Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:13]([NH2:15])=[O:14])=[CH:4][CH:3]=1.BrC[CH2:24][Cl:25]>>[Cl:25][CH2:24][CH2:20][O:19][C:18]1[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][C:10]=1[C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:21]
Reactant: COc1ccc(C(N)=O)cc1C(=O)Nc1ccc(Cl)cc1
Reactant: ClCCBr
Product: NC(=O)c1ccc(OCCCl)c(C(=O)Nc2ccc(Cl)cc2)c1

Procedure:
The captioned compound was synthesized from 3-N-(4-chlorophenyl)-4-methoxyisophthalamide and 1-bromo-2-chloroethane by the same procedure as in the manufacturing method described in Example 1-1-2.
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][NH:8][C:9]3[CH:15]=[C:14]([C:16]([O:18]CC)=[O:17])[CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[K+].CO>O>[CH:1]1[C:6]2[CH2:7][NH:8][C:9]3[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1ccc2c(c1)NCc1ccccc1O2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2c(c1)NCc1ccccc1O2
Yield: 92 %

Procedure:
A mixture of ethyl 10,11-dihydrodibenz[b,f][1,4]oxazepine-8-carboxylate (5.4 g), potassium hydroxide (1.1 g), methanol (70 ml) and water (5 ml) was refluxed for 3 hours. After distilling off the solvents under reduced pressure, the residue was dissolved in distilled water (20 ml). The solution was washed with ethyl acetate and acidified with diluted hydrochloric acid. The separated crystals were collected by filtration and then recrystallized from methanol to give 10,11-dihydrodibenz[b,f][1,4]oxazepine-8-carboxylic acid.
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:48]=[C:49]([CH:91]=[CH:92][CH:93]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:66]=[CH:67][C:68]([CH:71]5[CH2:76][CH2:75][N:74]([CH2:77][C@@H:78]([OH:80])[CH3:79])[CH2:73][CH2:72]5)=[N:69][CH:70]=4)[CH:63]=3)[N:58](S(C3C=CC(C)=CC=3)(=O)=O)[CH:57]=2)[CH:53]=[N:52]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[CH:48]=[C:49]([CH:91]=[CH:92][CH:93]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:66]=[CH:67][C:68]([CH:71]5[CH2:72][CH2:73][N:74]([CH2:77][C@@H:78]([OH:80])[CH3:79])[CH2:75][CH2:76]5)=[N:69][CH:70]=4)[CH:63]=3)[NH:58][CH:57]=2)[CH:53]=[N:52]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCN(C[C@H](C)O)CC5)nc4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C[C@H](O)CN1CCC(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cn2)CC1
Yield: 25.8 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, (S)-1-(4-(5-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperidin-1-yl)propan-2-ol (86 mg, 0.129 mmol) was hydrolyzed by lithium hydroxide (54 mg, 1.293 mmol) in THF/methanol/water (15/7/4 ml) to yield 17 mg (25.7% yield) of the titled compound. 1H NMR (CD3OD, 300 MHz): δ 9.01-9.00 (d, 1H), 8.56-8.55 (m, 2H), 8.45-8.42 (dd, 1H), 8.23 (s, 1H), 7.72 (s, 1H), 7.69-7.66 (d, 1H), 7.39-7.32 (m, 1H), 7.11-6.98 (m, 3H), 5.43 (s, 2H), 4.30-4.20 (m, 1H), 3.87-3.77 (t, 2H), 3.30-3.05 (m, 4H), 2.40-2.10 (m, 4H), 1.27-1.24 (d, 3H). MS: m/z=511.3 (M+1), HPLC: 96.17% in method A.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[NH:30][N:29]=[N:28][N:27]=4)[CH2:23][CH2:22][C:21]([C:31]([O:33]C)=[O:32])=[CH:20][C:19]=3[CH:35]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>C1COCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[NH:30][N:29]=[N:28][N:27]=4)[CH2:23][CH2:22][C:21]([C:31]([OH:33])=[O:32])=[CH:20][C:19]=3[CH:35]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2nnn[nH]2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2nnn[nH]2)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 185.4 %

