Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)=[CH:12][N:11]=[C:10]([Cl:22])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:23](Cl)(=[O:26])[CH:24]=[CH2:25].C(N(CC)CC)C>>[Cl:22][C:10]1[N:9]=[C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:23](=[O:26])[CH:24]=[CH2:25])[CH:7]=[CH:6][CH:5]=2)[C:13]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[CH:12][N:11]=1
Reactant: Nc1cccc(-c2nc(Cl)ncc2Nc2cccc(F)c2)c1
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1cccc(-c2nc(Cl)ncc2Nc2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 18.4 %

Procedure:
4-(3-Aminophenyl)-2-chloro-N-(3-fluorophenyl)pyrimidin-5-amine (15 mg, 0.048 mmol) was added to a solution of acryloyl chloride (4.24 μL, 0.052 mmol) in the presence of triethylamine (0.013 mL, 0.095 mmol) at 0° C., and the reaction mixture was stirred for 12 h at rt. The reaction was monitored by TLC. After completion of the reaction, the compound was purified by column chromatography to give the title compound (3.26 mg, 16% yield). ESI-MS: m/z 369.09 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:26]([C:27](=[O:29])[NH2:28])=[C:25](Cl)[N:24]=[C:23]([S:31][CH3:32])[N:22]=3)=[CH:16][C:15]=2[CH3:33])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:35][NH2:36]>O1CCOCC1>[C:27]([C:26]1[C:21]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([N:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]3)=[C:15]([CH3:33])[CH:16]=2)=[N:22][C:23]([S:31][CH3:32])=[N:24][C:25]=1[NH:35][NH2:36])(=[O:29])[NH2:28]
Reactant: CSc1nc(Cl)c(C(N)=O)c(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)c(C)c2)n1
Reactant: NN
Solvent: C1COCCO1
Solvent: O
Product: CSc1nc(NN)c(C(N)=O)c(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)c(C)c2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of the product of Example 17C (246 mg, 0.5 mmol) in 1,4-dioxane (10 mL) was added 85% hydrazine hydrate (125 mg, 2.5 mmol) dropwise. The mixture was stirred at room temperature for 3 hours, extracted with ethyl acetate and the organic layer was washed with water, dried over sodium sulfate, filtered and concentrated. The residue was washed with petroleum ether to provide the title compound. MS: 489 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:3]=1[C:4]([C:6]1[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:12]([C:18](=O)[C:19]2[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=2[CH3:26])=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])=O.[H][H]>O1CCCC1.[Pd]>[CH3:1][C:2]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:3]=1[CH2:4][C:6]1[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:12]([CH2:18][C:19]2[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=2[CH3:26])=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: Cc1ccc(C)c(C(=O)c2cc(C(=O)O)c(C(=O)c3cc(C)ccc3C)cc2C(=O)O)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1ccc(C)c(Cc2cc(C(=O)O)c(Cc3cc(C)ccc3C)cc2C(=O)O)c1
Temperature: 117 °C

Procedure:
A mixture of 92 grams of 2,5-bis(2,5-dimethybenzoyl)terephthalic acid in 1.5 L of tetrahydrofuran was treated with 9.2 grams of 10% palladium on carbon (as a catalyst) in an atmosphere of hydrogen at 270 kPa and 65° C. for 17 hours. The reaction mixture was filtered through Celite™ diatomaceous earth filter agent to remove the catalyst. The filtrate was concentrated in vacuo to give a solid. The solid was triturated with ethyl acetate, collected by filtration, and dried. To 75 grams of the solid was added 1250 grams of acetic acid, and the resulting mixture was heated to 117° C. for 30 minutes and cooled to room temperature. The resulting solid was collected by filtration and washed with acetic acid followed by heptane. The resulting residue was dried to give 2,5-bis(2,5-dimethybenzyl)terephthalic acid.
Reaction SMILES: [CH3:1][C@@:2]12[C:8]([CH3:10])([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[C:4](=O)[C:3]2=O.COP([CH2:19][C:20](=O)[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)(=O)OC.O.[NH2:31][NH2:32]>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][C:20]2[CH:19]=[C:4]3[C:3]([C@:2]4([CH3:1])[C:8]([CH3:10])([CH3:9])[C@H:5]3[CH2:6][CH2:7]4)=[N:32][N:31]=2)=[CH:23][CH:24]=1
Reactant: COP(=O)(CC(=O)Cc1ccc(Cl)cc1)OC
Reactant: NN
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2=O
Solvent: O
Product: CC1(C)[C@H]2CC[C@]1(C)c1nnc(Cc3ccc(Cl)cc3)cc12

