Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[N:11]=[C:12]([NH2:19])[N:13]=[C:14](SC)[C:15]=3[N:16]=2)=[CH:4][CH:3]=1.Cl.[CH3:21][O:22][CH2:23][CH2:24][OH:25]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[N:11]=[C:12]([NH2:19])[N:13]=[C:14]([O:25][CH2:24][CH2:23][O:22][CH3:21])[C:15]=3[N:16]=2)=[CH:4][CH:3]=1
Reactant: COCCO
Reactant: CSc1nc(N)nc2sc(-c3ccc(F)cc3)nc12
Agent: Cl
Product: COCCOc1nc(N)nc2sc(-c3ccc(F)cc3)nc12
Temperature: 80 °C
Yield: 80 %

Procedure:
To a solution of Na (2.0 mg, 0.07 mmol) in 2-methoxyethanol (1 ml) was added 2-(4-fluorophenyl)-7-methylthio-thiazolo[5,4-d]pyrimidin-5-amine (40 mg, 0.14 mmol). The reaction mixture was heated at 80° C. for 20 hours. After cooling, the mixture was neutralized with 1N HCl and the solvent was removed under reduced pressure. The crude residue was extracted by ethyl acetate, brine and dried over Na2SO4. After removing the solvents under reduced pressure, the residue was purified by flash chromatography on silica (CH2Cl2/MeOH 100:1) to yield the title compound as a white solid (35 mg, 80%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]1[CH2:7][O:8][N:9]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>CO.ClCCl>[O:1]1[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]1[CH2:7][O:8][NH2:9]
Reactant: O=C1c2ccccc2C(=O)N1OC[C@H]1COCCO1
Agent: NN
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: NOC[C@H]1COCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.4 %

Procedure:
2L (4.30 g, 12.4 mmol) was dissolved in 90 mL of methanol/dichloromethane 1/9 ratio. Hydrazine hydrate (1.67 mL, 22.4 mmol) was added and the reaction was stirred at room temperature for 2 h at which time the deprotection was done. The precipitate byproduct was filtered, and the filtrate was concentrated down to an oil and then purified by flash column chromatography, using chloroform/methanol 99/1 ratio to yield (R)—O-((1,4-dioxan-2-yl)methyl)hydroxylamine (2M, 0.915 g, 61.4% yield over 2 steps). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.41 (t, J=10.86 Hz, 1H) 3.57-3.71 (m, 4H) 3.71-3.82 (m, 3H) 3.83-3.92 (m, 1H) 5.55 (br. s., 2H).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:11]2[N:12]=[C:13]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[C:17](S(C)=O)[N:16]=3)=[C:10]2[CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[NH2:31][CH2:32][CH2:33][CH2:34][OH:35]>O1CCCC1>[CH2:1]([NH:5][C:6]1[N:11]2[N:12]=[C:13]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:31][CH2:32][CH2:33][CH2:34][OH:35])[N:16]=3)=[C:10]2[CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: NCCCO
Reactant: CCCCNc1cccc2c(-c3ccnc(S(C)=O)n3)c(-c3ccc(F)cc3)nn12
Solvent: C1CCOC1
Product: CCCCNc1cccc2c(-c3ccnc(NCCCO)n3)c(-c3ccc(F)cc3)nn12
Temperature: 25 °C
Yield: 88.8 %

