Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]([C@@H:10]([C@H:14]([CH2:20][CH3:21])[CH2:15][C:16]([F:19])([F:18])[F:17])[C:11](O)=[O:12])=[N+]=[N-]>C1COCC1>[NH2:7][C@@H:10]([C@H:14]([CH2:20][CH3:21])[CH2:15][C:16]([F:17])([F:18])[F:19])[CH2:11][OH:12]
Reactant: CC[C@H](CC(F)(F)F)[C@H](N=[N+]=[N-])C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[C@H](CC(F)(F)F)[C@H](N)CO
Reaction time: 19 h
Yield: 0.1 %

Procedure:
To a gray slurry of lithium aluminum hydride (LAH—110.6 mg, 2.91 mmol) in THF (2 mL) at 0° C. was added dropwise over 5 min (2S,3R)-2-azido-3-ethyl-5,5,5-trifluoropentanoic acid (130 mg, 583 mmol). The resulting slurry was allowed to warn to 25° C. for 19 h. The reaction was quenched by sequential addition of H2O (0.5 mL), 1N NaOH (1.5 mL) and H2O (0.5 mL) at 0° C. The white precipitate that formed after 5 h was filtered off, the organic solvent was dried over MgSO4, filtered and concentrated to obtain (2S,3R)-2-amino-3-ethyl-5,5,5-tlifluoropentan-1-ol as a crude oil (120 mg, 96%). Mass Spectrum (+ESI): 186 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:18][C:19](=[O:25])[C:20]([O:22]CC)=[O:21])[CH:7]=[C:8]([NH:10][C:11](=[O:17])[C:12]([O:14]CC)=[O:13])[CH:9]=1)([OH:3])=[O:2].Cl>[OH-].[Na+].O>[C:1]([C:4]1[CH:9]=[C:8]([NH:10][C:11](=[O:17])[C:12]([OH:14])=[O:13])[CH:7]=[C:6]([NH:18][C:19](=[O:25])[C:20]([OH:22])=[O:21])[CH:5]=1)([OH:3])=[O:2]
Reactant: CCOC(=O)C(=O)Nc1cc(NC(=O)C(=O)OCC)cc(C(=O)O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C(=O)Nc1cc(NC(=O)C(=O)O)cc(C(=O)O)c1

Procedure:
Diethyl N,N'-(5-carboxy-m-phenylene)dioxamate (1.0 gram) is stirred in 1.0N aqueous sodium hydroxide (50 ml.) for 0.5 hour. The reaction mixture is diluted with water (100 ml.) and the pH adjusted to 3 with concentrated hydrochloric acid. The resulting precipitate is collected by filtration (0.80 gram, M.P. >320°).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[CH2:11][C:10]([F:14])([F:13])[CH2:9][CH2:8][C:7]=2[CH:6]=[C:5]1[C:15]([O:17]CC)=O.C(O)(=O)C>C1(C)C=CC=CC=1>[F:13][C:10]1([F:14])[CH2:11][C:12]2[N:4]3[CH2:3][CH2:2][NH:1][C:15](=[O:17])[C:5]3=[CH:6][C:7]=2[CH2:8][CH2:9]1
Reactant: CCOC(=O)c1cc2c(n1CCN)CC(F)(F)CC2
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: O=C1NCCn2c1cc1c2CC(F)(F)CC1
Yield: 53.3 %

