Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.II.[O:15]1CC[CH2:17][CH2:16]1>BrCCBr>[CH3:17][CH:16]([C:2]1[CH:12]=[CH:11][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1)[OH:15]
Reactant: C1CCOC1
Reactant: Brc1ccc2c(c1)OCCCC2
Agent: II
Solvent: BrCCBr
Product: CC(O)c1ccc2c(c1)OCCCC2
Temperature: -10 °C
Reaction time: 2 h

Procedure:
7.3 g of 8-bromo-2,3,4,5-tetrahydro-1-benzoxepine in 30 ml of absolute tetrahydrofuran were added under argon to 930 mg of Mg shavings and a granule of iodine. The reaction was initiated by the addition of a few drops of 1,2-dibromoethane and had finished after 2 hours. Thereafter, the reaction mixture was cooled to -10° C. and excess acetaldehyde was distilled into the reaction vessel. After 10 minutes, the mixture was hydrolyzed with saturated sodium bicarbonate (NaHCO3 ) solution, extracted with ether, washed with water, dried and evaporated to dryness. Chromatography on silica gel (petroleum ether/ethyl acetate 3:1) yielded 4.93 g of 2,3,4,5-tetrahydro-α-methyl-1-benzoxepine-8-methanol as a colorless oil.
Reaction SMILES: [CH3:1][C:2]([NH:14][C@@H:15]1[CH2:19][C@H:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)[N:17]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[C:16]1=[O:37])([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[N:5]=1)[CH3:3].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:45][CH2:46][CH2:47][F:48]>CN(C=O)C.CCOC(C)=O>[CH3:3][C:2]([NH:14][C@@H:15]1[CH2:19][C@H:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:45][CH2:46][CH2:47][F:48])[CH:21]=2)[N:17]([C:27]2[CH:28]=[CH:29][C:30]([C:33]([F:35])([F:34])[F:36])=[CH:31][CH:32]=2)[C:16]1=[O:37])([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[N:5]=1)[CH3:1]
Reactant: CC(C)(N[C@@H]1C[C@H](c2cccc(O)c2)N(c2ccc(C(F)(F)F)cc2)C1=O)c1cccc(C(F)(F)F)n1
Reactant: FCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(N[C@@H]1C[C@H](c2cccc(OCCCF)c2)N(c2ccc(C(F)(F)F)cc2)C1=O)c1cccc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 19.5 h
Yield: 77.4 %

Procedure:
Dissolve (3R,5R)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-2-yl)-ethylamino]-5-(3-hydroxy-phenyl)-1-(4-trifluoromethyl-phenyl)-pyrrolidin-2-one (520 mg, 0.99 mmol) in DMF (9 mL) and add cesium carbonate (1.9 g, 5.9 mmol) and 1-bromo-3-fluoro-propane (170 mg, 1.19 mmol). Stir the mixture at ambient temperature for 19.5 hours and dilute with EtOAc. Wash with brine, dry over sodium sulfate, filter, and concentrate the organic to residue. Purify the residue by silica gel chromatography (30% EtOAc-hexane) to obtain (3R,5R)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-2-yl)-ethylamino]-5-[3-(3-fluoro-propoxy)-phenyl]-1-(4-trifluoromethyl-phenyl)-pyrrolidin-2-one (447 mg, 77%) as a colorless oil. 1H NMR (400 MHz, DMSO-d6): δ 8.08 (d, J=7.9 Hz, 1H), 8.01 (dd, J=7.7, 7.7 Hz, 1H), 7.70 (d, J=7.5 Hz, 1H), 7.58 (d, J=8.8 Hz, 2H), 7.51 (d, J=8.8 Hz, 2H), 7.13 (dd, J=7.9, 7.9 Hz, 1H), 6.82-6.70 (m, 3H), 5.18 (dd, J=9.7, 6.6 Hz, 1H), 4.58 (t, J=5.9 Hz, 1H), 4.46 (t, J=5.9 Hz, 1H), 4.02-3.88 (m, 2H), 3.47-3.39 (m, 1H), 2.96 (d, J=3.5 Hz, 1H), 2.73-2.63 (m, 1H), 2.06-1.92 (m, 2H), 1.63 (dd, J=22.0, 10.5 Hz, 1H), 1.47 (s, 3H), 1.42 (s, 3H). LC-MS ESI m/z: 584.0 (M+H)+, Tr=3.61 min., method 1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH:6]=[C:5]2[CH2:11][C@@H:12]1[CH2:15][CH2:16][CH2:17][N:13]1[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Brc1ccc2[nH]cc(CCN3CCCC3)c2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: CN1CCC[C@H]1Cc1cn([Si](C)(C)C(C)(C)C)c2ccc(Br)cc12