Procedure:
A solution of N-butyl-2-(4-fluorophenyl)-3-[2-(methylsulfinyl)-4-pyrimidinyl]pyrazolo[1,5-α]pyridin-7-amine (50 mg, 0.12 mmol) and 3-amino-1-propanol (0.45 mL, 5.9 mmol) in 2 mL tetrahydrofuran was heated to reflux for 4 hours, then the mixture was cooled to room temperature and concentrated. Flash column chromatography eluting with a gradient of 0% to 100% ethyl acetate in hexanes afforded 3-({4-[7-(butylamino)-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-pyrimidinyl}amino)-1-propanol (46.3 mg, 90%) as a yellow foam. 1H NMR (CDCl3): δ 7.97 (d, 1H), 7.67–7.61 (m, 3H), 7.35 (t, 1H), 7.16 (t, 2H), 6.34 (d, 1H), 6.04 (m, 2H), 3.67–3.60 (m, 4H), 3.39 (q, 2H), 1.79–1.45 (m, 6H), 1.00 (t, 3H); 19F NMR (CDCl3): δ −113.10; MS m/z 435 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@:15]3([N:20]=[C:19]([NH:21][CH:22]=[O:23])[CH2:18][O:17][CH2:16]3)[C:14]3[CH:13]=[C:12]([O:24][CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[N:11]=[CH:10][C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[F:30][C:31]1[C:36](B(O)O)=[CH:35][CH:34]=[CH:33][N:32]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[F:30][C:31]1[C:36]([C:2]2[CH:3]=[C:4]3[C@:15]4([N:20]=[C:19]([NH:21][CH:22]=[O:23])[CH2:18][O:17][CH2:16]4)[C:14]4[CH:13]=[C:12]([O:24][CH2:25][C:26]([CH3:28])([CH3:29])[CH3:27])[N:11]=[CH:10][C:9]=4[O:8][C:5]3=[CH:6][CH:7]=2)=[CH:35][CH:34]=[CH:33][N:32]=1
Reactant: CC(C)(C)COc1cc2c(cn1)Oc1ccc(Br)cc1[C@@]21COCC(NC=O)=N1
Reactant: OB(O)c1cccnc1F
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Product: CC(C)(C)COc1cc2c(cn1)Oc1ccc(-c3cccnc3F)cc1[C@@]21COCC(NC=O)=N1
Temperature: 100 °C
Yield: 41.2 %

Procedure:
A microwave vial was charged with (S)—N-(7-bromo-3-(neopentyloxy)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazine]-5′-yl)formamide (0.075 g, 0.163 mmol), 2-fluoropyridin-3-ylboronic acid (0.046 g, 0.326 mmol), potassium phosphate (0.104 g, 0.489 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (5.77 mg, 8.15 μmol). The vial was flushed with Ar (g), then dioxane (0.611 mL) and water (0.204 mL) were added in sequence. The vial was sealed and heated in a Biotage Initiator microwave reactor for 30 min at 100° C. The reaction was diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine, dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (0-10% MeOH:DCM w/1% NH4OH) to afford 32 mg of (S)—N-(7-(2-fluoropyridin-3-yl)-3-(neopentyloxy)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazine]-5′-yl)formamide as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)[CH2:10][CH2:9]1)=[O:7].C([Li])CCC.[N+:35]([C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=1)([O-:37])=[O:36].O>O1CCCC1>[N+:35]([C:38]1[CH:39]=[CH:40][C:41]([C:42]([N:20]2[C:21]3[C:16](=[CH:15][C:14]([N:11]4[CH2:10][CH2:9][N:8]([C:6](=[O:7])[C:5]5[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:3]([O:2][CH3:1])[CH:4]=5)[CH2:13][CH2:12]4)=[CH:23][CH:22]=3)[CH2:17][CH2:18][C:19]2=[O:24])=[O:43])=[CH:45][CH:46]=1)([O-:37])=[O:36]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(C(=O)N2CCN(c3ccc4c(c3)CCC(=O)N4)CC2)cc1OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=O)N2CCN(c3ccc4c(c3)CCC(=O)N4C(=O)c3ccc([N+](=O)[O-])cc3)CC2)cc1OC
Yield: 18.9 %