Procedure:
In THF (6.7 ml)/methanol (6.7 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(tetrazol-5-ylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylate (0.25 g). To the solution was added 1N sodium hydroxide solution (6.7 ml), and the mixture was stirred at 50° C. for 4 hours. pH was adjusted to approximate 4 with 1N hydrochloric acid, and the solvent was concentrated to half under reduced pressure. The concentrated material was extracted with ethyl acetate/THF, and the extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was washed with hexane/ethyl acetate (2/1) to give 7-[4-(2-butoxyethoxy)phenyl]-1-(tetrazol-5-ylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (0.45 g).
Reaction SMILES: [C:1]([O:5][CH2:6][C@@H:7]([NH:16][C:17](=[O:45])[CH2:18][CH2:19][C@@H:20]([CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1)[NH:21][CH2:22][C:23]1[C:28]([N+:29]([O-])=O)=[CH:27][N:26]=[C:25]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:24]=1)[C:8]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[O:9])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[NH2:29][C:28]1[C:23]([CH2:22][NH:21][C@H:20]([CH:39]2[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]2)[CH2:19][CH2:18][C:17]([NH:16][C@H:7]([CH2:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])=[O:45])=[CH:24][C:25]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:26][CH:27]=1
Reactant: CC(C)(C)OC[C@@H](NC(=O)CC[C@H](NCc1cc(Oc2ccccc2)ncc1[N+](=O)[O-])C1CCCCC1)C(=O)N1CCOCC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC[C@@H](NC(=O)CC[C@H](NCc1cc(Oc2ccccc2)ncc1N)C1CCCCC1)C(=O)N1CCOCC1
Reaction time: 2 h

Procedure:
To a solution of N-(1-(R)-tert-butoxymethyl-2-morpholin-4-yl-2-oxo-ethyl)-4-(S)-cyclohexyl-4-[(5-nitro-2-phenoxy-pyridin-4-ylmethyl)-amino]-butyramide (0.4 g, 0.6 mmol) in MeOH (10 mL) was added 10% Pd on activated carbon (0.1 g) under N2. The reaction mixture was subjected to hydrogenation under 5 psi for 2 h. The catalyst was filtered out, and the MeOH was evaporated to yield 4-[(5-amino-2-phenoxy-pyridin-4-ylmethyl)-amino]-N-(1-(R)-tert-butoxymethyl-2-morpholin-4-yl-2-oxo-ethyl)-4-(S)-cyclohexyl-butyramide as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:28]>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:10]([F:28])=[O:11])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1nc(F)nc(F)n1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)F
Reaction time: 1.5 h

Procedure:
To a solution of (S)-2-tert-butoxycarbonylamino-3-phenyl-propionic acid (1.0 g, 3.77 mmol) in dichloromethane (18 mL) at −35° C. was added dry pyridine (320 μL, 3.96 mmol) and cyanuric fluoride (477 μL, 5.65 mmol) under an atmosphere nitrogen. The mixture was stirred for 1.5 hours while maintaining the temperature between −35 and −25° C. Ice was added to the reaction mixture and the mixture was stirred for 15 minutes. The organic layer was separated and the aqueous layer extracted with dichloromethane (2×10 mL). The combined organic extracts were washed with ice cold water (15 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give ((S)-1-fluorocarbonyl-2-phenyl-ethyl)-carbamic acid tert-butyl ester which was used in the subsequent step without further purification.
Reaction SMILES: [CH3:1][O:2][CH:3]([P:6]([CH3:10])(=[O:9])[O:7]C)[O:4][CH3:5].[I-].[Na+:12]>C(C(C)=O)C>[CH3:1][O:2][CH:3]([P:6]([CH3:10])(=[O:7])[O-:9])[O:4][CH3:5].[Na+:12]
Reactant: COC(OC)P(C)(=O)OC
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: COC(OC)P(C)(=O)[O-]