Procedure:
light yellow oil. MS (EI): 313.2 (M+). Prepared from (1S,4R)-1,7,7-trimethyl-bicyclo[2.2.1]heptane-2,3-dione, [3-(4-Chloro-phenyl)-2-oxo-propyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[NH:52]1[CH2:57][CH2:56][CH:55]([O:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[C:65](=[O:67])[CH3:66])[CH2:54][CH2:53]1>CN(C=O)C.O>[C:65]([C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][C:59]=1[O:58][CH:55]1[CH2:56][CH2:57][N:52]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:18]2[CH:17]=[C:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:20][N:19]=2)=[O:22])[CH2:53][CH2:54]1)(=[O:67])[CH3:66]
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Reactant: CC(=O)c1ccccc1OC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1ccccc1OC1CCN(C(=O)CNC(=O)c2cc(-c3ccccc3)[nH]n2)CC1
Reaction time: 8 h
Yield: 50.9 %

Procedure:
DIPEA (232 mg, 1.8 mmol) was added to a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (144 mg, 0.6 mmol) in DMF (2 mL) followed by HOBt (97 mg, 0.7 mmol) and EDCI.HCl (137 mg, 0.7 mmol). After 2 minutes 1-[2-(piperidin-4-yloxy)-phenyl]-ethanone dihydrochloride (prepared according to Step 1 and 5 of the General Scheme) (150 mg, 0.6 mmol) was added and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate and dried over sodium sulfate. The organic layer was concentrated under reduced pressure. Purification by column chromatography (using 60-120 silica gel and 5% MeoH in CHCl3 as eluent) to afford 112 mg (50.9% Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-acetyl-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 447.2, 95.68%. 1H NMR (300 MHz, DMSO-d6): δ13.8 (s, 1H), 8.2 (bs, 1H), 7.8 (d, 2H), 7.5 (m, 4H), 7.4 (m, 1H), 7.3 (m, 1H), 7.2 (s, 1H), 7.0 (t, 1H), 4.8 (m, 1H), 4.4 (m, 2H), 3.8 (m, 1H), 3.4 (m, 1H), 3.5 (m, 2H), 2.5 (s, 3H), 2.0 (m, 2H), 1.7 (m, 2H).
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][CH:9]([C:18]1[N:19]=[CH:20][N:21](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:22]=1)[CH2:10][C:11]([O:13]C(C)(C)C)=[O:12]>ClCCl>[OH:8][CH:9]([C:18]1[N:19]=[CH:20][NH:21][CH:22]=1)[CH2:10][C:11]([OH:13])=[O:12]
Reactant: CC(C)(C)OC(=O)CC(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC(O)c1c[nH]cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3 ml of trifluoroacetic acid are added to a solution of 1.4 g (3 mmol) of tert-butyl 3-hydroxy-3-(1-trityl-1H-imidazol-4-yl)propanoate in 7 ml of dichloromethane. After stirring for 4 hours at ambient temperature, the reaction medium is concentrated. 0.5 g of crude product is used directly in the next stage.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].O>C(O)(C)C>[CH:12]1[C:8]2[CH:9]=[CH:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH:6]([OH:16])[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: O=c1c2ccccc2ccc2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: OC1c2ccccc2C=Cc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
5H-Dibenzo[a,d]cyclohepten-5-one (10 g) is dissolved in 80 ml of isopropyl alcohol and sodium borohydride (1.8 g) is added at once. The mixture is stirred at room temperature for two hr. 5 ml of water are added to quench the reaction and the solvent is evaporated. The residue is taken up in diethyl ether and washed with water, dried over MgSO4 and evaporated. 9.8 g (98% yield) of 5H-dibenzo[a,d]cyclohepten-5-ol is obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.Cl.[CH3:20][C:21]1[C:22]([CH2:28][NH2:29])=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([NH:29][CH2:28][C:22]2[C:21]([CH3:20])=[CH:26][C:25]([CH3:27])=[CH:24][N:23]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: Cc1cnc(CN)c(C)c1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Agent: Cl
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cnc(CNc2nc(N)nc(-c3ccco3)c2C#N)c(C)c1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, C-(3,5-dimethyl-pyridin-2-yl)-methylamine dihydrochloride and DBU in DME. ES-MS m/e (%): 321 (M+H+, 100).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([Cl:27])[CH:21]=3)[CH:17]=[C:16]([N:28]3[CH2:33][CH2:32][N:31]([C:34]4[C:39]([C:40]([F:43])([F:42])[F:41])=[CH:38][CH:37]=[CH:36][N:35]=4)[CH2:30][CH2:29]3)[N:15]=2)[C:10](=[O:44])[CH2:9]1)=O)(C)(C)C.Cl.O1CCO[CH2:48][CH2:47]1>>[Cl:27][C:22]1[CH:21]=[C:20]([C:18]2[CH:17]=[C:16]([N:28]3[CH2:33][CH2:32][N:31]([C:34]4[C:39]([C:40]([F:42])([F:43])[F:41])=[CH:38][CH:37]=[CH:36][N:35]=4)[CH2:30][CH2:29]3)[N:15]=[C:14]([N:11]3[CH2:12][CH2:13][N:8]([CH2:6][CH2:47][CH3:48])[CH2:9][C:10]3=[O:44])[N:19]=2)[CH:25]=[CH:24][C:23]=1[F:26]
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccc(F)c(Cl)c3)cc(N3CCN(c4ncccc4C(F)(F)F)CC3)n2)C(=O)C1
Agent: Cl
Product: CCCN1CCN(c2nc(-c3ccc(F)c(Cl)c3)cc(N3CCN(c4ncccc4C(F)(F)F)CC3)n2)C(=O)C1