Procedure:
To a suspension of 6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril (10 g) in anhydrous tetrahydrofuran (250 ml) was added slowly n-butyllithium (20 ml, 1.5N hexane solution) with stirring and under ice-cooling. After completion of addition, the mixture was stirred at room temperature for 2 hours. Then, to the mixture was added slowly a solution of p-nitrobenzoyl chloride (6.1 g) in anhydrous tetrahydrofuran (25 ml) with stirring and under ice-cooling. After completion of addition, the mixture was stirred at the same temperature for 30 minutes. After completion of reaction, the reaction mixture was poured into water and extracted with chloroform. The chloroform layer was washed successively with water and saturated saline solution and dried over magnesium sulfate. The choloroform extract was evaporated under reduced pressure and the resultant residue was purified by silica-gel column chromatography (eluent:dichloromethane:methanol=100:1) to give 1-(4-nitrobenzoyl)-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]3,4-dihydrocarbostyril (2.6 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]3[N:16]=[C:17]([CH2:20][O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18](I)=[C:12]3[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=[NH:93])(C1C=CC=CC=1)C1C=CC=CC=1.Cl>C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+].O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:93][C:18]1[C:17]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:16][N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[O:9])[CH2:11][C:12]=12
Reactant: O=C(c1ccc(F)cc1)N1CCn2nc(COc3ccccc3)c(I)c2C1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1c(COc2ccccc2)nn2c1CN(C(=O)c1ccc(F)cc1)CC2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 49.1 %

Procedure:
Tris(dibenzylideneacetone)dipalladium(0) (9.6 mg, 0.01 mmol) was added to a stirred suspension of (4-fluoro-phenyl)-(3-iodo-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-methanone (50 mg, 0.1 mmol), sodium tert-butoxide (30 mg, 0.31 mmol) and rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (19.6 mg, 0.031 mmol) in toluene (2 mL) in a sealed tube and under N2. The mixture was stirred at room temperature for 5 minutes and then benzophenone imine (0.035 mL, 0.21 mmol) was added. The mixture was stirred at 100° C. for 2.5 hours. Then a 1M aqueous solution of HCl (3 mL) was added and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with a saturated solution of Na2CO3 and water and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; MeOH in DCM 0/100 to 6/94). The desired fractions were collected and the solvents evaporated in vacuo. The desired product was triturated with diethyl ether to yield (3-amino-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-(4-fluoro-phenyl)-methanone (18 mg, 47% yield) as a white solid. C20H19FN4O2 1H NMR (500 MHz, CDCl3) δ ppm 1.53 (s, 1H), 2.86 (br. s., 1H), 3.99 (br. s., 2H), 4.18 (br. s., 2H), 4.70 (br. s., 2H), 5.08 (s, 2H), 6.97 (t, J=7.4 Hz, 1H), 7.02 (d, J=8.1 Hz, 2H), 7.15 (t, J=8.7 Hz, 2H), 7.30 (dd, J=8.4, 7.5 Hz, 2H), 7.49 (dd, J=8.5, 5.3 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[O:5][C:6]1[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][C:7]=1[C:8]#[N:9].Cl[C:21]1[CH:22]=[C:23]2[N:30]([CH:31]3[CH2:33][CH2:32]3)[CH2:29][CH2:28][N:24]2[C:25](=[O:27])[N:26]=1>>[CH:31]1([N:30]2[C:23]3[N:24]([C:25](=[O:27])[N:26]=[C:21]([O:15][CH2:14][C:11]4[CH:12]=[CH:13][C:6]([O:5][C:4]5[CH:16]=[CH:17][C:18]([F:19])=[C:2]([F:1])[CH:3]=5)=[C:7]([CH:10]=4)[C:8]#[N:9])[CH:22]=3)[CH2:28][CH2:29]2)[CH2:33][CH2:32]1
Reactant: O=c1nc(Cl)cc2n1CCN2C1CC1
Reactant: N#Cc1cc(CO)ccc1Oc1ccc(F)c(F)c1
Product: N#Cc1cc(COc2cc3n(c(=O)n2)CCN3C2CC2)ccc1Oc1ccc(F)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from 2-(3,4-difluorophenoxy)-5-(hydroxymethyl)benzonitrile and 7-chloro-1-cyclopropyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:9](#[N:17])[C:10]1[C:11](=[CH:13][CH:14]=[CH:15][CH:16]=1)[NH2:12].Cl>O>[Cl:1][C:2]1[N:7]=[C:6]([NH:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]#[N:17])[CH:5]=[CH:4][N:3]=1
Reactant: N#Cc1ccccc1N
Reactant: Clc1ccnc(Cl)n1
Agent: Cl
Solvent: O
Product: N#Cc1ccccc1Nc1ccnc(Cl)n1
Temperature: 40 °C
Reaction time: 12 h
Yield: 111.4 %

