Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]([O:13][C:14]([C:16]1[C:21]([O:22][CH2:23][CH3:24])=[C:20]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:19]=[C:18]([C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[N:17]=1)=[O:15])[CH3:12]>CCN(CC)CC.C(Cl)Cl>[CH2:11]([O:13][C:14]([C:16]1[C:21]([O:22][CH2:23][CH3:24])=[C:20]([N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)[N:19]=[C:18]([C:31]2[CH:32]=[CH:33][C:34]([NH:37][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])=[CH:35][CH:36]=2)[N:17]=1)=[O:15])[CH3:12]
Reactant: CCOC(=O)c1nc(-c2ccc(N)cc2)nc(N2CCOCC2)c1OCC
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc(-c2ccc(NS(=O)(=O)c3ccccc3)cc2)nc(N2CCOCC2)c1OCC
Yield: 23.7 %

Procedure:
Phenyl sulfonyl chloride (0.02 ml, 1.3 eq.), Et3N (1 drop) was added to a stirred solution of 2-(4-amino-phenyl)-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylic acid ethyl ester (40 mg, 1 eq.) in CH2Cl2 (2 ml) and the mixture was reacted overnight at r.t. The reaction mixture was extracted with EA and washed with brine. The crude was purified by chromatography to give a product (13 mg, 23.7%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([NH2:14])[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:15]1[O:17][CH:16]1[CH2:18][OH:19]>C(O)(C)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([NH:14][CH2:15][CH:16]([OH:17])[CH2:18][OH:19])[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: OCC1CO1
Reactant: COc1ccc(CC(C)N)cc1OC
Solvent: CC(C)O
Product: COc1ccc(CC(C)NCC(O)CO)cc1OC
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-(3,4-dimethoxyphenyl)-2-propylamine (20.0 g, 0.10 m) in isopropanol (20 ml) is heated to 50° C. while a solution of glycidol (5.0 g, 0.067 m) in isopropanol (5 ml) is added over 15 minutes. The mixture is stirred at 50° C. for 0.5 hours and then at 70° C. for 16 hours. The solvent is concentrated under reduced pressure and the residue is chromatographed on silica gel, eluting with 10% MeOH-CHCl3 saturated with NH3 to yield (I) weighing 14.37 g (80%).
Reaction SMILES: [I:1][C:2]1[CH:8]=[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:6]=[CH:5][C:3]=1N.N([O-])=O.[Na+].[OH-].[K+].C(=S)=[S:24]>Cl.O.CCO>[I:1][C:2]1[CH:8]=[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:6]=[CH:5][C:3]=1[SH:24]
Reactant: CCCCCCCCc1ccc(N)c(I)c1
Reactant: S=C=S
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCCCCCCCc1ccc(S)c(I)c1
Temperature: 55 °C
Reaction time: 5 h
Yield: 23.7 %

Procedure:
To a stirred mixture of the product of Step A (0.4 g; 1.21 mmol) in 35% HCl (0.2 ml) an ice cold solution of NaNO2 (0.1 g, 1.3 mmol) in H2O (1 ml) was added at 0° C., followed by a solution of K-ethylxhanthate, freshly prepared by rapid stirring of a mixture of KOH (0.085 g, 1.5 mmol) and CS2 (0.173 g, 1.5 mmol) in a mixture of EtOH and H2O (1 ml:1.5 ml) for 2.5 h at room temperature. The resulting mixture was stirred for 5 h at 55° C., than cooled to room temperature and extracted with EtOAc (50 ml). The organic layer was separated, washed with H2O, dried over MgSO4 and filtered. The filtrate was evaporated and the residue was diluted to 20 ml with EtOH and KOH (0.5 g, 3.62 mmol) was added. This was stirred for 5 h at reflux and the mixture was evaporated to dryness and the residue was treated with 1M HCl and extracted with EtOAc (20 ml). The organic layer was separated, dried over MgSO4 and filtered. The filtrate was evaporated and the residue was purified by FCC (SiO2; hexane/EtOAc) to give the title compound (0.1 g, 24%), as a yellow paste, which was used as such in next step. 1H NMR (CDCl3) 7.75 (b, 1H); 7.28 (d, 1H, J=7.95 Hz); 7.00 (dd, 1H, J=7.95, 2.0 Hz); 7.02 (s, 1H); 2.51-2.45 (m, 2H); 1.53 (b, 2H); 1.25 (b, 10H); 0.86 (t, 3H, J=6.42 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7](=[O:14])[C:6]2=[CH:15]O.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:22][NH2:23].C(O)(=O)C>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7](=[O:14])[C:6]2=[CH:15][NH:23][CH2:22][C:21]1[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[C:19]([O:18][CH3:17])[CH:20]=1
Reactant: COc1ccc(CN)cc1OC
Reactant: COc1cc2c(cc1OC)C(=CO)C(=O)N2
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: COc1ccc(CNC=C2C(=O)Nc3cc(OC)c(OC)cc32)cc1OC

