Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20]1)[N:13]=2)[CH:5]=[O:6].[CH2:28]([Mg]Br)[CH3:29]>O1CCCC1.C(OC)(C)(C)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[CH2:28][CH3:29])[CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:20][CH2:21]1)[N:13]=2
Reactant: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: CC[Mg]Br
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CCC(O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a mixture of 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzaldehyde (1.00 g, 2.7 mmol) in tetrahydrofuran (20 ml) at 0° C. was added ethylmagnesium bromide soln in t-butylmethyl ether. (4.0 ml, 4.0 mmol) dropwise over 5 min. The reaction was allowed to stir 20 min at 0° C. The reaction was quenched with NH4Cl aq. sat soln. The solid was removed by filtration. The filtrate was concentrated and purified by silica gel chromatography: ISCO, 120 g column, 20-30% EtOAc/Hex, followed by 40% (3% EtN3 in EtOAc)/Hex to give 1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)propan-1-ol. MS (ESI) m/z: Calculated: 404.1; Observed: 405.1 (M++H).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CS(C)=O.O>[CH2:13]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([Br:3])=[CH:12][CH:11]=2)[CH:7]=[CH:8]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: Brc1ccc2[nH]ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Brc1ccc2c(ccn2Cc2ccccc2)c1
Yield: 60.8 %

Procedure:
To a stirred mixture of NaOH (204 mg., 5.1 mmol., 1 eq.) in DMSO (10 mL.) was added 5-bromoindole (1.0 g., 5.1 mmol., 1 eq.). The solution was stirred for 20 hours upon complete dissolution of the NaOH (approximately 1 h.). To this solution was added benzyl bromide (0.606 mL., 5.1 mmol., 1 eq.) via syringe. After 7 h. the mixture was diluted with water and extracted 4× with diethyl ether. The organic extracts were combined, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The product was purified by crystallization (ether/hexanes) affording 888 mg of 1-benzyl-5-bromoindole.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5]C[CH2:3][CH2:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C.[CH:22]([O:29][CH2:30][CH3:31])([O:26][CH2:27][CH3:28])OCC>O>[CH2:30]([O:29][C:22]1([O:26][CH2:27][CH3:28])[CH2:5][CH2:6][CH2:1][CH2:2][CH2:3]1)[CH3:31]
Reactant: O=C1CCCCC1
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: CCOC1(OCC)CCCCC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
In a round bottom flask 6 g (6.4 ml) Cyclohexanone, a pinch of p-toluene sulfonic acid and 10 ml absolute ethanol was taken. Stirred the mixture at R.T. for 5 min. Then add to it 18.12 g (20.3 ml) triethyl orthoformate and stir for 3 hr at R.T. Then distilled on rotavapour to get a thick mass. Add to it 30 ml water and extract with (25 ml×ethyl acetate, wash the organic layer with water, dried it by adding sodium sulfate and concentrate it on rotavapour to give a colorless liquid product.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([F:23])[CH:21]=3)[C:16]([C:24]3[N:25]=[C:26]4[C:32]([C:33](=[O:48])[NH:34][CH:35]5[CH2:39][CH2:38][CH:37]([NH:40]C(OC(C)(C)C)=O)[CH2:36]5)=[CH:31][N:30](COCC[Si](C)(C)C)[C:27]4=[N:28][CH:29]=3)=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(N)CN.O>ClCCl.C(OCC)(=O)C>[NH2:40][CH:37]1[CH2:38][CH2:39][CH:35]([NH:34][C:33]([C:32]2[C:26]3[C:27](=[N:28][CH:29]=[C:24]([C:16]4[C:17]5[C:22](=[CH:21][C:20]([F:23])=[CH:19][CH:18]=5)[N:14]([CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)[N:15]=4)[N:25]=3)[NH:30][CH:31]=2)=[O:48])[CH2:36]1
Reactant: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cn(COCC[Si](C)(C)C)c3ncc(-c4nn(C5CCN(C(=O)OC(C)(C)C)CC5)c5cc(F)ccc45)nc23)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: NC1CCC(NC(=O)c2c[nH]c3ncc(-c4nn(C5CCNCC5)c5cc(F)ccc45)nc23)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.5 %