Procedure:
2,4-Dichloropyrimidine (3 g, 0.02 mol), anthranilonitrile (2.38 g, 0.02 mol) and concentrated hydrochloric acid (cat. amount) were added to water (5 ml). The reaction mixture was warmed to 40° C. to dissolve the starting materials and the resulting solution was stirred at room temperature for 12 hours. The solid precipitate that had formed was collected filtration and dried in vacuo to yield a pale yellow solid (5.14 g). NMR: 6.78 (d, 1H), 7.39 (t, 1H), 7.61 (d, 1H), 7.71 (t, 1H), 7.85 (d, 1H), 8.20 (d, 1H), 10.22 (br s, 1H); MS (M+H)+: 231.1, 233.1.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N:20]3[C:28]4[CH:27]=[C:26]([C:29]5[CH:34]=[N:33][CH:32]=[C:31]([CH2:35][CH3:36])[N:30]=5)[N:25]=[CH:24][C:23]=4[CH:22]=[N:21]3)[N:15]=2)[CH2:9]1)(C)(C)C.O1CCOCC1>Cl>[CH2:35]([C:31]1[N:30]=[C:29]([C:26]2[N:25]=[CH:24][C:23]3[CH:22]=[N:21][N:20]([C:16]4[N:15]=[C:14]([N:10]5[CH2:11][CH2:12][CH2:13][C@H:8]([NH2:7])[CH2:9]5)[CH:19]=[CH:18][CH:17]=4)[C:28]=3[CH:27]=2)[CH:34]=[N:33][CH:32]=1)[CH3:36]
Reactant: CCc1cncc(-c2cc3c(cn2)cnn3-c2cccc(N3CCC[C@H](NC(=O)OC(C)(C)C)C3)n2)n1
Agent: Cl
Solvent: C1COCCO1
Product: CCc1cncc(-c2cc3c(cn2)cnn3-c2cccc(N3CCC[C@H](N)C3)n2)n1
Yield: 73.3 %