Procedure:
Into a 250-mL round-bottom flask was placed a solution of 113n (10 g, 36.73 mmol, 1.00 equiv) in toluene (100 mL) and acetic acid (1.1 g, 18.32 mmol, 0.50 equiv). See FIG. 14. The resulting solution was heated to reflux for 2 h, cooled and concentrated under vacuum. The residue was triturated in 100 mL of dry ether. The crude product was purified by recrystallization from ethanol to afford 4.43 g (53%) of 113o as a white solid. MS-ESI: [M+H]+ 227. 1H NMR (300 MHz, DMSO) δ 2.10-2.24 (2H, m), 2.59-2.64 (2H, m), 3.17-3.27 (2H, m), 3.43-3.48 (2H, m), 3.88-3.92 (2H, m), 6.44 (1H, s), 7.56 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:12]([CH3:23])([CH3:22])[C:4]=2[N:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.CCN(C(C)C)C(C)C.Cl.[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40](Cl)=[O:41]>C(Cl)Cl>[CH3:23][C:12]1([CH3:22])[C:4]2[N:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=[C:2]([NH:1][C:40](=[O:41])[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][N:34]=3)[C:3]=2[CH2:14][N:13]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: CCOC(=O)n1nc(N)c2c1C(C)(C)N(C(=O)OC(C)(C)C)C2
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)n1nc(NC(=O)c2ccccn2)c2c1C(C)(C)N(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a solution of 5-tert-butyl 1-ethyl 3-amino-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-1,5-dicarboxylate, A1(I), (7.32 g, 22.56 mmol) and DIPEA (12 mL) in CH2Cl2 (60 mL), picolinoyl chloride hydrochloride, A1(II), (4.82 g, 27.07 mmol) was added slowly. The reaction was stirred at room temperature for 2 hrs. The reaction mixture was diluted with CH2Cl2(50 mL), washed with water (2×30 mL), sat. NaCl (brine), and dried over MgSO4, filtered and concentrated to give A1(III) (9.12 g, 94% yield). 1H NMR (400 MHz, CDCl3-d) δ ppm 1.39-1.50 (m, 2 H) 1.49-1.58 (m, 10 H) 1.72 (s, 3 H) 1.78 (s, 3 H) 4.63 (q, J=7.07 Hz, 2 H) 4.81 (d, J=19.45 Hz, 2 H) 7.46-7.58 (m, 1 H) 7.82-7.97 (m, 1 H) 8.25 (dd, J=7.71, 3.41 Hz, 1 H) 8.73 (dd, J=9.60, 4.55 Hz, 1 H).
Reaction SMILES: FC1C(O[C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=C(F)C(F)=C(F)C=1F.[CH3:29][C:30]1[CH2:34][CH:33]([CH2:35][O:36][NH2:37])[O:32][N:31]=1>>[CH3:29][C:30]1[CH2:34][CH:33]([CH2:35][O:36][NH:37][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)[O:32][N:31]=1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1ccccc1NCc1ccncc1
Reactant: CC1=NOC(CON)C1
Product: CC1=NOC(CONC(=O)c2ccccc2NCc2ccncc2)C1

Procedure:
Prepared by a similar method as described for example 415. Starting materials: 2-[(Pyridin-4-ylmethyl)-amino]-benzoic acid pentafluorophenyl ester (preparation 7C) and O-(3-methyl-4,5-dihydro-isoxazol-5-ylmethyl)-hydroxylamine (see preparation 89).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([NH:18][CH3:19])=[O:17])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=O)[CH:9]=2)=[CH:6][N:7]=1.[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[NH2:30].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C1COCC1>[NH2:1][C:2]1[C:3]([C:16]([NH:18][CH3:19])=[O:17])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:30][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:20]=3)[CH:9]=2)=[CH:6][N:7]=1
Reactant: Nc1ccc2ccccc2c1
Reactant: CNC(=O)c1nc(-c2cccc(C=O)c2)cnc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CNC(=O)c1nc(-c2cccc(CNc3ccc4ccccc4c3)c2)cnc1N
Yield: 26.2 %