Procedure:
5-Bromo-1-(t-butyldimethylsilyl)-3-(2-pyrrolidin lethyl)indole: (1.02 g, 73%) as a brown oil from 5-bromo-3-(2-pyrrolidinylethyl)-1H-indole (Example 3b, 1.00 g, 3.4 mmol), sodium hexamethyldisilazide (82 mL, 6.82 mmol) and t-butyidimethylsilyl chloride (6.82 mL. 6.82 mmol). 13C NMR (CDCl3): 140.1, 132.9, 129.4, 124.1, 121.5, 116.3, 115.2, 112.7, 6.9, 54.3, 26.3, 25.1, 23.5, 19.5, −3.98.
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([N+]([O-])=O)[CH:3]=1.[CH3:14][O-:15].[Na+].O>CO>[I:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([O:15][CH3:14])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(I)cc([N+](=O)[O-])c1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(I)cc([N+](=O)[O-])c1
Temperature: 65 °C
Reaction time: 52 h
Yield: 99 %

Procedure:
1-Iodo-3,5-dinitrobenzene (1.8 g, 6.1 mmol) are dissolved in methanol (12 ml) and treated with a solution of sodium methoxide in methanol (5.4M, 1.2 ml). The mixture is then stirred at 65° C. for 52 h. After cooling to ambient temperature, water (50 ml) is added and the mixture extracted three times with ethyl acetate (50 ml). The combined organic layers are extracted with brine (100 ml), dried and evaporated to dryness. Flash chromatography (silica, eluent ethyl acetate/cyclohexane 1:1) affords the product (1.7 g, 99%) as light yellow solid. MS: m/e=279 (M+).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.Cl.Cl.[CH2:13]([O:15][C:16]1[CH:17]=[C:18]([CH:35]=[CH:36][CH:37]=1)[CH2:19][N:20]1[C:24]2=[N:25][CH:26]=[N:27][C:28]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[C:23]2[CH:22]=[N:21]1)[CH3:14].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(N(CC)CC)C.C(Cl)Cl>[CH2:13]([O:15][C:16]1[CH:17]=[C:18]([CH:35]=[CH:36][CH:37]=1)[CH2:19][N:20]1[C:24]2=[N:25][CH:26]=[N:27][C:28]([N:29]3[CH2:30][CH2:31][N:32]([C:6](=[O:8])[C:5]4[CH:4]=[CH:3][C:2]([OH:1])=[CH:10][CH:9]=4)[CH2:33][CH2:34]3)=[C:23]2[CH:22]=[N:21]1)[CH3:14]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CCOc1cccc(Cn2ncc3c(N4CCNCC4)ncnc32)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1cccc(Cn2ncc3c(N4CCN(C(=O)c5ccc(O)cc5)CC4)ncnc32)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 80.2 %

Procedure:
To 4-hydroxybenzoic acid (1.06 g) is added successively methylene chloride (30 mL), 1-(3-ethoxybenzyl)-4-piperazin-1-yl-1H-pyrazolo[3,4-d]pyrimidine dihydrochloride (3.02 g), 1-hydroxybenzotriazole (1.25 g), triethylamine (3.7 mL) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.78 g). The mixture is stirred at room temperature for 17 hours. The reaction mixture is diluted with chloroform and thereto is added a saturated sodium hydrogencarbonate solution. After stirring, the organic layer is separated and evaporated to remove solvent. The resultant residue is purified by flash column chromatography on silica gel (Solvent; chloroform:methanol=50:1) to give 1-(3-ethoxybenzyl)-4-[4-(4-hydroxybenzoyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine (2.70 g, yield; 80%) as an amorphous powder. MS (APCI) m/z: 459 [M+H]+
Reaction SMILES: [C:1]1([CH:7]([C:13]2[NH:17][N:16]=[N:15][N:14]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>C(#N)C>[CH2:37]([N:15]1[N:16]=[N:17][C:13]([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:14]1)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH3:26]
Reactant: CCOC(=O)C(c1ccccc1)c1nnn[nH]1
Reactant: CCCCCCCCCCCCBr
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCn1nnc(C(C(=O)OCC)c2ccccc2)n1
Temperature: 25 °C