Procedure:
A solution of (5)-tert-butyl(1-(6-(6-(6-ethylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)piperidin-3-yl)carbamate (80 mg, 0.16 mmol) in hydrogen chloride (4 mol/l) in 1,4-dioxane (2.0 ml, 8.0 mmol) and 1,4-dioxane 2.0 mL was stirred at RT 18 h. The reaction was concentrated and submitted for reverse phase HPLC to give 156 (47 mg) in 50% yield. 1H NMR (400 MHz, DMSO) δ 9.55 (s, 1H), 9.49 (s, 1H), 9.33 (s, 1H), 8.66 (d, J=4.9 Hz, 2H), 7.75 (t, J=8.1 Hz, 1H), 7.21 (d, J=7.7 Hz, 1H), 6.82 (d, J=8.5 Hz, 1H), 4.42 (d, J=13.1 Hz, 1H), 4.12 (d, J=10.6 Hz, 1H), 3.17-3.06 (m, 1H), 2.93 (q, J=7.5 Hz, 2H), 2.88-2.71 (m, 2H), 1.84 (ddd, J=17.0, 13.4, 8.1 Hz, 2H), 1.58 (dd, J=24.7, 11.5 Hz, 1H), 1.35 (t, J=7.6 Hz, 3H). MS (ESI) m/z: 401.2.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:13][C:14]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]3[CH:39]=[CH:38][C:28]([CH2:29][P:30](=[O:37])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])=[CH:27][CH:26]=3)[N:15]=2)=[C:6]2[C:10]=1[CH2:9][N:8]([CH3:11])[C:7]2=[O:12].[C:40]([O:44][C:45](=[O:53])[CH2:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)([CH3:43])([CH3:42])[CH3:41]>>[CH2:35]([O:34][P:30]([CH2:29][C:28]1[CH:27]=[CH:26][C:25]([NH:24][C:16]2[N:15]=[C:14]([NH:13][C:5]3[CH:4]=[CH:3][C:2]([N:50]4[CH2:49][CH2:48][N:47]([CH2:46][C:45]([O:44][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:53])[CH2:52][CH2:51]4)=[C:10]4[C:6]=3[C:7](=[O:12])[N:8]([CH3:11])[CH2:9]4)[C:19]([C:20]([F:21])([F:22])[F:23])=[CH:18][N:17]=2)=[CH:39][CH:38]=1)([O:31][CH2:32][CH3:33])=[O:37])[CH3:36]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)c4c3C(=O)N(C)C4)n2)cc1)OCC
Reactant: CC(C)(C)OC(=O)CN1CCNCC1
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(N4CCN(CC(=O)OC(C)(C)C)CC4)c4c3C(=O)N(C)C4)n2)cc1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 199 using Diethyl [4-({4-[(7-bromo-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)amino]-5-(trifluoromethyl) pyrimidin-2-yl}amino)benzyl]phosphonate and piperazine-1-acetic acid tert-butyl ester. MS (ES+): m/z 748.41 (100) [MH+]; HPLC: tR=0.85 min (UPLC, purity).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:6](=[O:7])[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[C:4](=[O:20])[NH:3]1.[Br:22][C:23]1[C:30]([Cl:31])=[CH:29][C:28]([Cl:32])=[CH:27][C:24]=1[CH2:25]Br>>[Br:22][C:23]1[C:30]([Cl:31])=[CH:29][C:28]([Cl:32])=[CH:27][C:24]=1[CH2:25][N:3]1[C:2]([CH3:21])([CH3:1])[C:6](=[O:7])[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:17])[F:18])[CH:9]=2)[C:4]1=[O:20]
Reactant: CC1(C)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Reactant: Clc1cc(Cl)c(Br)c(CBr)c1
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1Cc1cc(Cl)cc(Cl)c1Br
Yield: 55 %

Procedure:
Compound 38.2 was prepared as described for example 6.2, by reacting compound 1.1 with 2-bromo-3,5-dichlorobenzyl bromide. 4-[3-(2-Bromo-3,5-dichlorobenzyl)-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl]-2-trifluoromethylbenzonitrile was obtained in a yield of 55%. 1H NMR: 8.35, d, 1H, 8.25, s, 1H, 8.1, d, 1H, 7.7, s, 1H, 7.65, s, 1H; 4.65, s, 2H, 1.45, s, 6H.
Reaction SMILES: S1C=CC=C1.ClCCC(Cl)=O.[Sn](Cl)(Cl)(Cl)Cl.[Cl:17][CH2:18][CH2:19][C:20]([C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)=[O:21].[BH4-].[Na+].ClCCC(C1SC=CC=1)O.C(OC=C)(=O)CCC>C1C=CC=CC=1.C(O)C.CCCCCC>[Cl:17][CH2:18][CH2:19][C@@H:20]([C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)[OH:21]
Reactant: O=C(CCCl)c1cccs1
Agent: C=COC(=O)CCC
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)CCCl
Solvent: CCCCCC
Solvent: c1ccsc1
Solvent: CCO
Product: O[C@@H](CCCl)c1cccs1