Procedure:
A solution of 3-amino-6-(3-formylphenyl)-N-methylpyrazine-2-carboxamide (0.075 g, 0.29 mmol), naphthalen-2-amine (0.21 g, 1.5 mmol), glacial AcOH (0.033 mL, 0.56 mmol) and NaBH(OAc)3 (0.093 g, 0.44 mmol) in THF (1.1 mL) was heated to 80° C. for 12 h. Upon cooling, saturated NaHCO3 (aq) was added (25 mL). The aqueous layer was extracted with EtOAc (2 x 25 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The crude mixture was purified via HPLC (reverse-phase, CH3CN/H2O with 0.1% TFA). Upon removal of CH3CN/H2O, the product was taken up in MeOH and treated with Bio-Rad AG 1-X8 resin (hydroxide form) until pH 8. The product was filtered and concentrated in vacuo, to provide 29.1 mg (26% yield) of 3-amino-N-methyl-6-{3-[(naphthalen-2-ylamino)methyl]phenyl}pyrazine-2-carboxamide: 1H NMR (400 MHz, 4-DMSO): 8.84 (s, 1H), 8.77 (d, 1H), 8.22 (s, 1H), 8.05 (dt, 1H), 7.62 (t, 2H), 7.51 (d, 1H), 7.41 (d, 2H), 7.27 (dt, 1H), 7.10 (dt, 2H), 6.77 (d, 1H), 6.57 (t, 1H), 4.46 (d, 2H), 2.85 (d, 3H); MS (EI) for C23H21N5O: 384 (MH+)
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([N:17](C(OC(C)(C)C)=O)[NH:18][C:19](OC(C)(C)C)=O)=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH3:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34](O)(=O)C>>[CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][C:13]3[N:12]([C:19]([CH3:34])=[N:18][N:17]=3)[C:11]=2[N:10]=[C:9]1[CH3:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: Cc1nc2nc(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc2n1Cc1ccccc1
Product: Cc1nc2c(ccc3nnc(C)n32)n1Cc1ccccc1
Temperature: 180 °C
Yield: 59 %

Procedure:
di-tert-Butyl 1-(1-benzyl-2-methyl-1H-imidazo[4,5-b]pyridin-5-yl)hydrazine-1,2-dicarboxylate (0.075 g, 0.16 mmol, from Step 3) was dissolved in acetic acid (3 mL) and was heated in the microwave to 180° C. for 5 minutes. Solvent was removed in vacuo, the crude product was reconstituted in MeCN and purified via preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) to afford product (27 mg, 59%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:16]([O:18][CH3:19])=[O:17])=[N:11][C:12](Cl)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1(OB(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH2:1]([O:8][C:9]1[C:10]([C:16]([O:18][CH3:19])=[O:17])=[N:11][C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1nc(Cl)ccc1OCc1ccccc1
Reactant: OB(O)Oc1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1nc(-c2ccccc2)ccc1OCc1ccccc1
Reaction time: 1 h

Procedure:
0.6 g (0.5 mmol) of tetrakis(triphenylphosphine)palladium(O) and 5 ml of 1,2-dimethoxyethane were charged in a 100 ml three-forked flask equipped with a thermometer, a cooling tube and a nitrogen-introducing tube. Thereafter, 2.7 g (10.0 mmol) of methyl 3-benzyloxy-6-chloropicolinate was dissolved in 1,2-dimethoxyethane (20 ml) under nitrogen stream, and was added to the flask at one time. After stirring the resultant mixture at room temperature for 3 hours, 1.8 g (15.0 mmol) of phenylboric acid was dissolved in 1,2-dimethoxyethane (15 ml) and was added to the reaction mixture, which was further stirred for 1 hour. Thereafter, 2M-sodium carbonate aqueous solution (40 ml) was added to the reaction mixture, and the resultant mixture was heat-refluxed for 50 minutes. After cooling, an appropriate amount of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer thus obtained was washed with water and saturated salt water, dried and concentrated, and the residue thus obtained was purified by column chromatography to obtain an aimed compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5](Br)[C:6]([C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[O:15][CH3:16])=O)[CH3:2].[C:19]([NH2:22])(=[S:21])[CH3:20]>>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([O:15][CH3:16])=[C:8]([C:6]2[N:22]=[C:19]([CH3:20])[S:21][C:5]=2[C:4]([O:3][CH2:1][CH3:2])=[O:18])[CH:13]=1
Reactant: CCOC(=O)C(Br)C(=O)c1cc(Cl)ccc1OC
Reactant: CC(N)=S
Product: CCOC(=O)c1sc(C)nc1-c1cc(Cl)ccc1OC

