Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:3]([CH2:14][CH3:15])[C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[CH3:12])C.[Li]CCCC.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][N:35]([C:37](=[O:46])[C:38]2[CH:43]=[CH:42]C(C#N)=[CH:40][CH:39]=2)[CH3:36])[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>C1COCC1>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][N:35]([CH3:36])[C:37](=[O:46])[C:38]2[CH:39]=[CH:40][C:15]([C:14]3[NH:3][C:4](=[O:13])[C:5]4[C:6]([CH:12]=3)=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=4)=[CH:42][CH:43]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: CCN(CC)C(=O)c1cccc(C)c1C
Reactant: CN(CC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)c1ccc(C#N)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cccc2c(=O)[nH]c(-c3ccc(C(=O)N(C)CC4CCN(C(=O)OC(C)(C)C)CC4)cc3)cc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
N,N-Diethyl-2,3-dimethyl-benzamide (200 mg, 0.97 mmol) was dissolved in anhydrous THF (4 mL) under a N2 and cooled to −78° C. n-BuLi (2.5M in n-hexanes, 0.82 mL, 2.04 mmol) was added dropwise to yield a deep red coloured solution and the reaction mixture was stirred at −78° C. for 30 minutes. 4-{[(4-Cyano-benzoyl)-methyl-amino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester (348 mg, 0.97 mmol) was dissolved in anhydrous THF (4 mL) and added dropwise, and the reaction stirred at −78° C. for 2 h. The reaction mixture was quenched with ice/water, allowed to warm to RT and extracted with CH2Cl2 and EtOAc. The combined organic phase was passed through a phase separation cartridge and concentrated in vacuo. The crude compound was triturated with isohexane/diethyl ether (80:20), the solid filtered and dried in vacuo to give 4-({methyl-[4-(5-methyl-1-oxo-1,2-dihydro-isoquinolin-3-yl)-benzoyl]-amino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester as a light beige solid (171 mg, 36%).
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][CH:11]1[CH2:14][N:13]([CH2:15][C@H:16]([OH:27])[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=2)=[O:18])[CH2:12]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].Cl[C:29]1[N:34]=[CH:33][N:32]=[C:31]2[N:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[Cl:44])[N:36]=[CH:37][C:30]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O.CCOC(C)=O>[Si:3]([O:10][CH:11]1[CH2:12][N:13]([CH2:15][C@H:16]([O:27][C:29]2[N:34]=[CH:33][N:32]=[C:31]3[N:35]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[Cl:44])[N:36]=[CH:37][C:30]=23)[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=2)=[O:18])[CH2:14]1)([C:6]([CH3:9])([CH3:7])[CH3:8])([CH3:5])[CH3:4]
Reactant: Clc1ccccc1-n1ncc2c(Cl)ncnc21
Reactant: CC(C)(C)[Si](C)(C)OC1CN(C[C@H](O)C(=O)Nc2ccc(F)cn2)C1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC1CN(C[C@H](Oc2ncnc3c2cnn3-c2ccccc2Cl)C(=O)Nc2ccc(F)cn2)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 88.3 %