Procedure:
Huiling et al. describe a preparation of (S)-(−)-3-N-methylamino-1-(2-thienyl)-1-propanol from thiophene. Thiophene is converted with 3-chloropropanoyl chloride in the presence of tin tetrachloride in benzene to 3-chloro-1-(2-thienyl)-1-propanone, which is reduced with sodium borohydride in ethanol to 3-chloro-1-(2-thienyl)-1-propanol. Kinetic resolution by transesterification using vinyl butanoate and lipase B from Candida antarctica as catalyst in hexane yielded (S)-3-chloro-1-(2-thienyl)-1-propanol, which is converted to (S)-3-iodo-1-(2-thienyl)-1-propanol using sodium iodide in acetone. Subsequent treatment with methylamine in tetrahydrofuran afforded (S)-(−)-3-N-methylamino-1-(2-thienyl)-1-propanol.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[C:10]=1[CH2:9][NH:8][C:7]1[CH:11]=[CH:12][CH:13]=[N:14][C:6]=1[CH2:5]2.[CH3:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[Br:25])[C:19](Cl)=[O:20].C(N(CC)CC)C>ClCCl>[Br:25][C:24]1[CH:23]=[CH:22][C:18]([C:19]([N:8]2[CH2:9][C:10]3[N:4]([CH:3]=[CH:2][CH:1]=3)[CH2:5][C:6]3[N:14]=[CH:13][CH:12]=[CH:11][C:7]2=3)=[O:20])=[CH:17][C:16]=1[CH3:15]
Reactant: c1cnc2c(c1)NCc1cccn1C2
Reactant: Cc1cc(C(=O)Cl)ccc1Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(=O)N2Cc3cccn3Cc3ncccc32)ccc1Br
Reaction time: 2.5 h
Yield: 111.4 %

Procedure:
To a stirred solution of the 9,10-dihydro-4H-3a,5,9-triaza-benzo[f]azulene of Step D (1.0 g) in dichloromethane (10 mL) was added 3-methyl-4-bromobenzoyl chloride (1.39 g) and triethylamine (1.1 mL). After stirring for 2.5 hours, the reaction mixture was washed with water, dried over anhydrous magnesium sulfate, filtered and the solvent removed in vacuo to provide the title product as a tan crystalline solid (2.3 g), which was used without further purification.
Reaction SMILES: [CH2:1]1[CH2:18][O:17][C:3]2([CH2:10][C@@H:9]3[C@@H:5]([CH2:6][C:7](=[O:16])[CH:8]3C(OCC)=O)[CH2:4]2)[O:2]1.[OH-].[Na+].Cl>O.C(O)C>[CH2:18]1[CH2:1][O:2][C:3]2([CH2:4][C@@H:5]3[C@@H:9]([CH2:8][C:7](=[O:16])[CH2:6]3)[CH2:10]2)[O:17]1
Reactant: CCOC(=O)C1C(=O)C[C@H]2CC3(C[C@@H]12)OCCO3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C1C[C@@H]2CC3(C[C@@H]2C1)OCCO3
Temperature: 90 °C
Reaction time: 4 h