Procedure:
The tetrazole ester (a) (47 g; 0.20 moles) was dissolved in acetonitrile (550 mL) containing one equivalent of triethylamine (20.2 g; 0.20 moles). The solution was heated to reflux and then 1-bromododecane (49.8 g; 0.20 moles) was added dropwise over 20 minutes. Upon completion, the solution was heated to reflux for 16 hours, cooled to room temperature, and concentrated in vacuo. The residue was triturated with ethyl acetate (1L), filtered, and the filtrate was washed with aqueous HCl (1N), brine, and dried over magnesium sulfate. The drying agent was removed by filtration and the solvent concentrated in vacuo, leaving a viscous liquid containing both 1- and 2-isomers. The regioisomers were separated by silica gel chromatography using 75% hexane and 25% ethyl acetate as the eluent, obtaining the title compound as a colorless liquid. Yield: 33 g (41%).
Reaction SMILES: [F:1][C:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[C:5]([O:15]C)=[CH:4][CH:3]=1.Cl.N1C=CC=CC=1.[OH-].[NH4+]>>[F:1][C:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[C:5]([OH:15])=[CH:4][CH:3]=1
Reactant: COc1ccc(F)c2[nH]c3ccccc3c12
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccncc1
Product: Oc1ccc(F)c2[nH]c3ccccc3c12
Reaction time: 0.33 h
Yield: 114.5 %

Procedure:
A mixture of 1-fluoro-4-methoxycarbazole (438 mg, 2.04 mmol) and pyridine hydrochloride (3 g) was placed into an oil bath that was preheated to 220° C. After 20 minutes, the reaction was poured onto a mixture of ice and concentrated ammonium hydroxide. The product was extracted into ethyl acetate and the extract was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was azeotroped with toluene to give 470 mg of the title compound. Yield: >100%. MS(FD).
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[N:25]([C:28]1[CH:37]=[CH:36][C:31]2[O:32][CH2:33][CH2:34][O:35][C:30]=2[CH:29]=1)=[C:26]=[O:27]>O1CCCC1>[O:32]1[C:31]2[CH:36]=[CH:37][C:28]([NH:25][C:26]([N:15]3[CH2:16][CH2:17][N:12]([C:10]4[S:9][N:8]=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[N:11]=4)[CH2:13][CH2:14]3)=[O:27])=[CH:29][C:30]=2[O:35][CH2:34][CH2:33]1
Reactant: O=C=Nc1ccc2c(c1)OCCO2
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2c(c1)OCCO2)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.8 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 6-isocyanato-1,4-benzodioxan (167 ml, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. The residue was purified by high performance liquid chromatography (YMC HPLC Column eluted with 10% to 100% Liquid A; Liquid A: a 0.1% solution of trifluoroacetic acid in acetonitrile; Liquid B: an aqueous 0.1% trifluoroacetic acid solution) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 161 mg (46.9%) of the desired product as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][NH:14][C:15]3[C:20]([CH3:21])=[C:19]([CH3:22])[N:18]=[C:17]([N:23]([CH2:33][C:34]4[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=4)[CH2:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[C:16]=3[NH2:42])[O:10][N:9]=2)=[CH:4][CH:3]=1.[C:43](OCC)(OCC)(OCC)[CH2:44][CH3:45].Cl>C1(C)C=CC=CC=1>[CH2:44]([C:45]1[N:14]([CH2:13][C:11]2[O:10][N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH:12]=2)[C:15]2[C:20]([CH3:21])=[C:19]([CH3:22])[N:18]=[C:17]([N:23]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[CH2:33][C:34]3[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=3)[C:16]=2[N:42]=1)[CH3:43]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)c(C)c(NCc3cc(-c4ccc(F)cc4)no3)c2N)cc1
Reactant: CCOC(CC)(OCC)OCC
Agent: Cl
Solvent: Cc1ccccc1
Product: CCc1nc2c(N(Cc3ccc(OC)cc3)Cc3ccc(OC)cc3)nc(C)c(C)c2n1Cc1cc(-c2ccc(F)cc2)no1
Yield: 39.2 %