Procedure:
Sodium hydride (60% dispersion in mineral oil) (0.682 g, 17.05 mmol) was added to (S)-3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-N-(5-fluoropyridin-2-yl)-2-hydroxypropanamide (Intermediate AX2) (3.0 g, 8.12 mmol) in anhydrous THF (80 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 4-chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B1) (2.63 g, 8.93 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 3 hours. The reaction mixture was neutralised with 1M citric acid and then diluted with water (50 mL) and EtOAc (100 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (100 mL). The combined organics were washed with saturated brine (75 mL),dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 30 to 70% EtOAc in isohexane to afford the product (4.29 g, 88%). 1H NMR (400 MHz, CDCl3) δ 0.04 (6H, s), 0.88 (9H, s), 3.06-3.10 (2H, m), 3.15-3.19 (1H, m), 3.27-3.31 (1H, m), 3.87-3.90 (2H, m), 4.41-4.48 (1H, m), 5.89-5.92 (1H, m), 7.40-7.55 (4H, m), 7.61-7.63 (1H, m), 8.15 (1H, d), 8.22-8.26 (1H, m), 8.36 (1H, s), 8.59 (1H, s), 9.82 (1H, s); m/z (ES+) (M+H)+=598; HPLC tR=2.82 min.
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]3[CH2:15][CH2:14][C:13]4=[C:16]([C:23]([O:25]CC)=[O:24])[S:17][C:18]([S:19][CH2:20][CH2:21][CH3:22])=[C:12]4[C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.[OH-].[Na+].Cl>O.O1CCCC1>[C:1]1([C:7]2[S:8][C:9]3[CH2:15][CH2:14][C:13]4=[C:16]([C:23]([OH:25])=[O:24])[S:17][C:18]([S:19][CH2:20][CH2:21][CH3:22])=[C:12]4[C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCSc1sc(C(=O)OCC)c2c1-c1nc(-c3ccccc3)sc1CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CCCSc1sc(C(=O)O)c2c1-c1nc(-c3ccccc3)sc1CC2
Temperature: 50 °C
Reaction time: 3 h
Yield: 98.6 %

Procedure:
Ethyl 4,5-dihydro-2-phenyl-8-propylthiothieno[3,4-e]benzothiazole-6-carboxylate (3.62 g) was suspended in a mixed solvent of ethanol (25 ml) and tetrahydrofuran (15 ml); a 2 N aqueous solution of sodium hydroxide (13.3 ml) was added at 50° C. After the reaction mixture was stirred at 50° C. for 3 hours, the solution obtained was poured over water (400 ml), acidified with concentrated hydrochloric acid, and extracted with ethyl acetate-tetrahydrofuran (3:1, v/v). The organic layer was washed with water and dried (MgSO4), after which the solvent was distilled off to yield 4,5-dihydro-2-phenyl-8-propylthiothieno[3,4-e]benzothiazole-6-carboxylic acid (3.33 g, 98.5%), which was then recrystallized from chloroform-methanol. Light-yellow prisms. Melting point 236-237° C. (decomposed).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:10][CH2:11]Cl.CC(C)([O-])C.[K+]>O1CCCC1>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH:10]=[CH2:11]
Reactant: Fc1ccc(OCCCl)c(Br)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=COc1ccc(F)cc1Br
Temperature: 0 °C
Reaction time: 72 h
Yield: 72.6 %

Procedure:
To an ice cooled solution of the 2-bromo-1-(2-chloroethoxy)-4-fluorobenzene (Preparation 87, 1.2 g, 4.73 mmol) in anhydrous tetrahydrofuran (15 ml) under nitrogen was added solid potassium tert-butoxide (1.06 g, 9.47 mmol) portion-wise over 5 minutes. The resultant solution was allowed to attain room temperature then stirring was continued for 72 hours. The reaction mixture was evaporated in vacuo. tert-Butyldimethyl ether (25 ml) and water (25 ml) were added and the layers were separated. The organic extract was washed with saturated brine solution (20 ml) then dried over anhydrous MgSO4 (s), filtered and evaporated in vacuo to afford the crude title compound as a yellow oil (745 mg, 73%). Material was taken on without further purification.
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:6]=[CH:7][C:8]2[S:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[C:11](OS(C(F)(F)F)(=O)=O)[C:9]=2[N:10]=1)(=[O:4])=[O:3].[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>C1(C)C=CC=CC=1>[CH3:1][S:2]([C:5]1[N:6]=[CH:7][C:8]2[S:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[C:11]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:9]=2[N:10]=1)(=[O:3])=[O:4]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1sc2cnc(S(C)(=O)=O)nc2c1OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1sc2cnc(S(C)(=O)=O)nc2c1-c1ccccc1
Temperature: 90 °C
Yield: 69.2 %