Procedure:
Treat 4-{4-(3-chloro-4-fluoro-phenyl)-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidin-2-yl}-3-oxo-piperazine-1-carboxylic acid tert-butyl ester with HCl/dioxane (4M) using the procedure described in Example 1-J step 3 to afford the title piperazine-one.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([O:11][CH2:12][C:13]([OH:15])=O)=[CH:9][CH:10]=[C:5]2[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:3]1.CC(C)N=C=NC(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:41][C@H:42]([NH2:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C=O)C>[CH3:1][N:2]1[C:6]2=[N:7][C:8]([O:11][CH2:12][C:13]([NH:49][C@H:42]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH3:41])=[O:15])=[CH:9][CH:10]=[C:5]2[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:3]1
Reactant: Cn1nc(-c2ccccc2)c2ccc(OCC(=O)O)nc21
Reactant: C[C@H](N)c1ccccc1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)COc1ccc2c(-c3ccccc3)nn(C)c2n1)c1ccccc1
Reaction time: 8 h
Yield: 69.7 %

Procedure:
A solution of 2-(1-methyl-3-phenyl-1H-pyrazolo[3,4-b]pyridin-6-yloxy)acetic acid (0.14 g, 0.494 mmol), DIC (0.094 g, 0.744 mmol) and HOBt (0.087 g mg, 0.644 mmol) in DMF (4.0 ml) was stirred at rt for 15 min. (S)-(−)-α methyl benzyl amine (0.072 g, 0.594 mmol) was added to the reaction mixture at rt and stirring was continued overnight. The reaction mixture was concentrated. Diethyl ether was added and the mixture was washed with water, followed by brine and dried over Na2SO4. Concentration of the organic layer furnished the crude product as an off-white solid. The product was purified by preparative HPLC using acetonitrile/water as mobile phase to yield the title compound as a white solid (0.133 g, 68%). [1H-NMR (CDCl3, 300 MHz) δ 8.22 (d, 1H), 7.96-7.89 (m, 2H), 7.55-7.38 (m, 3H), 7.37-7.21 (m, 5H), 6.73 (d, 1H), 6.61 (d, 1H), 5.35-5.21 (m, 1H), 4.99 (s, 2H), 4.03 (s, 3H), 1.53 (d, 3H); HPLC RtA=5.273 min (98%) LCMS RtE=1.921 min; [M+H]+=387.1; Mp=55-56° C.]
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:16])=O>CCOCC.CN(C)C=O>[F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: O=C(O)c1cc(F)c(F)cc1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(F)c(F)cc1F
Reaction time: 0.5 h