Procedure:
Using 2-bromo-3-(5-chloro-2-methoxy-phenyl)-3-oxo-propionic acid ethyl ester and thioacetamide, the title compound was prepared following the synthetic procedures described for ethyl 2-amino-4-(5-chloro-2-methoxyphenyl)thiazole-5-carboxylate with additional purification by flash chromatography on silica gel (50 to 100% DCM in cyclohexane) to give ethyl 4-(5-chloro-2-methoxyphenyl)-2-methylthiazole-5-carboxylate. LCMS (ESI) m+H=321.4; 1H NMR (400 MHz, CDCl3): δ 7.38 (d, 1H); 7.33 (dd, 1H); 6.87 (d, 1H); 4.20 (q, 2H); 3.75 (s, 3H); 2.76 (s, 3H); 1.20 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:15]([OH:17])=O)[N:5]([C:7]2[C:12]([C:13]#[N:14])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:6]=1.[NH2:18][C:19]1[C:27]([Br:28])=[CH:26][C:25]([Br:29])=[CH:24][C:20]=1[C:21](O)=[O:22].BrC1C=C(C(O)=O)N(C2C(Cl)=CC=CN=2)C=1.NC1C(C)=CC(Cl)=CC=1C(O)=O>>[Br:29][C:25]1[CH:26]=[C:27]([Br:28])[C:19]2[N:18]=[C:15]([C:4]3[N:5]([C:7]4[C:12]([C:13]#[N:14])=[CH:11][CH:10]=[CH:9][N:8]=4)[CH:6]=[C:2]([Br:1])[CH:3]=3)[O:17][C:21](=[O:22])[C:20]=2[CH:24]=1
Reactant: Nc1c(Br)cc(Br)cc1C(=O)O
Reactant: N#Cc1cccnc1-n1cc(Br)cc1C(=O)O
Agent: Cc1cc(Cl)cc(C(=O)O)c1N
Agent: O=C(O)c1cc(Br)cn1-c1ncccc1Cl
Product: N#Cc1cccnc1-n1cc(Br)cc1-c1nc2c(Br)cc(Br)cc2c(=O)o1

Procedure:
According to the same manner as that of Reference Preparation Example 71-(5), 4-bromo-1-(3-cyano-2-pyridinyl)-1H-pyrrole-2-carboxylic acid and 2-amino-3,5-dibromobenzoic acid were used in place of 4-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrrole-2-carboxylic acid and 2-amino-5-chloro-3-methylbenzoic acid respectively to obtain 6,8-dibromo-2-[4-bromo-1-(3-cyano-2-pyridinyl)-1H-pyrrol-2-yl]-4H-3,1-benzoxazine-4-one of the formula:
Reaction SMILES: [Li+].[OH-:2].C[O:4][C:5]([C@H:7]1[CH2:12][CH2:11][C@H:10]([CH2:13][N:14]2[C:20](=[O:21])[CH2:19][C:18]3[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=3[N:16]([CH3:26])[C:15]2=[O:27])[CH2:9][CH2:8]1)=[O:6]>O1CCOCC1.O>[C:15]([N:16]([CH3:26])[C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[CH2:19][C:20]([NH:14][CH2:13][C@H:10]1[CH2:11][CH2:12][C@H:7]([C:5]([OH:4])=[O:6])[CH2:8][CH2:9]1)=[O:21])([OH:27])=[O:2]
Reactant: [OH-]
Reactant: COC(=O)[C@H]1CC[C@H](CN2C(=O)Cc3ccccc3N(C)C2=O)CC1
Agent: [Li+]
Solvent: O
Solvent: C1COCCO1
Product: CN(C(=O)O)c1ccccc1CC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
LiOH (1.3 mmol, 0.03 g) was added to a solution of trans-4-(1-Methyl-2,4-dioxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-ylmethyl)-cyclohexane carboxylic acid methyl ester (0.84 mmol, 0.29 g) in dioxane (3 mL) and water (3 mL) at 0° C. The mixture was stirred at 0° C. for 2 h. The reaction mixture was washed with DCM, then HCl (1N) was added until reached pH 1, then extract with DCM (3×10 mL) and AcOEt (3×10 mL). The organic layers were washed with brine (2×10 mL) dried over Na2SO4 collected together and concentrated under reduced pressure to give the title compound in quantitative yield (0.29 g).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([I:13])=[CH:9][C:8]=1[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22])=[O:15].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[Br:1][CH2:2][C:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([I:13])=[CH:9][C:8]=1[C:14](=[O:15])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22])=[O:4]
Reactant: Nc1ccc(I)cc1C(=O)c1ccccc1Cl
Reactant: O=C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CBr)Nc1ccc(I)cc1C(=O)c1ccccc1Cl
Temperature: 0 °C
Yield: 90 %