Procedure:
N4-{[3-(4-Fluorophenyl)isoxazol-5-yl]methyl}-N2,N2-bis(4-methoxybenzyl)-5,6-dimethylpyridine-2,3,4-triamine (6.00 g, 10.6 mmol), triethyl orthopropionate (3.2 mL, 16 mmol), concentrated hydrochloride acid (0.2 mL), and toluene (30 mL) were combined and treated according to the method described in Part E of Example 18 with the modification that no additional triethyl orthopropionate was added. 2-Ethyl-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-N,N-bis(4-methoxybenzyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine (2.52 g) was obtained as a yellow solid.
Reaction SMILES: [C:1]([CH2:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>S(=O)(=O)(O)O.O>[C:2]1([C:1]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:10](=[O:11])[CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CC(=O)c1ccccc1)Nc1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=c1cc(-c2ccccc2)c2ccccc2[nH]1

Procedure:
Benzoylacetanilide (150 g) (prepared according to the method of Brown et al., J. Am. Chem. Sot., 79, 2919, (1957)) in concentrated sulphuric acid (76%) (130 cc) is heated for 4 hours at 100° C. The reaction mixture is slowly poured with stirring in distilled water (3150 cc). The precipitate obtained is filtered, washed with water and then with acetone, and dried at 40° C. under reduced pressure. The residue obtained is recrystallised in ethanol. (white solid; m.p.=268°-269° C.)
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:3]=1[O:4][CH2:5][C:6]#[N:7].[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([Cl:21])=[CH:16][N:15]=1>>[Cl:13][C:14]1[N:19]=[C:18]([NH:1][C:2]2[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:3]=2[O:4][CH2:5][C:6]#[N:7])[C:17]([Cl:21])=[CH:16][N:15]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: Cc1cccc(OCC#N)c1N
Product: Cc1cccc(OCC#N)c1Nc1nc(Cl)ncc1Cl

Procedure:
[2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-methyl-phenoxy]-acetonitrile was prepared from (2-Amino-3-methyl-phenoxy)-acetonitrile and 2,4,5-Trichloropyrimidine in an analogous manner to Example 1230a. Title product obtained as an off-white solid, 365 mg, 29%. MP: 134-136, LCMS 309.07 (M+H), HPLC purity 75%, 1H-NMR (CDCl3, 400 MHz) δ 8.20 (s, 1H), 7.31-7.27 (m, 1H), 7.07 (d, J=7.7 Hz, 1H), 6.95 (d, J=8.2 Hz, 1H), 6.82 (s, 1H), 4.79 (s, 2H), 2.27 (s, 3H).
Reaction SMILES: ClN1C(=O)CCC1=O.[CH3:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[SH:16].[CH2:17]([O:19][C:20]([C:22]1[NH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([O:31][CH3:32])=[C:26]([O:33][CH3:34])[CH:25]=2)=[O:21])[CH3:18]>ClCCl>[CH2:17]([O:19][C:20]([C:22]1[NH:23][C:24]2[C:29]([C:30]=1[S:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH3:9])=[CH:28][C:27]([O:31][CH3:32])=[C:26]([O:33][CH3:34])[CH:25]=2)=[O:21])[CH3:18]
Reactant: CCOC(=O)c1cc2cc(OC)c(OC)cc2[nH]1
Reactant: Cc1ccccc1S
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c2cc(OC)c(OC)cc2c1Sc1ccccc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65.4 %