Procedure:
5.00 g. of 5,6-Dimethoxy-3-hydroxymethylene oxindole, 6.00 g. of 3,4-dimethoxy benzylamine and 2.20 g. of acetic acid in 40 ml. benzene were reacted as described in Example 5 to give 5.44 g. of product, m.p. 198°-200° C.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([C:13]([O:15]C)=[O:14])=[CH:10]2)=[CH:5][CH:4]=1.Br>CC(O)=O>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([C:13]([OH:15])=[O:14])=[CH:10]2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc2ccc(OC)cc2c1
Agent: Br
Solvent: CC(=O)O
Product: O=C(O)c1ccc2ccc(O)cc2c1
Temperature: 100 °C
Yield: 99.8 %

Procedure:
A suspension of methyl 7-methoxy-2-naphthoate (37.21 g, 172 mmol) in 48% aqueous HBr (195 mL, 1.72 mol) and AcOH (190 mL) was heated at 100° C. for 4 h. The mixture gradually went into solution and then precipitated. The reaction mixture was cooled to rt, and water was added. The solid was filtered and washed with water. The solid was dissolved in 1N NaOH and washed with Et2O. The aqueous solution was acidified to pH 1 with concentrated HCl. The precipitate was filtered and washed with water, then dried under vacuum to give 7-hydroxy-2-naphthoic acid as an off-white solid (32.3 g, 99%). LCMS: (FA) ES− 187.1.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:28]1[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[CH:29]=1)\[CH2:4][C@H:5]([C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][CH:22]([C:25]([OH:27])=[O:26])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12].ClC1C=CC=C(C(OO)=[O:43])C=1>ClCCl.CO.C(=O)([O-])O.[Na+].[Cl-].[NH4+]>[C:25]([CH:22]1[CH2:21][CH2:20][N:19]([C:16]2[CH:15]=[CH:14][C:13]([C@H:5]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[CH3:12])[CH2:4]/[C:3](/[C:28]3[CH:33]=[CH:32][N+:31]([O-:43])=[C:30]([CH3:34])[CH:29]=3)=[N:2]\[OH:1])=[CH:18][CH:17]=2)[CH2:24][CH2:23]1)([OH:27])=[O:26]
Reactant: Cc1cc(/C(C[C@H](c2ccc(N3CCC(C(=O)O)CC3)cc2)c2ccccc2C)=N/O)ccn1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: ClCCl
Product: Cc1ccccc1[C@H](C/C(=N\O)c1cc[n+]([O-])c(C)c1)c1ccc(N2CCC(C(=O)O)CC2)cc1
Reaction time: 3 h
Yield: 49.7 %

Procedure:
A solution of (R,E)-1-(4-(3-(hydroxyimino)-3-(2-methylpyridin-4-yl)-1-o-tolylpropyl)-phenyl)piperidine-4-carboxylic acid (example 266; 95 mg, 208 μmol) in dichloromethane (3 mL) and methanol (0.75 mL) was treated with 3-chloroperbenzoic acid (42 mg, 241 μmol) at 0° C. The reaction mixture was allowed to reach room temperature over 3 h, then after addition of sat. aq. sodium hydrogencarbonate solution (3 drops) and sat. aq. ammonium chloride solution (5 drops) concentrated under vacuum. The residue was purified by preparative HPLC to afford the title compound (49 mg, 50%). White foam, MS (ESI+): m/z=474.1 ([M+H]+).
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)=[O:20])[CH:12]=1)[C:5]([O:7]CC)=[O:6])[CH3:2].[OH-].[Na+].Cl>C(O)C>[CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([C:19]([NH:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:28]=2)=[O:20])[CH:12]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(OC)c(C(=O)NCc2ccc(C(F)(F)F)cc2)c1)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(Cc1ccc(OC)c(C(=O)NCc2ccc(C(F)(F)F)cc2)c1)C(=O)O
Temperature: 25 °C
Reaction time: 14 h
Yield: 76.7 %