Procedure:
A mixture of 253 mg of methyl 2-(methylsulfonyl)-7-{[(trifluoromethyl)sulfonyl]oxy}thieno[3,2-d]pyrimidine-6-carboxylate 5 (example 2), 110 mg of benzeneboronic acid, 392 mg of caesium carbonate and 49 mg of dichloropalladium(II)bis(diphenylphosphino)ferocene in 3.5 ml of toluene is heated at 90° C. for 30 min. The mixture is cooled and poured into water. The aqueous phase is extracted three times with dichloromethane. The organic phases are dried over magnesium sulfate, filtered, and then concentrated under vacuum. The residue is purified on 25 g of silica, elution being carried out with dichloromethane, so as to obtain 145 mg of methyl 2-(methylsulfonyl)-7-phenylthieno[3,2-d]pyrimidine-6-carboxylate in the form of a beige solid.
Reaction SMILES: [NH2:1][C:2]1[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:15](Cl)(=[O:19])[O:16][CH2:17][CH3:18]>CC1C=CC=CC=1C>[Cl:13][C:12]1[C:2]([NH:1][C:15]([O:16][CH2:17][CH3:18])=[O:19])=[C:3]([CH:9]=[C:10]([Cl:14])[CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)c1cc(Cl)cc(Cl)c1N
Solvent: Cc1ccccc1C
Product: CCOC(=O)Nc1c(Cl)cc(Cl)cc1C(=O)OCC
Reaction time: 8 h

Procedure:
To a stirred mixture of 25 parts of ethyl 2-amino-3,5-dichlorobenzoate and 180 parts of dimethylbenzene are added dropwise 30 parts of ethyl carbonochloridate. Upon completion, stirring is continued for 8 hours at reflux temperature. The reaction mixture is evaporated and the residue is crystallized from petroleumether. The product is filtered off and dried, yielding 30 parts of ethyl 3,5-dichloro-2-(ethoxycarbonylamino)benzoate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[CH:16]=[C:17]([C:20]([OH:22])=O)[NH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH:24]([NH2:27])([CH3:26])[CH3:25]>>[CH:24]([NH:27][C:20]([C:17]1[NH:18][N:19]=[C:15](/[CH:14]=[CH:13]/[C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][O:10][C:11]=2[CH3:23])[CH:16]=1)=[O:22])([CH3:26])[CH3:25]
Reactant: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(=O)O)[nH]n1
Reactant: CC(C)N
Product: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(=O)NC(C)C)[nH]n1
Yield: 53 %

Procedure:
As described for example 132, 5-{(E)-2-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-vinyl}-2H-pyrazole-3-carboxylic acid was converted, using isopropylamine instead of morpholine, to the title compound (28 mg, 53%) which was obtained as an off white solid. MS: m/e=355.2 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]([C:30](Cl)=[O:31])[CH:21]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:30]([C:22]3[CH:21]=[N:20][C:29]4[C:24]([CH:23]=3)=[CH:25][CH:26]=[CH:27][CH:28]=4)=[O:31])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Reactant: O=C(Cl)c1cnc2ccccc2c1
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)c1cnc2ccccc2c1

