1OCCCCCCC
Temperature: 25 °C
Reaction time: 60 h
Yield: 100.1 %

Procedure:
To a room temperature mixture of 5 g of product from Example 110 in 80 ml of methylene chloride and 5 drops of dimethylformamide is added 2.72 g of oxalyl chloride. The reaction is stirred at room temperature for 2.5 days and concentrated in vacuo. The residue is dissolved in diethyl ether, passed through a pad of diatomaceous earth and concentrated in vacuo to give 5.27 g of the desired product as colorless crystals.
Reaction SMILES: [O:1]1CCCO[CH:2]1[C:7]1[CH:8]=[C:9]([C:13]2[NH:21][C:16]3=[N:17][CH:18]=[CH:19][N:20]=[C:15]3[CH:14]=2)[CH:10]=[CH:11][CH:12]=1.FC(F)(F)C(O)=O>ClCCl>[N:20]1[CH:19]=[CH:18][N:17]=[C:16]2[NH:21][C:13]([C:9]3[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=3)[CH:2]=[O:1])=[CH:14][C:15]=12
Reactant: c1cc(-c2cc3nccnc3[nH]2)cc(C2OCCCO2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=Cc1cccc(-c2cc3nccnc3[nH]2)c1
Yield: 47.3 %

Procedure:
A solution of 6-(3-[1,3]dioxan-2-yl-phenyl)-5H-pyrrolo[2,3-b]pyrazine [1.6 g, Example 1(g)] in dichloromethane (50 mL) was treated with trifluoroacetic acid (5 mL). The resultant mixture was heated at reflux for 6 hours, then allowed to cool overnight and then evaporated. The residue was triturated with diethyl ether to give a yellow solid, which was recrystallised from ethyl acetate to give the title compound (0.6 g) as a yellow crystalline solid, m.p. 268-270° C. [Elemental analysis:— C, 69.96; H, 3.92; N, 18.69%. Calculated for C13H9N3O:— C, 69.95; H, 4.06; N, 18.82%].
Reaction SMILES: [CH2:1]([C:4]1[C:13]([OH:14])=[C:12]([O:15][CH3:16])[CH:11]=[C:10]2[C:5]=1[C:6]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[CH:19]=1)=[N:7][CH:8]=[N:9]2)[CH:2]=[CH2:3].[C:26]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH2:1]([C:4]1[C:13]([O:14][CH3:26])=[C:12]([O:15][CH3:16])[CH:11]=[C:10]2[C:5]=1[C:6]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[CH:19]=1)=[N:7][CH:8]=[N:9]2)[CH:2]=[CH2:3]
Reactant: O=C([O-])[O-]
Reactant: C=CCc1c(O)c(OC)cc2ncnc(Nc3ccc(F)c(Cl)c3)c12
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: C=CCc1c(OC)c(OC)cc2ncnc(Nc3ccc(F)c(Cl)c3)c12
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To a solution of 5-allyl-4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-ol (0.59 g, 1.63 mmol) (from Example 18, Step D, supra) in acetone (175 mL) was added K2CO3 (0.68 g, 4.91 mmol) and methyl iodide (2.32 g, 16.4 mmol) (Aldrich). The reaction mixture was heated with stirring at 90° C. for 3 hours. The mixture was cooled to room temperature, filtered and the filtrate was concentrated. The residue was purified by chromatography using EtOAc/CH2Cl2/Et3N (1:3:0.01) as eluent to give the desired (5-allyl-6,7-dimethoxy-quinazolin-4-yl)-(3-chloro-4-fluoro-phenyl)-amine as an off white solid. (Yield 0.29 g, 48%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]3[O:27][CH2:28][CH2:29][O:30][C:23]=3[CH:22]=2)[C:11]2[CH:16]=[C:15]([CH2:17][CH3:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]4[O:27][CH2:28][CH2:29][O:30][C:23]=4[CH:22]=3)[C:11]3[CH:16]=[C:15]([CH2:17][CH3:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: CCc1cc2c(NCc3ccc4c(c3)OCCO4)nc(Cl)nc2s1
Reactant: Cc1ncc[nH]1
Product: CCc1cc2c(NCc3ccc4c(c3)OCCO4)nc(-n3ccnc3C)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-ethyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-ethyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])[CH:4]=[N:3][CH:2]=1.[CH3:12]O.Cl>O1CCOCC1>[N:1]1[CH:6]=[C:5]([CH:7]=[CH:8][C:9]([O:11][CH3:12])=[O:10])[CH:4]=[N:3][CH:2]=1
Reactant: CO
Reactant: O=C(O)C=Cc1cncnc1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)C=Cc1cncnc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
3-(5-Pyrimidyl)acrylic acid (100 g) was added to a mixture of dry methanol (2 L) and 4M hydrogen chloride in dioxan (445 ml) and allowed to stir at 60° C. under argon for 18 h. The mixture was cooled, and the solvent removed under reduced pressure. The residue was partitioned between dichloromethane (500 ml) and was washed with saturated sodium bicarbonate (300 ml). The aqueous layer was extracted with dichloromrethane and the combined dichloromethane layers were dried over magnesium sulfate and evaporated in vacuo to give methyl 3-(5-pyrimidinyl)acrylate (85 g). 1H-NMR (d6-DMSO) δ 3.82(3H, s), 7.03(1H, d), 7.75(1H, d) and 9.28(3H, s).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:16][C:15]3[CH:17]=[C:18]([C:21]4[CH:22]=[C:23]([NH2:28])[C:24]([NH2:27])=[N:25][CH:26]=4)[CH:19]=[CH:20][C:14]=3[O:13][CH2:12][CH2:11]2)=[O:9])[CH2:4][CH2:3]1.[CH3:29][O:30][C:31]([NH:33][C:34](=NC(OC)=O)SC)=[O:32]>C(O)(=O)C.C(OCC)C>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:16][C:15]3[CH:17]=[C:18]([C:21]4[CH:22]=[C:23]5[NH:28][C:34]([NH:33][C:31](=[O:32])[O:30][CH3:29])=[N:27][C:24]5=[N:25][CH:26]=4)[CH:19]=[CH:20][C:14]=3[O:13][CH2:12][CH2:11]2)=[O:9])[CH2:4][CH2:3]1
Reactant: CC1CCN(C(=O)N2CCOc3ccc(-c4cnc(N)c(N)c4)cc3C2)CC1
Reactant: COC(=O)N=C(NC(=O)OC)SC
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2ncc(-c3ccc4c(c3)CN(C(=O)N3CCC(C)CC3)CCO4)cc2[nH]1
Temperature: 80 °C
Yield: 11.7 %