Procedure:
In a round-bottomed flask, 4-{3-[7-(3-tert-butoxycarbonylamino-cyclopentylcarbamoyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-6-fluoro-indazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (113 mg, 0.13 mmol) was dissolved in dichloromethane (0.7 ml) and trifluoroacetic acid (0.40 ml, 5.2 mmol) was added. The reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was dissolved in dichloromethane (0.7 ml) and ethylenediamine (0.52 ml, 7.7 mmol) was added. The light yellow reaction was stirred at room temperature for 1 h then water and ethyl acetate were added. The resulting suspension was filtered and washed with hot water and ethyl acetate then dried under high vacuum to provide 43 mg (73%) of 2-(6-fluoro-1-piperidin-4-yl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (3-amino-cyclopentyl)-amide as an off-white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[S:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[CH:21][C:20]=1[C:28]([F:31])([F:30])[F:29]>>[S:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:9]1[S:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[C:20]([C:28]([F:31])([F:29])[F:30])[CH:21]=2)=[S:27])=[CH:7][CH:6]=1
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Reactant: Nc1ccc(Sc2nc3ccccc3s2)cc1
Product: FC(F)(F)c1cc(NC(=S)Nc2ccc(Sc3nc4ccccc4s3)cc2)ccc1Cl

Procedure:
2-(4-Aminophenylthio)benzothiazole (10.0 moles, 2.6 g) and 4-chloro-3-trifluoromethylphenylisothiocyanate (10.0 moles, 2.4 g) were reacted according to procedure C to yield of the title compound, 1.5 g, 30%. Mass Spec (FD) 495. Calculated for C21H13ClF3N3S3 : C, 50.85 H, 2.64 N, 8.47. Found: C, 51.02; H, 2.71; N, 8.31.
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15](=[O:18])(O)[O-].[Na+]>ClC1C=CC=CC=1Cl>[C:1]([C:9]1[C:10](=[O:11])[O:12][C:13]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:14][C:15]=1[OH:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: Clc1ccccc1Cl
Product: O=C(c1ccccc1)c1c(O)cc(-c2ccccc2)oc1=O
Temperature: 0 °C

Procedure:
To a solution of ethyl benzoylacetate (150 g, 0.88 mmol) in 1,2-dichlorobenzene (150 mL) was added a trace amount of sodium bicarbonate. The reaction mixture was heated to reflux. A distillate of ethanol (approximately 20 mL) was collected. The reaction mixture was cooled to 0° C. Ether (100 mL) was added to induce crystallization. The reaction mixture was kept in the refrigerator overnight. The solid formed was collected and washed with ether: m.p. 171-173° C.; 1H NMR (250 MHz, DMSO-d6) δ6.91 (s, 1 H), 7.59 (m, 6 H), 7.87 (m, 4 H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]([OH:10])[CH2:7][S:8][CH:9]=1)=[O:4].S(Cl)(Cl)(=O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:10])=[CH:7][S:8][CH:9]=1)=[O:4]
Reactant: COC(=O)C1=CSCC1O
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1cscc1O
Reaction time: 0.5 h
Yield: 77 %