Procedure:
According to the general method of Example 14, 1-(4-arninobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and quinoline-3-carbonyl chloride were combined to provide N3-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-3-quinolinecarboxamide as a white crystalline solid, m.p. 116.0-118.0° C. (decomposition). 1H NMR (300 MHz, DMSO-d6) δ9.24 (d, J=2.1 Hz, 1H), 8.86 (t, J=5.1 Hz, 1H), 8.74 (d, J=2.1 Hz, 1H), 8.25 (s, 1H), 8.09-8.05 (m, 3H), 7.86 (dt, J=7.5, 1.0 Hz, 1H), 7.69 (t, J=7.5 Hz, 1H), 7.61 (d, J=7.5 Hz, 1H), 7.40 (t, J=7.5 Hz, 1H), 7.21 (t, J=7.5 Hz, 1H), 6.68 (s, 2H), 4.67 (t, J=6.9 Hz, 2H), 1.97 (quintet, J=7.2 Hz, 2H), 1.65 (quintet, J=7.2 Hz, 2H); MS (EI) m/e 410.1864 (410.1855 calcd for C24H22N6O).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[N:43][C:44]#[N:45])[NH:24][C@H:25]([CH2:33][N:34](C)[C:35](OC(C)(C)C)=O)[CH2:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:18]2)[O:9][CH2:10][CH2:11][NH:12][C:13](=[O:16])[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=1>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[N:43][C:44]#[N:45])[NH:24][C@H:25]([CH2:33][NH:34][CH3:35])[CH2:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:18]2)[O:9][CH2:10][CH2:11][NH:12][C:13](=[O:16])[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)NCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=NC#N)N[C@@H](CC2CCCCC2)CN(C)C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: CNC[C@H](CC1CCCCC1)NC(=NC#N)N1CCC[C@@H]([C@@H](OCCNC(=O)OC)c2cccc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
The methyl 2-((R)-(3-chlorophenyl)((R)-1-(N′-cyano-N—((S)-1-cyclohexyl-3-(N-methyl-N-(tert-butoxycarbonyl)amino)propan-2-yl)carbamimidoyl)piperidin-3-yl)methoxy)ethylcarbamate (8 mg, 0.0124 mmol) was dissolved in a solution of 4 N HCl/dioxane (5 mL). The reaction mixture was stirred at rt for 1 h and then concentrated in vacuo. The residue was purified by preparative HPLC to afford the product (4 mg, 59%).
Reaction SMILES: O[CH2:2][C:3]1[N:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][C:4]=1[CH3:11].S(Cl)([Cl:14])=O>ClCCl>[Cl:14][CH2:2][C:3]1[N:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][C:4]=1[CH3:11]
Reactant: Cc1ccc(C#N)nc1CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(C#N)nc1CCl
Yield: 99 %

Procedure:
A solution of 6-(hydroxymethyl)-5-methyl-2-pyridinecarbonitrile (184 mg) and thionyl chloride (0.16 ml) in dichloromethane (3.5 ml) was stirred at ambient temperature for 7 hours. Solvent was removed in vacuo and toluene (2 ml) added then removed in vacuo to afford the title compound (205 mg, 99%) as a pale buff solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[CH:7]1([CH2:10]OS(C)(=O)=O)[CH2:9][CH2:8]1>>[CH:7]1([CH2:10][N:4]2[CH:5]=[N:6][C:2]([NH2:1])=[N:3]2)[CH2:9][CH2:8]1
Reactant: CS(=O)(=O)OCC1CC1
Reactant: Nc1nc[nH]n1
Product: Nc1ncn(CC2CC2)n1

Procedure:
Prepared in analogy to example 3a) starting with 3-amino-1,2,4-triazole and methanesulfonic acid cyclopropylmethyl ester (Journal of the American Chemical Society 128, 3118 (2006)). The title compound was obtained as a brownish solid (Yield=25%). MS ISP (m/e): 138.1 (100) [M+].
Reaction SMILES: [NH:1]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C@@H:2]([C:10]([NH:12][C@H:13]([C:18]([N:20]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:21]1[C:22]([O:24]CC1C=CC=CC=1)=[O:23])=[O:19])[C@H:14]([CH2:16][CH3:17])[CH3:15])=[O:11])[CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1>CO.[Pd]>[NH:1]([C:36]([O:38][C:39]([CH3:41])([CH3:40])[CH3:42])=[O:37])[C@@H:2]([C:10]([NH:12][C@H:13]([C:18]([N:20]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:21]1[C:22]([OH:24])=[O:23])=[O:19])[C@H:14]([CH2:16][CH3:17])[CH3:15])=[O:11])[CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CC[C@H](C)[C@H](NC(=O)[C@@H](CC1CCCCC1)NC(=O)OC(C)(C)C)C(=O)N1CCCCC1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC[C@H](C)[C@H](NC(=O)[C@@H](CC1CCCCC1)NC(=O)OC(C)(C)C)C(=O)N1CCCCC1C(=O)O
Reaction time: 15 h
Yield: 96.9 %