Procedure:
The product of step (a) (7.4 g) in methyl ethyl ketone (75 ml) was refluxed for 2 hr with sodium iodide (7.0 g). The resulting suspension was cooled and the product filtered off, washed and dried (7.4 g). The n.m.r spectrum was consistent with the required material.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:9][CH:10]([OH:13])[CH2:11][CH3:12]>>[CH3:9][C:10]([OH:13])([CH2:11][CH3:12])[CH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCC(C)O
Reactant: C=Cc1ccccc1
Product: CCC(C)(O)CCc1ccccc1

Procedure:
A solution of styrene in 2-butanol (20% by weight, 100 g/h) was pumped continuously at an average temperature of 390° C. in the reactor through the laboratory plant. The conversion of styrene was 84.0% and, in the steady state, 14.7 g/h of 3-methyl-1-phenyl-3-pentanol were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH3:12])([CH3:11])[C:9]#[N:10].[OH-:13].[Na+].OO>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH3:12])([CH3:11])[C:9]([NH2:10])=[O:13]
Reactant: CC(C)(C#N)c1ccccc1F
Reactant: [OH-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: OO
Solvent: Cc1ccccc1
Product: CC(C)(C(N)=O)c1ccccc1F

Procedure:
2-(2-Fluorophenyl)-2-methylpropionitrile (0.211 g) was magnetically stirred with aqueous solutions of 5N sodium hydroxide (2 mL), 55% tetrabutylammonium hydrogensulfate (0.1 mL) and 30% hydrogen peroxide (3 mL) for 22 hours. The reaction mixture was diluted with toluene and extracted. The aqueous phase was neutralized with 5% hydrochloric acid and extracted twice with ethyl acetate. The combined organic extracts were washed with water, then brine, and dried over anhydrous magnesium sulfate. Filtration and evaporation gave 2-(2-fluorophenyl)isobutyramide as a pale-green oil that solidified on standing (0.173 g). GC/MS: m/z 181 (RT 9.80 min.). 1H-NMR (DMSO-d6): 7.39-7.27 (m, 2H), 7.19-7.07 (m, 2H), 6.83 and 6.78 (2 s, CONH2), 1.43 (s, 6H)
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:33]=[CH:32][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23](=[O:31])[C:24]3[CH:29]=[CH:28][C:27](F)=[CH:26][CH:25]=3)=[CH:18][CH:17]=2)=[O:14])=[CH:11][CH:10]=1)(=[O:4])[CH:2]=[CH2:3].[CH2:34]([O:38]C1C=CC(C(O)=O)=CC=1)[CH2:35][CH2:36][CH3:37]>>[C:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:33]=[CH:32][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23](=[O:31])[C:24]3[CH:29]=[CH:28][C:27]([O:38][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:26][CH:25]=3)=[CH:18][CH:17]=2)=[O:14])=[CH:11][CH:10]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OCCOc1ccc(C(=O)Oc2ccc(OC(=O)c3ccc(F)cc3)cc2)cc1
Reactant: CCCCOc1ccc(C(=O)O)cc1
Product: C=CC(=O)OCCOc1ccc(C(=O)Oc2ccc(OC(=O)c3ccc(OCCCC)cc3)cc2)cc1

Procedure:
3c was prepared by the same procedure as 3b except that 4-butoxybenzoic acid was used instead of 4-fluorobenzoic acid.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([C:10]1[CH:11]=[CH:12][C:13]([O:20][CH3:21])=[C:14]([S:16]([Cl:19])(=[O:18])=[O:17])[CH:15]=1)([CH3:9])([CH3:8])[CH3:7].[N+:22]([O-])([O-:24])=[O:23].[K+]>ClCCl>[C:6]([C:10]1[CH:11]=[C:12]([N+:22]([O-:24])=[O:23])[C:13]([O:20][CH3:21])=[C:14]([S:16]([Cl:19])(=[O:18])=[O:17])[CH:15]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: COc1ccc(C(C)(C)C)cc1S(=O)(=O)Cl
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: ClCCl
Product: COc1c([N+](=O)[O-])cc(C(C)(C)C)cc1S(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.3 %