Procedure:
80 parts of 3-hydroxy-dihydrothiophene-4-carboxylic acid methyl ester are dissolved in 800 parts by volume of methylene chloride. 74.3 parts of sulfuryl chloride in 200 parts by volume of methylene chloride are added in the course of one hour at from 10° to 15° C., whilst passing nitrogen into the mixture. The mixture is then stirred for 30 minutes at from 10° to 15° C., after which it is extracted by shaking with 500 parts of water and 300 parts by volume of a 5 percent strength by weight sodium bicarbonate solution. The organic phase is dried and evaporated. The residue is distilled. 60.5 parts (77% of theory) of 3-hydroxy-thiophene-4-carboxylic acid methyl ester of boiling point 76°-84° C./0.07-0.1 mbar are obtained.
Reaction SMILES: [OH:1][C:2]1([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:11][CH2:10][C:5]2(OCC[O:6]2)[CH2:4][CH2:3]1.C([O-])(O)=O.[Na+].C(OCC)(=O)C.CCCCCC>C1COCC1.Cl>[OH:1][C:2]1([C:12]2[CH:13]=[CH:14][C:15]([C:16]#[N:17])=[CH:18][CH:19]=2)[CH2:3][CH2:4][C:5](=[O:6])[CH2:10][CH2:11]1
Reactant: N#Cc1ccc(C2(O)CCC3(CC2)OCCO3)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: N#Cc1ccc(C2(O)CCC(=O)CC2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
4-(8-Hydroxy-1,4-dioxaspiro[4.5]dec-8-yl)benzonitrile (520 mg, 2.0 mmol) was dissolved in the mixed solvent of 10 mL of THF and 10 mL of 1 N HCl aqueous solution at room temperature. The reaction mixture was then stirred at 60° C. for 1 h. The solution was cooled down to room temperature, adjusted to pH 7-8 with saturated NaHCO3 aqueous solution. The organic layer was separated, and the aqueous layer was extracted twice with EtOAc (20 mL×2). The combined organic extracts were dried over MgSO4 and evaporated to give an oil residue. Chromatography on silica gel (flash chromatography grade) with 40% ethyl acetate-hexane gave 410 mg (95%) of the desired product: 1H NMR (CDCl3) δ 7.7 (2H, d, J=11.0 Hz), 7.42 (2H, d, J=10.7 Hz), 4.10 (H, s), 2.79-2.74 (2H, m), 2.63-2.49 (2H, m), 1.95-1.89 (2H, m), 1.67-1.59 (2H, m); MS: 216 (M+1)+.
Reaction SMILES: [C:1](=O)([O-])[OH:2].[NH4+].C([O-])(=O)C.[Zn+2:10].C([O-])(=O)C.[CH:15]1([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[C:28]1([OH:34])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C=O>>[Zn:10].[CH:15]1([C:21]2[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1.[C:28]1([OH:34])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[CH2:1]=[O:2]
Reactant: [Zn+2]
Reactant: O=C([O-])O
Agent: C=O
Agent: CC(=O)[O-]
Agent: Oc1ccc(C2CCCCC2)cc1
Solvent: Oc1ccccc1
Product: [Zn]

Procedure:
A powdery mixture of 10 g of ammonium hydrogen carbonate and 13 g of zinc acetate was added portionwise to 100 g of the resulting p-cyclohexylphenol/phenol/formaldehyde co-condensate kept at 170° C. with stirring. There was obtained a pale yellow transparent zinc salt of the p-cyclohexylphenol/phenol/formaldehyde co-condensate.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].Cl.Cl[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=[CH:18][C:17]=1[N+:26]([O-:28])=[O:27]>>[N+:26]([C:17]1[CH:18]=[N:19][C:20]2[C:25]([C:16]=1[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])=[CH:24][CH:23]=[CH:22][CH:21]=2)([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CC(C)(C)OC(=O)NCCCCN
Agent: Cl
Product: CC(C)(C)OC(=O)NCCCCNc1c([N+](=O)[O-])cnc2ccccc12
Yield: 99886.9 %

Procedure:
Using the general method of Example 1 Part A, tert-butyl N-(4-aminobutyl)carbamate (254 g, 1.35 mol) was reacted with 4-chloro-3-nitroquinoline hydrochloride (331 g, 1.35 mmol) to provide 486 g of tert-butyl N-(4-[(3-nitroquinolin-4-yl)amino]butyl)carbamate as yellow solid. Analysis: Calculated for C18H24N4O4: % C, 59.99; % H, 6.71; % N, 15.55; Found: % C, 59.68; % H, 6.59; % N, 15.74.
Reaction SMILES: COC(=O)[CH2:4][NH:5][C:6](=[O:37])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:35][CH2:34]3)[CH2:25][CH2:24]2)=[O:22])=[CH:9][C:8]=1[Cl:36].[CH2:39]([O:41][C:42]([C:44]1[S:48]C(N)=[N:46][C:45]=1[CH3:50])=[O:43])[CH3:40]>CCCCCCC.C(OCC)(=O)C>[CH2:39]([O:41][C:42]([C:44]1[S:48][C:4]([NH:5][C:6](=[O:37])[C:7]2[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3[C:21]([N:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]([CH:33]4[CH2:34][CH2:35]4)[CH2:25][CH2:24]3)=[O:22])=[CH:9][C:8]=2[Cl:36])=[N:46][C:45]=1[CH3:50])=[O:43])[CH3:40]
Reactant: COC(=O)CNC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Reactant: CCOC(=O)c1sc(N)nc1C
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCOC(=O)c1sc(NC(=O)c2cc(Cl)c(Oc3ccncc3C(=O)N3CCN(C4CC4)c4ccccc43)cc2Cl)nc1C