Procedure:
A solution of 294 mg of (1S,5R,6R,7S)-3,3-ethylenedioxy-7-hydroxy-6-ethoxycarbonylbicyclo [3.3.0]octane (III)' in methylene chloride (2 ml) as prepared in Example 1 was added to a solution of a chromic anhydride-pyridine complex in methylene chloride [prepared from chromic anhydride (688 mg), pyridine (1088 mg) and methylene chloride (18 ml)], and the mixture was stirred at room temperature for 10 minutes. The supernatant was separated, the residue was washed with ether, and the combined organic layer was extracted with 5% aqueous sodium hydroxide solution. The aqueous layer was neutralized with dilute hydrochloric acid and extracted with ether. The organic layer was successively washed with saturated aqueous copper sulfate solution, saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over sodium sulfate, and concentrated to obtain 92 mg of (1R,5S)-7,7-ethylenedioxy-2-ethoxycarbonylbicyclo[3.3.0]octan-3-one. To the thus obtained (1R,5S)-7,7-ethylenedioxy-2-ethoxycarbonylbicyclo [3,3,0]octan-3-one were added 20 mg of sodium hydroxide and 0.9 ml of water-ethanol mixed solution (4:1), and the mixture was stirred at 90° C. for 4 hours. After cooling, the reaction mixture was neutralized with dilute hydrochloric acid and extracted with ether. The organic layer was then washed with saturated brine, dried over sodium sulfate, and concentrated to give 42 mg of the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[C:29]([Cl:30])=[C:28]3[C:24]([CH2:25][N:26]([CH:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)[C:27]3=[O:31])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].[C:44]1([CH:50]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH2:51]CBr)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.CN(C)C=O>[Cl:30][C:29]1[C:21]([N:18]2[CH2:19][CH2:20][N:15]([CH2:13][CH2:51][CH:50]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[CH2:16][CH2:17]2)=[CH:22][CH:23]=[C:24]2[C:28]=1[C:27](=[O:31])[N:26]([CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[CH2:25]2
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2Cl)C(=O)N(C2CCCCC2)C3)CC1
Reactant: BrCCC(c1ccccc1)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1c2c(ccc(N3CCN(CCC(c4ccccc4)c4ccccc4)CC3)c2Cl)CN1C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.2 %

Procedure:
Trifluoroacetic acid (0.125 ml) was added at 0° C. to a solution of 6-[4-(t-butoxycarbonyl)piperazin-1-yl]-7-chloro-2-cyclohexyl-2,3-dihydro-1H-isoindol-1-one (43 mg, 0.1 mmol), obtained in Example 45, in dichloromethane (1 ml). The mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated under the reduced pressure. A saturated aqueous NaHCO3 solution was then added thereto. The mixture was extracted with chloroform. The extract was washed with saturated saline, and then dried over anhydrous MgSO4. The solvent was then removed by distillation under the reduced pressure. Potassium carbonate (28 mg, 0.2 mmol) and 3,3-diphenylpropyl bromide (30 mg, 0.11 mmol) were added at 0° C. to a solution of the crude product, thus obtained, in N,N-dimethylformamide (1 ml). The mixture was stirred at 50° C. for 5 hr. The temperature of the system was then returned to room temperature, and a 0.1 N aqueous citric acid solution was added thereto. The mixture was extracted with ethyl acetate, washed with saturated saline, and then dried over anhydrous MgSO4. The solvent was then removed by distillation under the reduced pressure. The residue was purified by preparative TLC (chloroform:methanol=30:1) to give 17 mg (32%) of the title compound.
Reaction SMILES: [Cl-].[Cl-].[CH2:3]([Ta+2:8]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:4]([CH3:7])([CH3:6])[CH3:5].[CH2:19]([Li])[C:20]([CH3:23])([CH3:22])[CH3:21]>CCCCC>[CH2:14]([Ta:8]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])([CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[CH:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)C[Ta+2](CC(C)(C)C)CC(C)(C)C
Reactant: [Li]CC(C)(C)C
Agent: [Cl-]
Solvent: CCCCC
Product: CC(C)(C)C=[Ta](CC(C)(C)C)(CC(C)(C)C)CC(C)(C)C
Reaction time: 24 h

Procedure:
a solution of 0.5 g of trineopentyltantalum dichloride and 0.17 g of neopentyllithium in 4 ml of pentane was allowed to stand at room temperature for 24 hr in a glass vessel wrapped in foil. (In later experiments it was found that the foil wrapping was unnecessary.) The lithium chloride that had precipitated was separated by filtration, and the filtrate was allowed to stand for another 24 hr at room temperature. No more solid precipitated during this time. Volatile materials were removed under reduced pressure to give trineopentyl(neopentylidene)tantalum, (C5H11)3Ta=C5H10, as an orange crystalline solid.