Procedure:
Boc-D-Cha-L-Ile-D,L-Pip-OBzl (565 mg, 0.96 mmol) was dissolved in MeOH (10 ml). Pd-C catalyst (250 mg) was added to the solution and the solution was stirred for 15 hours under hydrogen atmosphere to remove the benzyl ester group. After Pd-C catalyst was filtered off, MeOH was distilled off to give a residue, which was then vacuum dried to yield Boc-D-Cha-L-Ile-D,L-Pip-OH (459 mg, 0.93 mmol; yield 97%) as a foam.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6].[Br:22][CH2:23]/[CH:24]=[CH:25]/[CH2:26]Br>O>[Br:22][CH2:23]/[CH:24]=[CH:25]/[CH2:26][NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6]
Reactant: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Reactant: BrC/C=C/CBr
Solvent: O
Product: NS(=O)(=O)c1cc(C(=O)O)cc(NC/C=C/CBr)c1Oc1ccccc1

Procedure:
A solution of 3-amino-4-phenoxy-5-sulfamylbenzoic acid (2 g) and 1,4-trans-dibromo-2-butene (3.2 g) in dioxame (35 ml) was heated to reflux overnight. The solvent was removed under reduced pressure and the dark, gummy residue was chromatographed on a silica gel column using chloroform/benzene/acetic acid/methanol (80:10:10:2.5) as the eluting solvent. The fractions containing the product were combined and concentrated leaving an acetic acid solution of it. This was diluted with water to give a cream colored powder which was filtered, dried and washed with pet. ether to remove unreacted dibromobutene. The resulting 3-(4-bromo-trans-2-butenylamino)-4-phenoxy-5-sulfamylbenzoic acid was an off-white solid 0.75 g (26%) with m.p. 191°-194°; ir (Nujol) 3350, 3200, 2600 (broad), 1690, 1605, 1585, and 1530 cm-1 ; nmr (CDCl3 /d6 -DMSO) 3.7-4.5 (m, 5H incl. NH), 5.73 (t, 2H, vinyl), 6.27 (s, SO2NH2), 6.8-7.4 (m, C6H5), 7.57 (d, J=2, CH), and 8.03 ppm (d, CH); mass spectrum is of decomposition products.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:16]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)=[C:10]2[C:11](=[O:15])[O:12][CH2:13][CH2:14][N:9]2[N:8]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[OH:12][CH2:13][CH2:14][N:9]1[C:10]([CH2:11][OH:15])=[C:16]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:8]1
Reactant: O=C1OCCn2nc(-c3ccccn3)c(-c3ccnc4ccccc34)c21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCn1nc(-c2ccccn2)c(-c2ccnc3ccccc23)c1CO
Reaction time: 2 h