Procedure:
To a solution of 5.24 g of 2,4,5-trifluorobenzoic acid in 50 ml of ether containing two drops of N,N-dimethylformamide was added, under argon, oxalyl chloride dropwise over 30 minutes. Stirring was continued for an additional 30 minutes when gas evolution ceased. The ether was removed in vacuo and the residue vacuum distilled to give 5.07 g of the desired compound, bp 26°-27° C./0.75 mm.
Reaction SMILES: [O:1]1C=CC(=O)C1=O.[CH2:8]([P:12]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:20][CH2:21][CH2:22][CH3:23])=[C:13]1[CH2:17][C:16](=[O:18])[O:15][C:14]1=[O:19])[CH2:9][CH2:10][CH3:11].[ClH:28]>O>[Cl-:28].[CH2:8]([P+:12]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:20][CH2:21][CH2:22][CH3:23])[CH:13]([C:14]([OH:1])=[O:19])[CH2:17][C:16]([OH:15])=[O:18])[CH2:9][CH2:10][CH3:11]
Reactant: O=C1C=COC1=O
Reactant: Cl
Reactant: CCCCP(CCCC)(CCCC)=C1CC(=O)OC1=O
Solvent: O
Product: CCCC[P+](CCCC)(CCCC)C(CC(=O)O)C(=O)O
Product: [Cl-]

Procedure:
The title compound was prepared and identified by the procedures in Example 12 except that the furandione reactant here used was the tri-n-butylphosphoranylidene dihydro-2,5-furandione from Example 1 and HCl was used in place of HBr. It too was a water-soluble white crystalline solid.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:15][CH2:14][N:13]([O:16][CH3:17])[CH2:12][CH2:11][N:10]1C(OC(C)(C)C)=O)=O)(C)(C)C.Cl.O1CCOCC1>C(OCC)(=O)C>[ClH:1].[CH3:17][O:16][N:13]1[CH2:14][CH2:15][NH:9][NH:10][CH2:11][CH2:12]1
Reactant: CON1CCN(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CON1CCNNCC1
Temperature: 90 °C

Procedure:
A solution of 5-methoxy-[1,2,5]triazepane-1,2-dicarboxylic acid di-tert-butyl ester in diethyl ether was treated with gaseous hydrogen chloride to generate a white precipitate. The solid was filtered, washed with diethyl ether and dried to afford 5-methoxy-[1,2,5]triazepane-1,2-dicarboxylic acid di-tert-butyl ester hydrochloride salt. To a suspension of 5-methoxy-[1,2,5]triazepane-1,2-dicarboxylic acid di-tert-butyl ester hydrochloride salt (2.5 g, 6.8 mmol) in ethyl acetate (10 ml) was added a solution of hydrogen chloride in 1,4-dioxane (4 M, 9 ml, 36.0 mmol) at room temperature dropwise. The reaction mixture was heated at 90° C. for one hour, the solvent evaporated, the residue washed with diethyl ether and dried in vacuo. Yield: 1.4 g of 5-methoxy-[1,2,5]triazepane hydrochloride salt (compound P4.2) as a yellowish solid, this material was used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[C:10]3[S:17][C:16]([C:18]4[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:25])=[N:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:3]=1.Cl.N1[CH2:30][CH:29]([OH:31])[CH2:28]1.[CH:32](NC(C)C)(C)C>C(O)C>[Cl:24][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:25])[C:18]=1[C:16]1[S:17][C:10]2[C:9]([NH:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([CH:32]4[CH2:30][CH:29]([OH:31])[CH2:28]4)[CH:3]=3)=[N:14][CH:13]=[N:12][C:11]=2[N:15]=1
Reactant: OC1CNC1
Reactant: CC(C)NC(C)C
Reactant: Clc1cc(Nc2ncnc3nc(-c4c(Cl)cccc4Cl)sc23)ncn1
Agent: Cl
Solvent: CCO
Product: OC1CC(c2cc(Nc3ncnc4nc(-c5c(Cl)cccc5Cl)sc34)ncn2)C1
Temperature: 130 °C
Yield: 51 %