Procedure:
To a −78° C. solution of dichloromethane (30mL) and N-chlorosuccinimide was added 2-methyl benzenethiol (0.709 mL, 6.01 mmol) dropwise. The reaction was allowed to warm 0° C. and then stirred for 30 minutes. 5,6-dimethoxy-1H-indole-2-carboxylic acid ethyl ester (Lancaster Synthesis Inc., Windham, N.H.) (1.5 g, 6.01 mmol) was added drop wise in dichloromethane (15 mL). The reaction was allowed to warm to room temperature and stirred overnight. The reaction was concentrated under reduced pressure. Methanol (5 mL) was added to the residue and a solid formed. The solid was collected, washed with diethyl ether (20 mL) and air dried to yield a beige solid (1.46 g, 66%). MS: M+−1=370.2 Da.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.[S:27]([N:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39]([CH:46]=O)=[CH:38]1)([C:30]1[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=1)(=[O:29])=[O:28].N1CCCCC1>CO>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])/[C:8](=[CH:46]/[C:39]3[C:40]4[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=4)[N:37]([S:27]([C:30]4[CH:31]=[CH:32][C:33]([CH3:34])=[CH:35][CH:36]=4)(=[O:29])=[O:28])[CH:38]=3)/[O:9][C:5]=2[C:4]=1[CH2:13][N:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C=O)c3ccccc32)cc1
Reactant: COc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Solvent: CO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1cn(S(=O)(=O)c3ccc(C)cc3)c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 55.8 %

Procedure:
A solution of tert-butyl 4-[(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.488 g, 1.35 mmol) obtained in Example A40, Step 1 in methanol (5 mL) was added with 1-tosyl-1H-indole-3-carboxaldehyde (0.404 g, 1.35 mmol) obtained in Example A33, Step 1 and piperidine (0.0115 g, 0.135 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was cooled to room temperature, and then added with methanol (2 mL), and the precipitated solid was suspended in methanol and thereby washed. The reaction mixture was filtered to obtain tert-butyl (Z)-4-({6-methoxy-3-oxo-2-[(1-tosyl-1H-indol-3-yl)methylene]-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.485 g, 55%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31](=[O:35])[CH2:32][C:33]#[N:34])[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[CH3:36][C:37]([N:41]1[CH2:44][C:43]2([CH2:47][O:46][CH2:45]2)[CH2:42]1)([CH3:40])[CH:38]=O.N1CCCC1.Cl[Si](C)(C)C>C(Cl)Cl.C([O-])(O)=O.[Na+]>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31]([C:32](=[CH:38][C:37]([CH3:40])([N:41]4[CH2:42][C:43]5([CH2:47][O:46][CH2:45]5)[CH2:44]4)[CH3:36])[C:33]#[N:34])=[O:35])[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: CC(C)(C=O)N1CC2(COC2)C1
Reactant: N#CCC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCNC1
Solvent: ClCCl
Product: CC(C)(C=C(C#N)C(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1)N1CC2(COC2)C1
Reaction time: 2 h
Yield: 46.4 %

Procedure:
To a mixture of (R)-3-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-3-oxopropanenitrile (222 mg, 0.46 mmol), 2-methyl-2-(6-oxa-2-azaspiro[3.3]heptan-2-yl)propanal (231.17 mg, 1.37 mmol) and pyrrolidine (0.23 mL, 2.73 mmol) in DCM (10 mL) at room temperature was added chloro(trimethyl)silane (0.17 mL, 1.37 mmol). After stirring 2 h, the solution was diluted with sat. NaHCO3 and extracted with DCM. The organic layers were combined, dried (MgSO4), filtered and concentrated. The crude material was purified by chromatography to obtain 133 mg of 2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-(6-oxa-2-azaspiro[3.3]heptan-2-yl)pent-2-enenitrile. MS (pos. ion) m/z: 623 (M+1).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[C:18](=[O:19])[N:9]2[CH:10]=[CH:11][C:12]3[C:17]([C:8]2=[N:7][CH:6]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3.[CH2:20]([N:22]([CH2:25][CH2:26][Cl:27])[CH2:23][CH3:24])[CH3:21].[ClH:28]>CN(C)C=O.C(OCC)C>[ClH:27].[ClH:28].[CH2:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH2:24][O:3][CH2:4][C:5]1[C:18](=[O:19])[N:9]2[CH:10]=[CH:11][C:12]3[C:17]([C:8]2=[N:7][CH:6]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH3:21]
Reactant: CCN(CC)CCCl
Reactant: O=c1c(CO)cnc2c3ccccc3ccn12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCN(CC)CCOCc1cnc2c3ccccc3ccn2c1=O
Reaction time: 1 h
Yield: 28 %