Procedure:
Concentrated sulphuric acid (13 ml) was added dropwise to a cooled mixture of 5-t-butyl 2-methoxyphenylsulfonyl chloride (9.0 g) and potassium nitrate (6.90 g) in dichloromethane (100 ml). The reaction mixture was then stirred for 16 hours at ambient temperature. The mixture was then poured onto ice-cold water (200 ml) and the organic layer was separated and dried over sodium sulphate. Removal of solvent gave the title compound as a pale yellow solid (9.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]2[CH:15]=[C:16]([CH:18]=[O:19])[N:17]=[C:13]2[N:12]=[C:11]([CH3:20])[C:10]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].S([CH2:38][N+:39]#[C-:40])(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]2[CH:15]=[C:16]([C:18]3[O:19][CH:40]=[N:39][CH:38]=3)[N:17]=[C:13]2[N:12]=[C:11]([CH3:20])[C:10]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1nc2nc(C=O)cn2c(-c2ccc(Cl)cc2Cl)c1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1nc2nc(-c3cnco3)cn2c(-c2ccc(Cl)cc2Cl)c1C(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 66.3 %

Procedure:
To a stirred solution of tert-butyl 5-(2,4-dichlorophenyl)-2-formyl-7-methylimidazo[1,2-a]pyrimidine-6-carboxylate (90 mg, 0.22 mmol) in MeOH (4 mL) was added tosyl methyl isocyanide (52 mg, 0.27 mmol) and K2CO3 (61 mg, 0.44 mmol). After heating to 60° C. for 30 min, the reaction was concentrated under reduced pressure and purified by silica gel chromatography to provide tert-butyl 5-(2,4-dichlorophenyl)-7-methyl-2-(oxazol-5-yl)imidazo[1,2-a]pyrimidine-6-carboxylate (65 mg, 66%) as a light yellow solid.
Reaction SMILES: [N:1]1[C:6]([C:7](OC)=[O:8])=[CH:5][CH:4]=[CH:3][C:2]=1[C:11]([O:13][CH3:14])=[O:12].[BH4-].[Na+]>CO.O1CCCC1>[OH:8][CH2:7][C:6]1[N:1]=[C:2]([C:11]([O:13][CH3:14])=[O:12])[CH:3]=[CH:4][CH:5]=1
Reactant: COC(=O)c1cccc(C(=O)OC)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cccc(CO)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.9 %

Procedure:
A suspension of dimethyl 2,6-pyridine-dicarboxylate (100 g, 513 mmol) in methanol (800 mL) and tetrahydrofuran (300 mL) was heated to dissolve and while the solution was still hot, it was treated in portions with sodium borohydride (18.2 g, 479 mmol) over 1 hour. The mixture was stirred for 1 hour at room temperature, cooled to 0-5° C., and quenched with 10% citric acid (160 mL), stirred for another 15 minutes, and filtered. The filtrate was concentrated, dissolved in dichloromethane, dried (sodium sulfate), filtered, and concentrated to a white solid. The solid was heated to dissolve in ethyl acetate (100 mL), stirred for 16 hours at room temperature, filtered and concentrated to give the title compound (44.5 g, 56% yield). 1H NMR (CDCl3) δ ppm 3.50(s, 1H), 4.00 (s, 3 H), 4.86 (s, 2 H), 7.52 (d, 1 H), 7.85 (t, 1 H), 8.04 (d, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([O:19][CH3:20])[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([F:30])[C:23]=1[F:31].[Si:32](Cl)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].N1C=CN=C1>ClCCl>[Si:32]([O:18][CH2:17][C@H:10]1[O:9][C@:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([F:30])[C:23]=3[F:31])[CH:4]=2)([O:19][CH3:20])[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@@H:11]1[OH:16])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(Cc2cc([C@]3(OC)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)c(F)c1F
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COc1ccc(Cc2cc([C@]3(OC)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)c(F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
To a solution of (2S,3R,4S,5S,6R)-2-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol 21h (1.12 g, 2.38 mmol) in dichloromethane (20 mL) were added tert-butyldimethylsilyl chloride (0.54 g, 3.58 mmol) and imidazole (0.49 g, 7.16 mmol) in turn at room temperature. The mixture was stirred at room temperature for 3 hours. The mixture was partitioned between dichloromethane (40 mL) and water (40 mL). The organic layer was washed with saturated aqueous sodium chloride (30 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound 21i as yellow oil (1.37 g, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:6]=2[CH:20]=1.[Br:21][CH2:22][C:23](=O)[CH2:24][Cl:25]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:23]([CH2:24][Cl:25])[CH2:22][Br:21])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:6]=2[CH:20]=1
Reactant: O=C(CCl)CBr
Reactant: NNC1=Nc2ccc(Br)cc2C(c2ccccn2)=NC1
Solvent: C1CCOC1
Product: ClCC(CBr)=NNC1=Nc2ccc(Br)cc2C(c2ccccn2)=NC1