Procedure:
The title compound was prepared in analogy to Example 1, from 2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoic acid (Example 29, intermediate) and 2-amino-4-methyl-thiazole-5-carboxylic acid ethyl ester (commercially available, CAS RN 7210-76-6) and using a gradient of n-heptane:ethyl acetate (100:0 to 0:100) for the chromatographic purification. Yellow solid (0.182 g; 67%). MS (ESI): m/z=652.12 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][C:11](=[O:13])[CH2:10][C:9](=[O:14])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:15]Br>CC(O)=O>[Br:15][CH:10]1[C:9](=[O:14])[CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:12][C:11]1=[O:13]
Reactant: BrBr
Reactant: O=C1CC(=O)CC(c2ccccc2)C1
Solvent: CC(=O)O
Product: O=C1CC(c2ccccc2)CC(=O)C1Br

Procedure:
To a stirred solution of 5-phenylcyclohexane-1,3-dione (1.88 g, 10 mmol) in AcOH (20 mL) at r.t. was added bromine (1.6 g, 0.51 mL, 10 mmol) dropwise. The reaction was carried out according to Method A to give the title compound in quantitative yield as a light brown solid, which was used without further purification. LCMS (ES+) 266.8 (M+H)+.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:9][C@@H:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.I[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O)CO>[Cu]I.CCCCCC.C(OCC)(=O)C.CC(O)C>[C:19]1([NH:17][C@H:10]([CH3:9])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Ic1ccccc1
Reactant: C[C@@H](N)c1ccccc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: OCCO
Solvent: CCOC(C)=O
Product: C[C@@H](Nc1ccccc1)c1ccccc1
Yield: 76 %

Procedure:
The general procedure under argon was followed using copper(I) iodide (10 mg, 0.05 mmol), K3PO4 (425 mg, 2.00 mmol), (R)-α-methylbenzylamine (155 μL, 1.20 mmol), iodobenzene (112 μL, 1.00 mmol), ethylene glycol (111 μL, 2.00 mmol) and 2-propanol (1.0 mL). Column chromatography using a solvent mixture (hexane/ethyl acetate=20/1, Rf=0.5) afforded (R)-N-(phenyl)-α-methylbenzylamine (150 mg, 76% isolated yield, 99% ee) as colorless liquid. HPLC conditions: (column: Daicel OD-H; solvent: 10% iPrOH in hexane; flow rate: 0.7 mL/min; UV lamp: 254 nm; retention time: 6.74 min). The spectral data (1H NMR) matched with the literature references and GC analysis indicated >95% purity.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[CH:11]([N:14](C(C)C)[CH2:15]C)(C)C.CNC.O>O1CCCC1>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH3:10])[N:3]=[C:2]([N:14]([CH3:15])[CH3:11])[CH:7]=1
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: CCN(C(C)C)C(C)C
Agent: CNC
Solvent: C1CCOC1
Solvent: O
Product: CSc1nc(Cl)cc(N(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
4,6-dichloro-2-methylmercaptopyrimidine (10.0 g, 51 mmol) and diisopropyl ethylamine (17.5 ml, 102 mmol) was dissolved in tetrahydrofuran (400 ml), and a 50% aqueous dimethylamine solution (7.6 ml, 84 mmol) was dripped over the course of 1 hour into this solution under ice cooling. After this mixture liquid was agitated overnight at room temperature, water was added and extraction was carried out 2 times with ethyl acetate. After washing the organic layer with saturated saline, drying was done with MgSO4, the solvent was distilled away under reduced pressure, and 6-chloro-4-dimethylamino-2-methylmercaptopyrimidine was obtained. This was used for the next reaction without separation or refinement. Morpholine (100 ml) was added to this, and it was agitated overnight at 100 degrees Celsius. After allowing to cool, water was added and extraction was carried out 2 times with dichloromethane. After washing the organic layer with saturated saline, drying was done with MgSO4, the solvent was distilled away under reduced pressure. The residue was washed with ether and 11.3 g of coarse crystals of 4-dimethylamino-2-methylsulfanyl-6-morpholinopyrimidine was obtained (2 step yield: 87%).
Reaction SMILES: [CH3:1][C:2]1[O:17][C:11]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:5]2[CH:6]=[C:7](Br)[CH:8]=[CH:9][C:4]=2[N:3]=1.Br[C:19]1[CH:20]=[C:21]([C:24]#[N:25])[S:22][CH:23]=1>>[CH3:1][CH:2]1[O:17][C:11]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:5]2[CH:6]=[C:7]([C:19]3[CH:20]=[C:21]([C:24]#[N:25])[S:22][CH:23]=3)[CH:8]=[CH:9][C:4]=2[NH:3]1
Reactant: N#Cc1cc(Br)cs1
Reactant: CC1=Nc2ccc(Br)cc2C2(CCCCC2)O1
Product: CC1Nc2ccc(-c3csc(C#N)c3)cc2C2(CCCCC2)O1