Procedure:
To 0.7 g of sodium hydride (14.5 mmol) stirred in 40 ml of dry dimethylformamide under nitrogen was added dropwise over a 15 minute period a solution of 2.0 g of 3-(hydroxymethyl)-4H-pyrimido[2,1-a]isoquinolin-4-one (8.3 mmol) in 40 ml of warm dimethylformamide. After stirring for 1 hour, 1.58 g of diethylaminoethyl chloride (11.6 mmol) was added dropwise over a 15 minute period. The reaction mixture was stirred for 3 hours, then poured onto ice-water and extracted 3 times with 500 ml of methylene chloride. The extracts were dried and concentrated in vacuo to yield a semi-solid, to which 15 ml of isopropanolic hydrochloric acid solution and diethyl ether were added. The crystalline solid which formed was collected and washed with ether to yield 3-[[2-(diethylamino)ethoxy]methyl]-4H-pyrimido[2,1-a]isoquinolin-4-one dihydrochloride (0.973 g; 28% yield) of the formula: ##STR24## having a melting point of 128.7° C. and the following elemental analysis:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:17][CH:16]3[CH2:18][O:19][CH2:20][CH:15]3[N:14]=2)=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>CO.O>[CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:17][CH:16]3[CH2:18][O:19][CH2:20][CH:15]3[N:14]=2)=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(C2=NC3COCC3N2)c(C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C)c(C2=NC3COCC3N2)cc1C(=O)O
Temperature: 70 °C
Reaction time: 8 h
Yield: 93.1 %

Procedure:
Into around-bottom flask, was placed a solution of methyl 2,4-dimethyl-5-(3a,4,6,6a-tetrahydro-1H-furo[3,4-d]imidazol-2-yl)benzoate (compound 466.5, 100 mg, 0.330 mmol, 1.00 equiv, 90%) and sodium hydroxide (73 mg, 1.82 mmol, 5.00 equiv) in methanol/H2O (3/3 mL). The resulting solution was stirred overnight at 70° C., then concentrated in vacuum. The residue was diluted with H2O (5 mL) and the pH of the solution was adjusted to 2-3 with hydrogen chloride (12 N), then extracted with ethyl acetate (3×10 mL). The combined organics was concentrated in vacuo to obtain the title compound as a yellow solid (80.0 mg, 84%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][NH:13][C:14]([C:16]2[O:17][C:18]3[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=3[C:20]=2[CH3:21])=[O:15])=[CH:6][CH:5]=1.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:39]N1C(=O)CCC1=O>ClC1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][CH2:12][NH:13][C:14]([C:16]2[O:17][C:18]3[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=3[C:20]=2[CH2:21][Br:39])=[O:15])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(OCCNC(=O)c2oc3ccccc3c2C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Clc1ccccc1
Product: COC(=O)c1ccc(OCCNC(=O)c2oc3ccccc3c2CBr)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A solution of 4-{2-[(3-methylbenzofuran-2-carbonyl)amino]ethoxy}benzoic acid methyl ester (0.340 mol) in chlorobenzene (1000 ml) was treated with 2,2′-azobisisobutyronitrile (5.60 g, 0.017 mol) and N-bromosuccinimide (75.76 g, 0.426 mol). The resulting mixture is heated to 80° C. and stirred for one hour. After completion of reaction, the reaction mixture was cooled to ambient temperature and washed with water, 3% sodium hydrogensulfite, and again with water. Solvent was distilled under reduced pressure and after cooling to ambient temperature, dichloromethane was added and to give 4-{2-[(3-bromomethylbenzofuran-2-carbonyl)amino]ethoxy}benzoic acid methyl ester which was used in the next step.