Procedure:
0.25 g of ethyl 2-ethoxy-3-(4-methoxy-3-({[4-(trifluoromethyl)benzyl]amino}carbonyl)phenyl)propanoate was dissolved in 7 ml ethanol, and 3 ml of 1 N sodium hydroxide was added, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was ice-cooled, neutralized with 1N hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and the solvent was evaporated, to give 0.18 g of 2-ethoxy-3-(4-methoxy-3-({[4-(trifluoromethyl)benzyl]amino}carbonyl)phenyl)propanoic acid.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH2:26][CH2:27]Br)[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]>[OH-].[Na+].C(Cl)Cl>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH2:26][CH2:27][N:5]2[CH2:6][CH2:7][CH2:8][CH:3]([CH2:2][OH:1])[CH2:4]2)[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: OCC1CCCNC1
Reactant: COc1ccc(CCBr)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CCN2CCCC(CO)C2)cc1OC

Procedure:
A mixture of 2.30 g (0.02 mol) of 3-(hydroxymethyl)piperidine, 5.5 ml (0.04 mol) of triethylamine and 4.90 g (0.02 mol) of 2-(3,4-dimethoxy-phenyl)-ethyl bromide is refluxed for 2 hours. After cooling, the reaction mixture is dissolved in a mixture of 2 molar sodium hydroxide solution and methylene chloride. The organic phase is washed with water, separated off, dried over magnesium sulphate, evaporated down in vacuo and purified over 300 g of aluminium oxide (neutral, activity II-III) with methylene chloride and then with increasing amounts of ethanol (up to 2%). Yield: 4.4 g (78.7% of theory), Melting point: 87.5°-89° C.
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH:20]1[CH2:34][CH2:33][CH2:32][C@H:21]1[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C.CN(C)CCCN=C=NCC.Cl>ClCCl.C(OCC)C>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:2]([C:10]([N:20]1[CH2:34][CH2:33][CH2:32][C@H:21]1[C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 18 h

Procedure:
To a solution of Boc-D-Phe-OH (89.1 g, 336 mmol), Pro-OBzl.HCl (81.2g, 336 mmol), HOBT (50 g, 370 mmol) and N,N-diisopropylethylamine (176 mL, 1,008 mmol) at 0° C. in dichloromethane (600 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.HCl (71 g, 370 mmol). After stirring for 18 h, the mixture was diluted with diethyl ether 1 L) and washed three times with 1N citric acid (250 mL), once with water (250 mL), three times with sat'd aqueous NaHCO3 (250 mL) and once with sat'd aqueous NaCl (250 mL). The organic phase was dried (Na2SO4), filtered, and concentrated in vacuo to yield 140 g (92.5%) of a pale yelow foam.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:40])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[NH:24][N:23]=4)[N:20]=3)[N:15]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].C1COCC1.CC(C)([O-])C.[K+].Br[CH2:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55]>[NH4+].[Cl-].O>[C:57]([O:56][C:54](=[O:55])[CH2:53][N:24]1[C:25]2[C:30](=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=2)[C:22]([C:19]2[N:20]=[C:21]3[C:13]([C:11](=[O:12])[NH:10][C@H:8]([CH3:9])[C:7]([N:5]4[CH2:6][CH:3]([C:1]#[N:2])[CH2:4]4)=[O:40])=[CH:14][N:15]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:16]3=[N:17][CH:18]=2)=[N:23]1)([CH3:60])([CH3:59])[CH3:58]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(Cl)ccc34)nc12)C(=O)N1CC(C#N)C1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CC(=O)OC(C)(C)C)c4cc(Cl)ccc34)nc12)C(=O)N1CC(C#N)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.1 %