Procedure:
To a solution of 5-{4-[(4-methylpiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}pyridine-2,3-diamine (0.21 g, 0.55 mmol) in acetic acid (5 mL) was added 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (0.17 g, 0.82 mmol) and the resulting mixture was heated at 80° C. After 12 h the reaction mixture was diluted with ethyl ether (5 mL) and the resulting precipitate was collected by filtration. The resulting brown filter cake was dissolved in methanol and purified by preparative reverse phase HPLC to afford methyl (6-{4-[(4-methylpiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}-1H-imidazo[4,5-b]pyridin-2-yl)carbamate (0.030 g, 12% yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6): 12.02 (bs, 1H), 8.44 (s, 1H), 7.85 (s, 1H), 7.38-7.55 (m, 2H), 6.96-7.06 (m, 1H), 4.36-4.44 (m, 2H), 4.06-4.22 (m, 2H), 3.76 (s, 3H), 3.44-3.60 (m, 4H), 2.68 (t, 2H) 1.43-1.61 (m, 3H), 1.20 (q, 2H), 0.90 (d, 3H); MS (EI) for C24H28N6O4: 465 (MH+).
Reaction SMILES: C([O:5][C:6](=[O:43])[CH2:7][CH2:8][C@H:9]([NH:13][C:14]([C:16]1[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]2[CH2:29][CH2:28][CH2:27][C@H:26]2[C:30](=[O:36])[NH:31][CH:32]2[CH2:35][CH2:34][CH2:33]2)=[O:24])[N:18]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:17]=1)=[O:15])[C:10](O)=[O:11])(C)(C)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:77]([O:79][C:80]([N:82]1[CH2:87][CH2:86][NH:85][CH2:84][C@H:83]1[CH3:88])=[O:81])[CH3:78]>CN(C=O)C>[CH2:77]([O:79][C:80]([N:82]1[CH2:87][CH2:86][N:85]([C:10](=[O:11])[C@@H:9]([NH:13][C:14]([C:16]2[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]3[CH2:29][CH2:28][CH2:27][C@H:26]3[C:30](=[O:36])[NH:31][CH:32]3[CH2:33][CH2:34][CH2:35]3)=[O:24])[N:18]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:17]=2)=[O:15])[CH2:8][CH2:7][C:6]([OH:43])=[O:5])[CH2:84][C@H:83]1[CH3:88])=[O:81])[CH3:78]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)O
Reactant: CCOC(=O)N1CCNC[C@H]1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)C[C@H]1C
Reaction time: 36 h

Procedure:
To a solution of 100 mg (S)-2-({5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-pentanedioic acid 5-tert-butyl ester in 5 ml DMF were added 28 μl DIPEA, 64 mg HATU and 29 mg (R)-2-Methyl-piperazine-1-carboxylic acid ethyl ester. After stirring for 36 h the solution was concentrated, the residue dissolved in 1.5 ml dichloromethane and treated with 186 μl TFA. After stirring for 4 h the solvents were removed under reduced pressure and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product.