Procedure:
The mixture of N-(6-chloropyrimidin-4-yl)-2-(2,6-dichlorophenyl)-thiazolo[4,5-d]pyrimidin-7-amine (45 mg, 0.11 mmol), azetidin-3-ol hydrochloride (24 mg, 0.22 mmol) and diisopropylamine (45 mg, 0.35 mmol) in ethanol (1 mL) was heated at 130° C. under microwave radiation for 30 minutes. The reaction mixture was concentrated under reduced pressure. The crude product was purified by reverse phase HPLC (Gemini-NX, 3×10 cm, gradient: 5-85% CH3CN/H2O, 0.1% formic acid/H2O, flow rate 60 mL/min, 10 min) to give the desired compound as a white solid (25 mg, 51% yield). 1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.85 (s, 1H), 8.31 (d, J=0.8 Hz, 1H), 7.78-7.71 (m, 2H), 7.67 (dd, J=9.4, 6.7 Hz, 1H), 6.54 (s, 1H), 5.79 (d, J=6.5 Hz, 1H), 4.69-4.55 (m, 1H), 4.29-4.18 (m, 2H), 3.76 (dd, J=9.4, 4.4 Hz, 2H). LCMS (Method B): RT=3.55 min, m/z: 446.2 [M+H+].
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][C:5]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([CH3:15])=[CH:9][C:6]=1[CH:7]=[O:8].Cl>O1CCCC1.O>[CH3:14][O:13][C:11]1[C:10]([CH3:15])=[CH:9][C:6]([CH:7]([OH:8])[CH3:1])=[C:5]([CH3:4])[CH:12]=1
Reactant: C[Mg]Br
Reactant: COc1cc(C)c(C=O)cc1C
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C)c(C(C)O)cc1C
Yield: 74 %

Procedure:
Methyl magnesium bromide (2.4 mL, 1.2 eq) was dropwise added at −78° C. to a solution of 2,5-dimethyl-4-methoxybenzaldehyde (1.0 g, 6.0 mmol) in 30 mL of tetrahydrofuran (THF) with stirring and the reaction mixture was allowed to react at that temperature while being stirred. After completion of the reaction, the reaction mixture was adjusted to pH 7 at 0° C. with 1N-HCl and concentrated in a vacuum. The residue thus obtained was stirred in water (20 mL) and extracted twice with 20 mL of dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtrated and concentrated in a vacuum to remove the solvent. The concentrate was purified through silica gel chromatography to yield 1-(4-methoxy-2,5-dimethylphenyl)ethanol as a white oil (0.87 g, yield 74%).
Reaction SMILES: Cl[P:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[O:3]1.[CH:16]([Mg]Br)([CH3:18])[CH3:17].[CH3:21][C:22]1C=CC=C[C:27]=1C>O1CCCC1>[CH:16]([P:2]([CH:22]([CH3:27])[CH3:21])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:5]1[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=1[OH:3])([CH3:18])[CH3:17]
Reactant: Cc1ccccc1C
Reactant: CC(C)[Mg]Br
Reactant: ClP1Oc2ccccc2-c2ccccc21
Solvent: C1CCOC1
Product: CC(C)P(c1ccccc1-c1ccccc1O)C(C)C
Temperature: 120 °C
Yield: 68 %

Procedure:
46.9 g (0.2 mol) of 6-chloro-6H-dibenz[c,e][1,2]oxaphos-phorine in 250 ml of anhydrous o-xylene at 80° C. are introduced, in an argon atmosphere with stirring, and a solution of 0.45 mol of isopropylmagnesium bromide in 300 ml of tetrahydrofuran is added dropwise. Tetrahydrofuran is distilled off and the temperature slowly increased to 120° C. in the course of this. The mixture is then stirred for 3 hours at 120° C., cooled to room temperature and 100 ml of water are added. The mixture is neutralized with concentrated sulfuric acid, heated to 80° C. and the organic phase is separated off. During cooling, 51.7 g (90%) of colorless solid having melting point 82° to 84° C. crystallizes from the aqueous phase. 100 ml of 2N sodium hydroxide solution are added to this solid and the mixture is extracted with toluene. The toluene phase is separated off, washed with water, then dried with sodium sulfate and concentrated in vacuo. 38.9 g (68%) of colorless oil are obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Na].OC1C=NC=CC=1.C1([O:21][C:22](=O)[CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])C=CC=CC=1>C(OCC)(=O)C>[CH2:28]([O:27][C:25]([NH:24][CH2:23][C:22]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:21])=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(CNC(=O)OCc1ccccc1)Oc1ccccc1
Reactant: C1CCNCC1
Agent: Oc1cccnc1
Agent: [Na]
Solvent: CCOC(C)=O
Product: O=C(NCC(=O)N1CCCCC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
8.5 g. of piperidine and 1.2 g. of the sodium salt of 3-hydroxypyridine are added to 100 ml. of ethyl acetate, and 28.5 g. of benzyloxycarbonylglycine phenyl ester is added thereto with stirring at room temperature, whereupon reaction immediately starts and is complete in 2 hours. The product is worked up as previously described to give an oil which is crystallized from acetone-water. 18.7 g. of N-(benzyloxycarbonylglycyl)-piperidine are obtained (yield: 68%). m.p. 111°-112° C. A single spot is obtained therefrom by thin layer chromatography. An additional 5.9 g. of crystals are obtained from the mother liquor, (yield: 21%). m.p. 109.5°-112° C.
Reaction SMILES: N[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:31]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:29]=[CH:28][C:7]=1[C:8]([NH:10][C:11]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:12]=1[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=1)=[O:14])=[O:9].[CH2:38]=O.[C:40]([BH3-])#[N:41].[Na+].Cl>C(Cl)Cl.CC(O)=O.CO>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:13](=[O:14])[C:12]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:11]=2[NH:10][C:8](=[O:9])[C:7]2[CH:28]=[CH:29][C:30]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:31][C:6]=2[O:5][CH2:4][CH2:3][CH2:2][N:41]([CH3:40])[CH3:38])=[N:17][CH:18]=1
Reactant: [BH3-]C#N
Reactant: C=O
Reactant: NCCCOc1cc(N2CCOCC2)ccc1C(=O)Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN(C)CCCOc1cc(N2CCOCC2)ccc1C(=O)Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1
Reaction time: 8 h
Yield: 98.9 %