Procedure:
In a 20 mL pear-shaped flask, 2-(6-chloro-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (80 mg, 0.14 mmol) was combined with THF (3 ml) to give a light yellow solution. It was cooled to 0° C. and potassium tert-butoxide (19 mg, 0.17 mmol) was added. It was stirred at 0° C. for 30 min and tert-butyl 2-bromoacetate (22 μl, 0.14 mmol) was added dropwise and the reaction was stirred at 0° C. for 1 h. The reaction mixture was diluted with aqueous NH4Cl and water, then extracted with Et2O (2×30 ml). The combined organics were washed with water and brine then dried over MgSO4 and concentrated. The crude residue was purified by SiO2 chromatography (5% to 80% EtOAc/CH2Cl2) to isolate 35 mg (37%) {6-Chloro-3-[7-[(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethylcarbamoyl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-indazol-1-yl}-acetic acid tert-butyl ester as a foaming solid. MS: (M+H)+=694.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[Cl:15]N1C(=O)CCC1=O.Cl>CN(C)C=O>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[C:7]([Cl:15])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCCc1ccc(NC(C)=O)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCCCc1ccc(NC(C)=O)c(Cl)c1
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 103.4 %

Procedure:
A mixture of 67 (7.0 g; 36.6 mmol) and N-chlorosuccinimide (7.8 g; 58.6 mmol) was dissolved in N,N-dimethylformamide (70 mL). The reaction was heated at 70° C. for 6 hours, cooled to room temperature, then poured into aqueous hydrochloric acid (400 mL; 2M), and stirred for 15 minutes. The resulting precipitate was isolated by filtration and dried under vacuum to give the title product as an orange solid (8.54 g).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:19])[CH:8]=2)[N:3]=1.O.[NH2:21][NH2:22]>>[F:19][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:21][NH2:22])[CH:11]=[C:10]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18]
Reactant: NN
Reactant: Fc1ccc2nc(Cl)cc(-c3ccccc3Cl)c2c1
Solvent: O
Product: NNc1cc(-c2ccccc2Cl)c2cc(F)ccc2n1

Procedure:
In the manner given in Example 1, 2-chloro-6-fluoro-4-(o-chlorophenyl)quinoline is reacted with hydrazine hydrate at reflux to give 6-fluoro-4-(o-chlorophenyl)-2hydrazinoquinoline.
Reaction SMILES: CN(C=O)C.CC(N(C)C)=O.[CH3:12][O:13][C:14](=[O:30])[CH2:15][C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][C:20]=1[S:26](=[O:29])(=[O:28])[NH2:27])=[O:17].[CH3:31][S:32](Cl)(=[O:34])=[O:33]>N1C=CC=CC=1.CN1C(=O)CCC1.C1COCC1>[CH3:12][O:13][C:14](=[O:30])[CH2:15][C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][S:32]([CH3:31])(=[O:34])=[O:33])=[CH:21][C:20]=1[S:26](=[O:29])(=[O:28])[NH2:27])=[O:17]
Reactant: COC(=O)CC(=O)Nc1ccc(N)cc1S(N)(=O)=O
Reactant: CS(=O)(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: COC(=O)CC(=O)Nc1ccc(NS(C)(=O)=O)cc1S(N)(=O)=O

Procedure:
reducing the N-(4-nitro-2-sulfamoyl-phenyl)-malonamic acid methyl ester (III), via a catalyst in the presence of an polar aprotic solvent or polar aprotic solvent mixture, to form N-(4-amino-2-sulfamoyl-phenyl)-malonamic acid methyl ester (IV), wherein the aprotic solvent is selected from the group consisting of DMF, DMA, THF, NMP or solvent mixtures thereof, and is more preferably a solvent mixture, and d. mesylating the N-(4-amino-2-sulfamoyl-phenyl)-malonamic acid methyl ester (IV), via addition of methanesulfonyl chloride to a suspension of N-(4-amino-2-sulfamoyl-phenyl)-malonamic acid methyl ester (IV) and pyridine to form the intermediate compound N-(4-methanesulfonylamino-2-sulfamoyl-phenyl)-malonamic acid methyl ester (V).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[OH:10].Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[CH:16]=1)=[O:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:30][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[Cl:29])[CH2:22][O:21][C:17]1[CH:16]=[C:15]([C:13](=[O:14])[CH2:12][O:10][C:3]2[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=2[F:1])[C:6]#[N:7])[CH:20]=[CH:19][CH:18]=1
Reactant: N#Cc1ccc(F)c(O)c1
Reactant: O=C(CBr)c1cccc(OCc2ccc(Cl)c(Cl)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(F)c(OCC(=O)c2cccc(OCc3ccc(Cl)c(Cl)c3)c2)c1
Yield: 87.3 %