Procedure:
To a solution of 2-pyridin-2-yl-3-quinolin-4-yl-pyrazolo[5,1-c]morpholin-4-one (0.50 g, 1.46 mmol) in tetrahydrofuran (20 mL) is added LiAlH4 (0.50 g, 13.1 mmol) at room temperature. The mixture is stirred for 2 h quenched with 1 N sodium hydroxide solution, and partitioned between dichloromethane and water. The organic portion is dried (sodium sulfate), filtered, and concentrated in vacuo. The residue is chromatographed on SiO2 (10% methanol/dichloromethane) to yield the title compound, 0.35 g (70%), as an off-white solid.
Reaction SMILES: [CH:1]1[C:11]2[C:10](=[N:12][CH2:13][CH2:14][CH2:15][OH:16])[C:9]3[CH:17]=[CH:18][CH:19]=[CH:20][C:8]=3[CH2:7][S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.O>C(Cl)Cl>[S:33]([C:30]1[CH:31]=[CH:32][C:27]([CH3:37])=[CH:28][CH:29]=1)([O:16][CH2:15][CH2:14][CH2:13][N:12]=[C:10]1[C:9]2[CH:17]=[CH:18][CH:19]=[CH:20][C:8]=2[CH2:7][S:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]1=2)(=[O:35])=[O:34]
Reactant: OCCCN=C1c2ccccc2CSc2ccccc21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCN=C2c3ccccc3CSc3ccccc32)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
10.0 G. of 3-{ (dibenzo[b,e]thiepin-11(6H)-yliden)-amino}-1-propanol in 30 ml. of absolute pyridine are treated at 0° C. within 1 hour with 9.0 g. of p-toluenesulfonyl chloride. The solution is stirred at 0° C. for 1 hour and subsequently left to stand at 0° C. for 16 hours. The mixture is then diluted with methylene chloride and treated with water. The organic phase is washed with aqueous sodium bicarbonate solution, dried over sodium sulfate and evaporated under reduced pressure. There is obtained crude 3-{(dibenzo[b,e]thiepin-11(6H)-yliden)-amino}-propyl tosylate which is used in the reaction described in the first paragraph of this Example without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])[CH3:7])=[O:5])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[N:26]1[CH:31]=[CH:30][CH:29]=[N:28][C:27]=1[NH:32][CH2:33][C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35]>O1CCCC1>[CH2:1]([O:3][C:4]([C@@H:6]([NH:8][C@H:9]([C:11]([N:32]([C:27]1[N:26]=[CH:31][CH:30]=[CH:29][N:28]=1)[CH2:33][C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])=[O:13])[CH3:10])[CH3:7])=[O:5])[CH3:2]
Reactant: O=C(CNc1ncccn1)OCc1ccccc1
Reactant: CCOC(=O)[C@H](C)N[C@@H](C)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](C)N[C@@H](C)C(=O)N(CC(=O)OCc1ccccc1)c1ncccn1

Procedure:
N-[1-(S)-Ethoxycarbonylethyl]alanine and 1,1'-Carbonyldiimidazole were added to dry tetrahydrofuran. The resulting mixture was refluxed for fifteen minutes. To the resulting solution was added benzyl N-(2-pyrimidyl)glycinate. The resulting mixture was refluxed for three hours. The product was purified by HPLC chromatography to yield benzyl N-[1-(S)ethoxycarbonylethyl]alanyl-N-(2-pyrimidyl)glycinate.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:30])[N:6]2[C@H:22]1[CH2:27][CH2:26][C@H:25]([O:28]C)[CH2:24][CH2:23]1.ClCl.[F:33][C:34]1([F:38])[CH2:37][NH:36][CH2:35]1>ClC1C2C(=NC(=O)N=1)N=CN=2>[F:33][C:34]1([F:38])[CH2:37][N:36]([C:2]2[N:10]=[C:9]([N:11]3[C:15]4[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=4[N:13]=[CH:12]3)[N:8]=[C:7]3[C:3]=2[NH:4][C:5](=[O:30])[N:6]3[C@H:22]2[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24][CH2:23]2)[CH2:35]1
Reactant: FC1(F)CNC1
Reactant: CO[C@H]1CC[C@H](n2c(=O)[nH]c3c(Cl)nc(-n4cnc5ccc(C#N)cc54)nc32)CC1
Agent: ClCl
Agent: O=C1N=C(Cl)C2=NC=NC2=N1
Product: N#Cc1ccc2ncn(-c3nc(N4CC(F)(F)C4)c4[nH]c(=O)n([C@H]5CC[C@H](O)CC5)c4n3)c2c1