Procedure:
A mixture of 2-[2-(3-aminopropoxy)-4-(morpholin-4-yl)benzoylamino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide (400 mg, 0.76 mmol), paraformaldehyde (96 mg, 3.19 mmol) and MeOH (75 mL) was adjusted to pH 5-6 with AcOH. Sodium cyanoborohydride (96 mg, 1.57 mmol) was added. After stirring overnight, the reaction was acidified with 1 N HCl (pH=2) and stirred for 2 hours. Methylene chloride was added to the mixture and it was basified with 50% satd Na2 CO3. The organic layer was dried (Na2 SO4) and concentrated to give the desired product (418 mg, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[N:19]1[C:23]([CH2:24][N:25]2C(=O)C3=CC=CC=C3C2=O)=[N:22][N:21]=[C:20]1[CH2:36][N:37]([CH3:39])[CH3:38].O.NN>C(O)C>[F:18][C:15]([F:17])([F:16])[C:13]1[CH:12]=[CH:11][C:10]2[N:19]3[C:20]([CH2:36][N:37]([CH3:39])[CH3:38])=[N:21][N:22]=[C:23]3[CH2:24][N:25]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:9]=2[CH:14]=1
Reactant: CN(C)Cc1nnc(CN2C(=O)c3ccccc3C2=O)n1-c1ccc(C(F)(F)F)cc1C(=O)c1ccccc1Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: CN(C)Cc1nnc2n1-c1ccc(C(F)(F)F)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 27, 2'-chloro-5(trifluoromethyl)-2-[3-[(dimethylamino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone is heated in ethanol with hydrazine hydrate to give 8-trifluoromethyl-1-[(dimethylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo-[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH3:1][S-:2].[Na+].CO.[CH:6]([CH:8](Cl)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[CH2:7].C(OCC)C>O1CCCC1>[CH:6]([CH:8]([S:2][CH3:1])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[CH2:7]
Reactant: C=CC(Cl)c1ccccc1
Reactant: C[S-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CC(SC)c1ccccc1
Yield: 91 %

Procedure:
Sodium methanethiolate (24.67 g, 0.35 mol) was combined with methanol (250 ml) in a 1 liter round bottomed flask outfitted with an addition funnel and a nitrogen inlet. Vinylbenzyl chloride (41.0 ml, 60:40 mixture of p- and o-isomers, 0.29 mol) in tetrahydrofuran (100 ml) was added via addition funnel over 30 minutes. The reaction mixture grew slightly warm and a milky suspension resulted. This was allowed to stir at room temperature for 20 hours at which point only a small amount of vinylbenzyl chloride was still evident by thin layer chromatography (2:1 hexanes/CH2Cl2 eluent). Another portion of sodium methanethiolate was added (5.25 g, 7.49×10−2 mol) and after ten minutes, the reaction had proceeded to completion by thin layer chromatography. Diethyl ether (400 ml) was added and the resulting mixture was extracted twice with 600 ml of water and once with 600 ml of brine. The resulting organic extracts were dried over magnesium sulfate, a small amount (about 1 mg) of 3-t-butyl-4-hydroxy-5-methyl phenyl sulfide was added, and the solvents were stripped by rotary evaporation to afford a yellowish oil. Purification by vacuum distillation through a long Vigreux column yielded 43.35 g (91%) of the pure product as a clear liquid.