Procedure:
Bromoacetyl bromide, 15 ml, was added to a solution of 52 g (0.145 mol) of (2-amino-5-iodophenyl)(2-chlorophenyl) methanone in 300 ml of methylene chloride cooled to 0° C. A 10% aqueous solution of sodium carbonate, 150 ml, was added slowly with stirring and the two phase system was stirred in the cold for 30 minutes. The organic layer was separated, washed with water and dried over sodium sulfate. The solution was filtered and evaporated. Crystallization of the residue from methylene chloride/ether yielded 61 g (90%) of 2-bromo-N-[2-(2-chlorobenzoyl)-4-iodophenyl]acetamide with m.p. 150°-152° C. A solution of 50 g of this material in 1 liter of methylene chloride was added to 800 ml of liquid ammonia with dry-ice cooling. After refluxing for 16 hours, the cooling was discontinued and the ammonia was allowed to evaporate. The remaining solution was washed with water, dried over sodium sulfate and evaporated under reduced pressure. The residue was dissolved in 1 liter of ethanol and the solution was heated to reflux for 30 minutes after the addition of 15 ml of acetic acid. The crystals separated from the cooled reaction mixture were collected to leave 38 g (89%) of 5-(2-chlorophenyl)-1,3-dihydro-7-iodo-2H-1,4-benzodiazepin-2-one which melted at 260°-262° C. after recrysyallization from tetrahydrofuran/ethanol.
Reaction SMILES: Cl[S:2]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[C:10]([O:12][CH3:13])=[O:11])(=[O:4])=[O:3].C1COCC1.[CH3:19][NH2:20]>C(Cl)Cl>[CH3:19][NH:20][S:2]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[C:10]([O:12][CH3:13])=[O:11])(=[O:4])=[O:3]
Reactant: CN
Reactant: COC(=O)c1sccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccsc1C(=O)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-(chlorosulfonyl)thiophene-2-carboxylate (500 mg, 2.077 mmol) in DCM (20 ml), methanamine 2N solution in THF (4.155 ml, 8.31 mmol) was added and the reaction was stirred for 1 hour at RT. The mixture was partitioned between 2N HCl and DCM and the aqueous phase was extracted with DCM. The combined organic layers were dried over sodium sulfate and the solvent was removed affording methyl 3-(N-methylsulfamoyl)thiophene-2-carboxylate (Int. 32) (430 mg, 1.828 mmol, MS/ESI+235.8 [MH]+).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9](Br)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH:13]1(B(O)O)[CH2:15][CH2:14]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].P(C1CCCCC1)(C1CCCCC1)C1CCCCC1>C1(C)C=CC=CC=1.O>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]([CH:13]2[CH2:15][CH2:14]2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Br)ccc1N
Reactant: OB(O)C1CC1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(C2CC2)ccc1N
Temperature: 100 °C
Yield: 88.3 %