Procedure:
Synthesized from 3-(6-chloro-9-(trans-4-methoxycyclohexyl)-8-oxo-8,9-dihydro-7H-purin-2-yl)-3H-benzo[d]imidazole-5-carbonitrile by demethylation, followed by displacement of chlorine in the 6-chloropurinone with 3,3-difluoroazetidine. 1HNMR (300 MHz, CDCl3+CD3OD) δ, ppm: 9.12 (s, 1H), 8.92 (s, 1H), 7.90 (d, 1H), 7.64 (dd, 1H), 4.71 (t, 4H), 4.46-4.32 (m, 1H), 3.98-3.83 (m, 1H), 2.64-2.46 (m, 2H), 2.24-2.15 (m, 2H), 1.97-1.87 (m, 2H), 1.62-1.46 (m, 2H); MS (EI) m/z 467.0 (MH)+.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]([CH3:16])([CH2:14]C)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)=O.[Br:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:28])[CH3:27])=[CH:22][CH:21]=1.[Na]>C(O)C>[Br:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH:27]=[CH:1][C:3]2[CH:4]=[CH:5][C:6]([O:7][C:8]([CH3:14])([CH3:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:17][CH:18]=2)=[O:28])=[CH:22][CH:21]=1
Reactant: CCOC(=O)C(C)(CC)Oc1ccc(C=O)cc1
Reactant: CC(=O)c1ccc(Br)cc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(C=CC(=O)c2ccc(Br)cc2)cc1

Procedure:
Following the procedure in Example 1 using 7.1 parts of ethyl 2-(4-formylphenoxy)-2-methyl-2-ethylacetate and 4.9 parts of p-bromoacetophenone in 10 parts by volume of ethanol containing 0.1 part of sodium metal provides ethyl 2-[4-(2-p-bromobenzoylethenyl)phenoxy]-2,2-dimethylacetate. This compound has the following structural formula. ##SPC7##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:16][C:17]3[CH:22]=[C:21]([CH:23]=[O:24])[C:20]([O:25][CH3:26])=[CH:19][C:18]=3[N+:27]([O-])=O)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.[Cl-].[NH4+].O1CCC[CH2:33]1.COC(OC)OC>[Zn].C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:17]4[CH:22]=[C:21]([CH:23]=[O:24])[C:20]([O:25][CH3:26])=[CH:19][C:18]=4[N:27]=[CH:33]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc([N+](=O)[O-])c(Nc2nc(-c3cccc(Cl)c3)c(C(N)=O)s2)cc1C=O
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: COC(OC)OC
Solvent: CC(=O)O
Product: COc1cc2ncn(-c3nc(-c4cccc(Cl)c4)c(C(N)=O)s3)c2cc1C=O
Temperature: 25 °C

Procedure:
To a suspension of 0.100 g (0.23 mmole) of 4-(3-chloro-phenyl)-2-(5-formyl-4-methoxy-2-nitro-phenylamino)-thiazole-5-carboxylic acid amide (VI.46b), 3 mL of saturated ammonium chloride solution and 3 mL of tetrahydrofuran was added 0.100 g of zinc powder. The mixture was stirred room temperature until the organic layer became straw yellow in color (1 hour). The mixture was filtered, and the filtrate was partitioned between 30 mL of saturated ammonium chloride solution and 30 mL of tetrahydrofuran. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a red solid. The solid was stirred at room temperature with 5 mL of glacial acetic acid and 0.05 mL of trimethylorthoformate for 1 hour and then concentrated under reduced pressure. The residue was partitioned between 50 mL of ethyl acetate and 50 ml, of potassium carbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 0.053 g of 4-(3-chloro-phenyl)-2-(6-formyl-5-methoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid amide (I.46a) as a yellow solid.