Procedure:
Prepared according to the procedure for Example 13 from 2-methyl-6-bromospiro [4H-3,1-benzoxazine-4,1′-cyclohexane] and 4-bromo-2-thiophenecarbonitrile. A brown solid; mp 111-112° C.; 1H-NMR (DMSO-d6) δ 8.42 (s, 1H), 8.14 (s, 11H), 7.47 (s, 1H), 7.35 (dd, 1H, J=8.3, 1.1 Hz), 6.58 (d, 1H, J=8.4 Hz), 6.38 (s, 1H), 4.72 (m, 1H), 1.92-2.16 (m, 2H), 1.35-1.75 (m, 8H), 1.31 (d, 3H, J=5.3 Hz); MS (ESI) m/z 325 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1>C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc(/C=C/c2ccc(F)cc2F)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccccc1)c1ccc(CCc2ccc(F)cc2F)cc1
Reaction time: 2 h
Yield: 40.1 %

Procedure:
2,4-Difluoro-1-{(E)-2-[4-(phenylsulfonyl)phenyl]vinyl}benzene (Example 51, 57 mg, 0.16 mmol) and palladium (10% wt. on activated carbon, 20 mg) were combined in ethyl acetate (20 mL) and shaken in a Parr apparatus for 2 hours. The catalyst was removed by filtration and the filtrate evaporated in vacuo. The residue was purified by HPLC to yield the title compound as a white solid (23 mg, 40%). δH (400 z, CDCl3): 7.93-7.91 (2H, m), 7.84-7.82 (2H, m), 7.56-7.46 (3H, m), 7.27-7.24 (2H, m), 7.00-6.94 (1H, m), 6.76-6.70 (2H, m), 2.92-2.84 (4H, m).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7]1(B(O)O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:29]3[CH:30]=[C:31](OS(C(F)(F)F)(=O)=O)[CH:32]=[CH:33][C:28]=3[N:27]3[C:42]([CH3:45])=[N:43][N:44]=[C:26]3[C@H:25]([CH2:46][C:47]([O:49]CC)=[O:48])[N:24]=2)=[CH:19][CH:18]=1.O>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[C:29]3[CH:30]=[C:31]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[CH:32]=[CH:33][C:28]=3[N:27]3[C:42]([CH3:45])=[N:43][N:44]=[C:26]3[C@H:25]([CH2:46][C:47]([OH:49])=[O:48])[N:24]=2)=[CH:21][CH:22]=1
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(OS(=O)(=O)C(F)(F)F)ccc2-n2c(C)nnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nnc2n1-c1ccc(-c3ccccc3)cc1C(c1ccc(Cl)cc1)=N[C@H]2CC(=O)O
Temperature: 120 °C