Procedure:
4-Fluoro-3-hydroxy-benzonitrile (7.3 g), 2-bromo-1-[3-(3,4-dichloro-benzyloxy)-phenyl]-ethanone (22 g), and potassium carbonate (24.3 g) were suspended together in 400 mL acetone with stirring. The mixture continued to stir for 8 hours, then was concentrated to dryness. The solid residue was taken up in 150 mL diethyl ether and 150 mL water and stirred 2 hours. The solid product was collected by filtration and washed with 100 mL diethyl ether two times and dried in vacuum, 20 g of desired product was obtained. 1H NMR (400 MHz, DMSO-d6): 7.80-7.85 (m, 1H), 7.77 (d, 1H), 7.67 (m, 1H), 7.57-7.64 (m, 2H), 7.44-7.54 (m, 4H), 7.34-7.36 (m, 1H), 5.77 (s, 2H), 5.21 (s, 2H).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][N:7]([C:12]1[C:17]([N+:18]([O-])=O)=[CH:16][N:15]=[C:14]([Cl:21])[N:13]=1)[CH:8]1[CH2:11][CH2:10][CH2:9]1)C>C(OCC)(=O)C.Cl.O>[Cl:21][C:14]1[N:15]=[CH:16][C:17]2[NH:18][C:4](=[O:3])[CH2:5][CH2:6][N:7]([CH:8]3[CH2:11][CH2:10][CH2:9]3)[C:12]=2[N:13]=1
Reactant: CCOC(=O)CCN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCC1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1CCN(C2CCC2)c2nc(Cl)ncc2N1
Yield: 66.2 %

Procedure:
A solution of 1.7 g (0.0052 mole) of 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclobutyl-amino]-propanoic acid ethyl ester (IV-23) in 10 mL of ethyl acetate was added over 1 hour to a suspension of 3.5 g (0.016 mole) of stannous chloride dihydrate in 12 mL of ethyl acetate and 1 mL of hydrochloric acid at ambient temperature. The mixture was stirred for additional hour and then diluted with 30 mL of water, and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexanes-ethyl acetate (80:20-0:100) to give 0.87 g of 2-chloro-9-cyclobutyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-23)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]3[CH:13]=[N:14][CH:15]=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:2]=1.[Cl:16]N1C(=O)CCC1=O>ClCCl>[Cl:16][C:15]1[N:14]=[CH:13][N:12]2[C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:8][CH:9]=[N:10][C:11]=12
Reactant: c1cncc(-c2ccnc3cncn23)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: Clc1ncn2c(-c3cccnc3)ccnc12

Procedure:
A mixture of 0.01 mol of 4-(3-pyridyl)imidazo[1,5-a]pyrimidine (prepared as described in Example 24) and N-chlorosuccinimide (0.013 mol) in 50 ml. of dichloromethane can be refluxed on a steam bath for 3 hours. The reaction mixture can be poured into 100 ml. of ice cold 2.5 N sodium hydroxide solution, the organic layer separated, and dried over anhydrous sodium sulfate, and then passed through a short column of hydrous magnesium silicate. The effluent can be refluxed on a steam bath with the gradual addition of n-hexane until crystallization occurs. The mixture can be cooled and the desired product collected by filtration to produce 8-chloro-4-(3-pyridyl)imidazo[1,5-a]pyrimidine.
Reaction SMILES: C([C@H]([C@@H](C(OCCCC)=O)O)O)(OCCCC)=[O:2].[CH3:19][O:20][C:21]1[C:26]([CH3:27])=[C:25]([CH3:28])[C:24]([O:29][CH3:30])=[C:23]([CH3:31])[C:22]=1[CH2:32][CH:33]=[C:34]([CH3:37])[CH2:35][OH:36].C(OO)(C)(C)C.[OH-].[Na+]>C(Cl)Cl.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[CH3:19][O:20][C:21]1[C:26]([CH3:27])=[C:25]([CH3:28])[C:24]([O:29][CH3:30])=[C:23]([CH3:31])[C:22]=1[CH2:32][C@H:33]1[O:2][C@:34]1([CH3:37])[CH2:35][OH:36]
Reactant: CCCCOC(=O)[C@@H](O)[C@H](O)C(=O)OCCCC
Reactant: COc1c(C)c(C)c(OC)c(CC=C(C)CO)c1C
Agent: [Ti+4]
Agent: CC(C)(C)OO
Agent: CC(C)[O-]
Solvent: ClCCl
Product: COc1c(C)c(C)c(OC)c(C[C@H]2O[C@]2(C)CO)c1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
0.594 ml of titanium tetraisopropoxide is dissolved in 10 ml of dry methylene chloride. Thereupon, 524 ml of dibutyl D-tartrate are added dropwise at -20° C. and the mixture is left to stand at -20° C. for 10 minutes. 197 mg of 4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-methyl-2-butenol are then added and subsequently 180 mg of tert.butyl hydroperoxide (80%) are added dropwise (as a solution in 0.5 ml of methylene chloride). The thus-obtained yellow solution is left to stand at -20° C. for 4 to 5 days, then treated with 5 ml of 1N sodium hydroxide solution, left to warm to room temperature and stirred for 1 hour. The phases are then separated, and the aqueous phase is washed twice with methylene chloride. The combined organic phases are subsequently dried over anhydrous sodium sulphate and concentrated. The thus-obtained colourless oil is dissolved in 20 ml of diethyl ether and stirred with 5 ml of 1N sodium hydroxide solution for 1 hour. The phases are again separated, the aqueous phase is washed twice with diethyl ether and the organic phases are dried over anhydrous sodium sulphate and concentrated. There are obtained 188 mg (98%) of (2R,3R)-4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2,3-epoxy-2-methylbutanol, [α]D20 +18.2° (c=2% in CHCl3).
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:8][O:7][CH2:6][CH2:5][NH:4]1)[CH3:2].CCN(C(C)C)C(C)C.[Cl:18][C:19]1[CH:24]=[C:23](Cl)[N:22]=[C:21]([NH:26][CH3:27])[N:20]=1>CC#N>[Cl:18][C:19]1[CH:24]=[C:23]([N:4]2[CH2:5][CH2:6][O:7][CH2:8][C@H:3]2[CH2:1][CH3:2])[N:22]=[C:21]([NH:26][CH3:27])[N:20]=1
Reactant: CNc1nc(Cl)cc(Cl)n1
Reactant: CC[C@@H]1COCCN1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H]1COCCN1c1cc(Cl)nc(NC)n1
Temperature: 130 °C
Yield: 15.9 %

Procedure:
(3R)-3-Ethylmorpholine (5 g, 43.4 mmol) was taken up in CH3CN (100 mL) and Hunig's base (15.2 mL, 87 mmol), followed by the addition of 4,6-dichloro-N-methyl-2-pyrimidinamine (6.96 g, 39.1 mmol), and the reaction was heated to 130° C. overnight in a sealed tube. The reaction mixture was concentrated and then purified via flash chromatography (0-15% EtOAc/CHCl3, 400 g). Fractions were combined and concentrated to afford the title compound (1.6 g) as a colorless oil. LC-MS (ES) m/z=257 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:21][O:22][CH2:23][C:24](Cl)=[O:25].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:16][CH2:17][N:18]([C:24](=[O:25])[CH2:23][O:22][CH3:21])[CH2:19][CH2:20]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCNCC1
Reactant: COCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(=O)N1CCN(c2c(C(C)=O)cc(Cl)c3cccnc23)CC1
Reaction time: 2 h
Yield: 63.6 %

Procedure:
1-(5-chloro-8-piperazin-1-ylquinolin-7-yl)ethanone (0.030 g, 0.10 mmol, from Example 47, Step 1) was combined with methoxyacetyl chloride (0.014 mL, 0.16 mmol) and triethylamine (0.043 mL, 0.31 mmol) in methylene chloride (1.0 mL) at room temperature and stirred for 2 hours. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4 and then concentrated. The resulted residue was purified on silica gel (eluting with 0 to 5% methanol in dichloromethane) to give the desired product (23 mg, 61%). LCMS calculated for C18H21ClN3O3 (M+H)+: m/z=362.1; Found: 362.0