Procedure:
In a schlenck tube, a mixture of methyl 2-amino-5-bromobenzoate (43.47 mmol, 10 g), cyclopropylboronic acid (112.92 mmol, 9.700 g), K3PO4 (144.16 mmol, 30.6 g), Pd(AcO)2 (3.47 mmol, 0.780 g), P(Cy)3 (7.85 mmol, 2.2 g) in toluene (170 ml) and water (10 ml) was heated for 2 hours at 100° C., under nitrogen atmosphere. The reaction mixture was filtered through celite and the organic phase was separated and evaporated affording 7.34 g (yield 77%) of the expected product.
Reaction SMILES: ClC1C([F:20])=C(C(C2C=CC=CC=2)C2NC=NC=2)C=CC=1.Cl[C:22]1[C:23](C)=[C:24]([CH:28]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:29]2[NH:33][CH:32]=[N:31][CH:30]=2)[CH:25]=[CH:26][CH:27]=1>>[F:20][C:22]1[CH:23]=[C:24]([CH:28]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:29]2[NH:33][CH:32]=[N:31][CH:30]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: Cc1c(Cl)cccc1C(c1ccccc1)c1cnc[nH]1
Reactant: Fc1c(Cl)cccc1C(c1ccccc1)c1cnc[nH]1
Product: Fc1cccc(C(c2ccccc2)c2cnc[nH]2)c1

Procedure:
1H NMR (CD3OD, 300 MHz) 7.61 (s, 1H), 6.8-7.38 (m, 10H), 6.51 (s, 1H), 5.42 (s, 1H). 5-[(3-Chloro-2-fluoro-phenyl)-phenyl-methyl]-1H-imidazole: 1HNMR (CD3OD, 300 MHz) 7.61 (s, 1H), 6.95-7.38 (m, 9H), 6.51 (s, 1H), 5.71 (s, 1H). 5-[(3-Chloro-2-methyl-phenyl)-phenyl-m ethyl]-1H-imidazole: 1HNMR (CD3OD, 300 MHz) δ 7.96 (s, 1H), 7.01-7.96 (m, 9H), 6.40 (s, 1H), 5.92 (s, 1H), 2.06 (s, 3H).
Reaction SMILES: [C-]#N.[Na+].BrC[C:6]1[CH:21]=[CH:20][C:9]2[C:10](=[O:19])[C:11]3[CH:18]=[CH:17]C=[CH:15][C:12]=3[CH:13]=[CH:14][C:8]=2[CH:7]=1.[CH3:22][C:23]([CH3:27])(O)[C:24]#[N:25]>CCOCC>[CH:15]1[C:12]2[CH:13]=[CH:14][C:8]3[CH:7]=[CH:6][CH:21]=[CH:20][C:9]=3[C:10](=[O:19])[C:11]=2[CH:18]=[CH:17][C:22]=1[CH:23]([CH3:27])[C:24]#[N:25]
Reactant: O=c1c2ccccc2ccc2cc(CBr)ccc12
Reactant: CC(C)(O)C#N
Agent: [C-]#N
Agent: [Na+]
Solvent: CCOCC
Product: CC(C#N)c1ccc2c(=O)c3ccccc3ccc2c1

Procedure:
12.0 Gm. of sodium cyanide and 6.0 gm. of 2-bromomethyl-5H-dibenzo[a,d]cyclohepten-5-one are stirred at 100° C. for 40 minutes in 150 ml. of acetone cyanohydrin. The mixture is cooled and poured into ether. The ethereal layer is washed with water, dried and evaporated. The residue is chromatographed on 350 gm. of silica gel, eluting with hexane/ethyl acetate (3:2) to obtain 8.8 gm., 78%, of 5H-dibenzo[a,d]cyclohepten-5-on-2-yl acetonitrile which is recrystallized from ethyl acetate/hexane, m.p. 119°-121°- C. Use of 2-(α-bromoethyl)-5H-dibenzo[a,d]cyclohepten-5-one gives a similar yield of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)propionitrile, m.p. 108°-109° C.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[NH2:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][N:18]=[C:17]2[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Br:31])[CH:26]=1.[C:32](O)(=[O:35])[C:33]#[CH:34]>CN(C=O)C>[Br:31][C:27]1[CH:26]=[C:25]([NH:24][C:17]2[C:16]3[C:21](=[CH:22][CH:23]=[C:14]([NH:13][C:32](=[O:35])[C:33]#[CH:34])[CH:15]=3)[N:20]=[CH:19][N:18]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reactant: C#CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: C#CC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Temperature: 0 °C