Procedure:
Sodium carbonate (35.8 mg), phenylboronic acid (22.5 mg) and bis(triphenylphosphine)palladium(II) chloride (10.8 mg) were added to a 2-5 ml microwave vial. A solution of ethyl ((4S)-6-(4-chlorophenyl)-1-methyl-8-{[(trifluoromethyl)sulfonyl]oxy}-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)acetate (for a preparation see Intermediate 2) (83.4 mg) in DME (3 ml) and water (1 ml) was added to the microwave vial. The reaction mixture was heated at 120° C. for 90 min (microwave). Ethyl acetate (2 ml) was added and the water layer was separated and acidified with glacial acetic acid. The water layer was extracted with ethyl acetate (3×5 ml) and the organic layer was dried and the solvent evaporated. The residue was chromatographed (0-10% methanol:DCM) to give [(4S)-6-(4-chlorophenyl)-1-methyl-8-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]acetic acid as a white oil (30.1 mg), which was used without further purification in the subsequent reaction. LCMS (formate): MH+ 443/445, RT 1.09 min
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9]([C:11]1[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:13][O:14][C:15]=1[CH3:16])=O.P(Cl)(Cl)(Cl)=O.C(=O)(O)[O-].[Na+]>ClC(Cl)C.ClCCl>[CH3:16][C:15]1[O:14][N:13]=[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]=1[C:9]1[N:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]2=[CH:7][N:8]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NCc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1onc(-c2ccccc2)c1-c1ncc2ccccn12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 47.2 %

Procedure:
To a solution of 5-methyl-3-phenyl-isoxazole-4-carboxylic acid (pyridin-2-ylmethyl)-amide (0.293 g, 1 mmol) in dichloroethane (5 mL) was added phosphorus oxychloride (0.47 mL, 5 mmol) via a syringe and the resulting mixture heated under reflux overnight. After cooling to room temperature, the mixture was diluted with dichloromethane. Cold saturated sodium bicarbonate (15 mL) was then added slowly and the mixture was vigorously stirred for 15 min. The organic layer was separated and the aqueous was extracted with dichloromethane. The combined extracts were washed with water, dried over sodium sulphate, and evaporated. Purification by preparative HPLC on reversed phase [0.1% aq. ammonia (25%)] afforded the title compound (0.13 g, 47%) as an orange solid. MS: m/e: 276.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH3:15][O:16][C:17]1[C:18]([N+:28]([O-:30])=[O:29])=[C:19]([CH:25]=[CH:26][CH:27]=1)[CH:20]=[CH:21][C:22](O)=O>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:22](/[CH:21]=[CH:20]/[C:19]3[CH:25]=[CH:26][CH:27]=[C:17]([O:16][CH3:15])[C:18]=3[N+:28]([O-:30])=[O:29])=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: COc1cccc(C=CC(=O)O)c1[N+](=O)[O-]
Product: CCn1c(=O)c2[nH]c(/C=C/c3cccc(OC)c3[N+](=O)[O-])nc2n(CC)c1=O
Yield: 47 %

Procedure:
Substantially the same procedure as in Reference Example 70 was repeated using 2.50 g (12.6 mmol) of 5,6-diamino-1,3-diethyluracil and 3.10 g (13.9 mmol) of 3-methoxy-2-nitrocinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 2.28 g (yield 47%) of Compound 121 as orange needles.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([N:12]3[CH2:17][CH2:16][NH:15][C@@H:14]([CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:13]3)=[N:10][C:9]3[CH:26]=[CH:27][CH:28]=[CH:29][C:8]=3[NH:7][C:6]=2[CH:30]=1.C=O.[C:33](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([N:12]3[CH2:17][CH2:16][N:15]([CH3:33])[C@@H:14]([CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:13]3)=[N:10][C:9]3[CH:26]=[CH:27][CH:28]=[CH:29][C:8]=3[NH:7][C:6]=2[CH:30]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1ccc2c(c1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2ccccc2)C1
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1ccc2c(c1)Nc1ccccc1N=C2N1CCN(C)[C@@H](CCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84.5 %

Procedure:
Combine 3-methyl-11-[(S)-3-phenethyl-piperazin-1-yl]-5H-dibenzo[b,e][1,4]diazepine (375.0 mg, 0.95 mmol), formaldehyde (84.4 μL, 1.04 mmol, 37% in water), and 1,2-dichloroethane (30.0 ml). Stir the mixture at ambient temperature for 5 minutes and then add sodium triacetoxyborohydride (300.6 mg, 1.42 mmol). After stirring for 30 minutes at ambient temperature, quench the reaction with saturated sodium bicarbonate. Remove the organic portion and wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using dichloromethane/methanol (90:10) to give 329.5 mg (85%) of the title compound as a tan foam: mp 65°, dec; mass spectrum (ion spray): m/z=411.3 (M+1).