Procedure:
In the manner given in Example 1, 7-bromo-2-hydrazino-5-(2-pyridyl)-3H-1,4-benzodiazepine in tetrahydrofuran can be treated with 1 -bromo-3-chloro-propanone under nitrogen to give 7-bromo-2-[[2-bromo-1-(chloromethyl)ethylidene]hydrazino]-5-(2-pyridyl)-3H-1,4-benzodiazepine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([CH3:13])([CH3:12])[CH:10]=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:14][Mg+].[Br-]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([CH3:13])([CH3:12])[CH:10]([OH:11])[CH3:14])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C=O)c1ccc(F)c(Br)c1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(O)C(C)(C)c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.1 %

Procedure:
To a stirred solution of 2-(3-bromo-4-fluorophenyl)-2-methylpropanal (27 g, 110 mmol) in anhyd THF (300 mL) at 0° C. was added MeMgBr (3M in ether, 73 mL, 220 mmol, 2 eq) dropwise over 2 h. After stirring 1 h, the reaction was allowed to warm to room temperature, quenched carefully with 1N HCl and extracted with EtOAc. The combined extracts were washed with brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by column chromatography (Hex/EA=10:1) to give 3-(3-bromo-4-fluorophenyl)-3-methylbutan-2-ol (19 g, 66%). 1H NMR (400 MHz, CDCl3) δ 7.56-7.54 (m, 1H), 7.32-7.28 (m, 1H), 7.07 (t, J=8.4 Hz, 1H), 3.84-3.79 (m, 1H), 1.31 (d, J=6.4 Hz, 6H), 1.04 (d, J=6.4 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[N:12]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([N:23]3[CH2:28][CH2:27][N:26]([CH:29]([CH3:31])[CH3:30])[CH2:25][CH2:24]3)[CH:19]=2)[N:14]=[CH:13]1.[OH-].[Na+].Cl>CO.O>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N:12]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([N:23]3[CH2:24][CH2:25][N:26]([CH:29]([CH3:31])[CH3:30])[CH2:27][CH2:28]3)[CH:19]=2)[N:14]=[CH:13]1
Reactant: COC(=O)c1ccc(C)c(-n2cnc3ccc(N4CCN(C(C)C)CC4)cc3c2=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(N3CCN(C(C)C)CC3)cc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 135.5 %

Procedure:
Methyl 4-methyl-3-[6-(4-isopropylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]benzoate 7.56 g) was dissolved in a mixture of methanol (135 ml) and water (45 ml). 2N NaOH (36 ml) added and stirred at room temperature for 1 hour. The pH was adjusted to 2-3 using 2N HCl and the solvent evaporated in vacuo. The oil was triturated with a mixture of ethyl acetate (100 ml) and iso-hexane (100 ml) and the solid collected by filtration and dried under vacuum at 40° C. for 16 hours to give 4-methyl-3-[6-(4-isopropylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]benzoic acid (9.9 g); NMR Spectrum: (DMSOd6) 1.33 (d, 6H), 2.14 (s, 3H), 3.15 (m, 2H), 3.46 (m, 5H), 3.98 (m, 2H), 7.55 (m, 2H), 7.68 (m, 2H), 7.89 (m, 1H), 7.98 (m, 1H), 8.18 (t, 1H), 11.56 (s, 1H); Mass Spectrum: M+H+ 407.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[C@H:20]([CH2:21][C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][CH:23]=3)[CH2:19][N:18]3[C@@H:31]([CH2:34]O)[CH2:32][CH2:33][C@@H:17]3[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:58]>C(#N)C>[F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[C@H:20]([CH2:21][C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][CH:23]=3)[CH2:19][N:18]3[C@@H:31]([CH2:34][Cl:58])[CH2:32][CH2:33][C@@H:17]3[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1C[C@H]2CC[C@H](CO)N2C[C@H]1Cc1c[nH]c2ccccc12
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1C[C@H]2CC[C@H](CCl)N2C[C@H]1Cc1c[nH]c2ccccc12
Temperature: 70 °C

Procedure:
A mixture of (3,5-bis(trifluoromethyl)phenyl)-[(3R,6R,8aR)-6-hydroxymethyl-3-(1H-indol-3-ylmethyl)-hexahydropyrrolo[1,2-a]pyrazin-2-yl]-methanone (1.30 g), triphenylphosphine (1.2 g), carbontetrachloride (4 mL), and acetonitrile (40 mL) was heated at 70° C. for 6 hours. After cooling to room temperature the solvent was removed in vacuo. The residue was purified by ion-exchange chromatography on a strong cation exchange (SCX) column, to afford 3,5-bis(trifluoromethyl)phenyl-[(3R,6R,8aR)-6-chloromethyl-3-(1H-indol-3-ylmethyl)-hexahydropyrrolo[1,2-a]pyrazin-2-yl]-methanone (1.06 g) (Intermediate 5).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13].[OH-].[Na+]>O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(=O)C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)C(=O)C=Cc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
4-Chlorobenzaldehyde (140.5 g) and pinacolone (100 g) in industrial methylated spirit (IMS; 200 ml) were added dropwise over 25 minutes to sodium hydroxide (40 g) in water (70 ml) and IMS (150 ml) with external cooling (ice/water) applied to maintain a temperature of not more than 25°. The resulting creamy suspension was stirred for a further 3 hours at 18° and was then filtered. The residue was washed with aqueous IMS and dried to give 4-chlorobenzal pinacolone, m.p. 83°-84°. The filtrate was concentrated under reduced pressure and allowed to stand for 2 days to give more of the chalcone product, m.p. 83°-84°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C@@H:13]([NH:17][C:18]([C:20]2([NH2:23])[CH2:22][CH2:21]2)=[O:19])[CH2:12][CH2:11]3)[CH:7]=1.[CH3:31][C:32]1[O:36][C:35]([C:37](O)=[O:38])=[N:34][N:33]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C@@H:13]([NH:17][C:18]([C:20]2([NH:23][C:37]([C:35]4[O:36][C:32]([CH3:31])=[N:33][N:34]=4)=[O:38])[CH2:21][CH2:22]2)=[O:19])[CH2:12][CH2:11]3)[CH:7]=1
Reactant: Cc1nnc(C(=O)O)o1
Reactant: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)CC[C@@H]3NC(=O)C2(N)CC2)no1
Product: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)CC[C@@H]3NC(=O)C2(NC(=O)c3nnc(C)o3)CC2)no1

Procedure:
In analogy to the procedures described for the preparation of intermediate A-1 [B], 1-amino-cyclopropanecarboxylic acid{(S)-5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-indan-1-yl}-amide (example 24) was coupled with 5-methyl-[1,3,4]oxadiazole-2-carboxylic acid to yield the title compound as light yellow solid. MS: 534.2 (MH+, 1Cl).