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (200 mg, 1.04 mmol) was added to a solution of 6-amino-4-[(3-bromophenyl)-amino]quinazoline (158 mg, 0.5 mmol) and propiolic acid (0.08 mL, 1.1 mmol) in DMF (1.5 mL) stirred under N2 at 0° C. The resulting solution was stirred at 0° C. for 30 minutes and quenched with water. The formed fine solid was collected by Buchner filtration then dissolved in methanol and purified by preparative tlc on silica, eluting with 10% MeOH/CHCl3. The title compound was isolated as a yellow solid (21 mg, 12%), mp>310° C.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[C:8]([NH:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH:14]([OH:18])[CH2:13]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[N:19]1([C:24]2[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=2)[CH:23]=[CH:22][CH:21]=[N:20]1>>[N:19]1([C:24]2[CH:25]=[C:26]([C:2]3[N:6]4[CH:7]=[C:8]([NH:11][CH:12]5[CH2:17][CH2:16][CH2:15][CH:14]([OH:18])[CH2:13]5)[CH:9]=[CH:10][C:5]4=[N:4][CH:3]=3)[CH:27]=[CH:28][CH:29]=2)[CH:23]=[CH:22][CH:21]=[N:20]1
Reactant: OB(O)c1cccc(-n2cccn2)c1
Reactant: OC1CCCC(Nc2ccc3ncc(Br)n3c2)C1
Product: OC1CCCC(Nc2ccc3ncc(-c4cccc(-n5cccn5)c4)n3c2)C1

Procedure:
This compound is prepared from (1RS,3RS)-3-(3-Bromo-imidazo[1,2-a]pyridin-6-ylamino)-cyclohexanol (Intermediate J [step 1]) and 3-(1H-pyrazol-1-yl)-phenylboronic acid analogously to Example 2.1 (step 2)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Br:9][CH2:10][CH2:11][CH2:12]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:9][CH2:10][CH2:11][CH2:12][O:8][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=1
Reactant: BrCCCBr
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: BrCCCOc1cccc(Br)c1
Yield: 57.5 %

Procedure:
A mixture of 5.0 g (0.029 mol) of 3-bromophenol, 29 ml (0.29 mol) of 1,3-dibromopropane and 12 g (0.087 mol) of potassium carbonate in 75 ml of acetone was stirred at reflux for 22 ours. The reaction mixture was filtered and the filtrate was concentrated at reduced pressure. The residue was purified by HPLC using 3% ethyl acetate-hexane to give 4.9 g (58% yield) of 3-(3-bromopropoxy)bromobenzene. The structure was confirmed by the nmr spectrum.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:28])=[C:5]([C:23]2[O:24][CH:25]=[N:26][N:27]=2)[CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[Cl:22])[C:7]=1[C:8]([O:10]CCC#N)=[O:9].[OH-].[Na+]>O.C(COC)OC>[CH3:1][C:2]1[NH:3][C:4]([CH3:28])=[C:5]([C:23]2[O:24][CH:25]=[N:26][N:27]=2)[CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[Cl:22])[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: CC1=C(C(=O)OCCC#N)C(c2cccc(Cl)c2Cl)C(c2nnco2)=C(C)N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: CC1=C(C(=O)O)C(c2cccc(Cl)c2Cl)C(c2nnco2)=C(C)N1

Procedure:
30 g of the 2-cyanoethyl 1,4-dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-5-(1,3,4-oxadiazol-2-yl)-pyridine-3-carboxylate thus prepared are stirred in a solution of 8.7 g of NaOH in 220 ml of water and 110 ml of dimethoxyethane for 3 hours at room temperature. The mixture is diluted with 200 ml of water and is extracted by shaking with three times 100 ml of CH2Cl2. The water phase is acidified by adding concentrated hydrochloric acid. The precipitate which has been deposited is then filtered off with suction, washed with water until it is neutral and dried in vacuo at 50° C. This gives 22.0 g (corresponding to 91.1% of theory) of 1,4-dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-5-(1,3,4-oxadiazol-2-yl)-pyridine-3-carboxylic acid of melting point 187°-190° C. Analysis: