Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]2[O:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15]([Br:19])[CH:16]=[C:17]([Br:18])[C:9]=3[N:8]=2)[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1.[CH3:27][NH:28][NH2:29].O1CCCC1>O>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:8][C:9]2[C:17]([Br:18])=[CH:16][C:15]([Br:19])=[CH:14][C:10]=2[C:11]([N:28]([CH3:27])[NH2:29])=[O:13])=[O:12])[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1
Reactant: CNN
Reactant: O=c1oc(-c2cc(Br)nn2-c2ncccc2Cl)nc2c(Br)cc(Br)cc12
Solvent: C1CCOC1
Solvent: O
Product: CN(N)C(=O)c1cc(Br)cc(Br)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A mixture of 1.0 g of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6,8-dibromo-4H-3,1-benzoxazine-4-one, 0.28 ml of methylhydrazine and 16 ml of tetrahydrofuran was stirred at room temperature for 19 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography to obtain 0.97 g of 3-bromo-N-[4,6-dibromo-2-(N-methylhydrazinocarbonyl)phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide of the formula:
Reaction SMILES: [O:1]([C:9]1[CH:10]([CH:18]([CH:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[C:21]2[O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH3:19])[C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[Li]CCCC.Cl[Si:43]([CH3:46])([CH3:45])[CH3:44]>C1COCC1.CCCCCC>[CH3:44][Si:43]([CH3:46])([CH3:45])[CH:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:18]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]([Si:2]([CH3:5])([CH3:4])[CH3:3])[C:21]=2[O:29][Si:30]([C:33]([CH3:35])([CH3:34])[CH3:36])([CH3:31])[CH3:32])[CH3:19])=[C:9]1[O:1][Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: CC(C1C(O[Si](C)(C)C(C)(C)C)=Cc2ccccc21)C1C(O[Si](C)(C)C(C)(C)C)=Cc2ccccc21
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C1=C(O[Si](C)(C)C(C)(C)C)C([Si](C)(C)C)c2ccccc21)C1=C(O[Si](C)(C)C(C)(C)C)C([Si](C)(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of bis(2-(tert-butyldimethylsiloxy)indenyl)ethane (10.38 g, 20.0 mmol) in THF (100 mL) at −20° C. was added dropwise n-BuLi (16.1 mL of a 2.5 M solution in hexane, 40.2 mmol) and the reaction mixture was stirred for 3 hours at room temperature. To the resulting solution was added dropwise chlorotrimethylsilane (6.85 g, 63.0 mmol, 8.0 mL) at 0° C. After completed addition the reaction mixture was stirred overnight at room temperature and the solvents were evaporated. The remaining orange solid was extracted with CH2Cl2 and filtrated through celite. The solvent was evaporated and the product was dissolved in Et2O (150 mL). Concentration and cooling to 0° C. gave 10.29 g (77.6%) of a 2:1 diastereomeric mixture of the title compound as off-white crystals. EIMS (calcd/found): m/e 662.3827/662.3834. 1H NMR (CD2Cl2, δ, major/minor diastereomer): 7.51-7.49 (m, 2H, major); 7.42-7.40 (m, 2H, minor); 7.29-7.24 (m, 4+2H, major/minor); 7.22-7.17 (m, 2H, minor); 7.08-7.02 (m, 2+2H, major/minor); 3.29 (s, 1H, minor); 3.27 (s, 1H, major); 3.00-2.96 (m, AA′, 2H, minor); 2.72-2.65 (m, AA′BB′, 4H, major); 2.44-2.40 (m, BB′, 2H, minor); 1.02 (s, 18H, major); 1.01 (s, 18H, minor); 0.20 (s, 6H, minor); 0.19 (s, 6H, major); 0.10 (s, 6H, minor); 0.05 (s, 6H, major); 0.02 (s, 18H, minor); 0.01 (s, 18H, major). 13C NMR (CD2Cl2, δ, major diastereomer): 158.32; 144.56; 139.24; 125.09; 122.74; 121.98; 119.89; 118.08; 45.08; 26.14; 24.06; 18.52; −2.39; −3.40; −4.66. 13C NMR (CDCl3, δ, minor diastereomer): 158.08; 144.50; 139.14; 124.97; 122.62; 121.95; 119.95; 118.50; 45.13; 26.14; 23.86; 18.47; −2.29; −3.40; −4.24.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([CH3:34])[C:23](=[O:33])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:16]=3)=[CH:11][CH:10]=2)[S:3]1>O1CCOCC1>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([CH3:34])[C:23](=[O:33])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:16]=3)=[CH:11][CH:10]=2)[S:3]1
Reactant: CCCCCCCCCC(=O)N(C)Cc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1
Solvent: C1COCCO1
Product: CCCCCCCCCC(=O)N(C)Cc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1
Yield: 62.4 %

Procedure:
In a manner similar to that of Example 1(g), starting with 460 mg (1 mmol) of N-[4′-(2,4-dioxothiazolidin-5-ylidenemethyl)biphenyl-3-ylmethyl]-N-methyldecanamide in 8 ml of dioxane, 300 mg (65%) of the desired product are obtained in the form of a film.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.Br[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>CN(C=O)C>[CH:8]([C:7]1[CH:10]=[CH:11][C:4]([O:3][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:5][CH:6]=1)=[O:9]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc(C=O)cc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 89.5 %

Procedure:
A suspension of NaH (60% in mineral oil, 3.69 g, 92.2 mmol) in dry DMF (70 ml) was cooled to 0° C. A solution of 4-hydroxybenzaldehyde (10.0 g, 82.0 mmol) in dry DMF (35 ml) was added dropwise. The mixture was stirred at 0° C. for 40 minutes. tert-Butyl bromoacetate (12.1 ml, 82.5 mmol) was added and the mixture was stirred at room temperature for 17 h. The mixture was concentrated under reduced pressure. Diethyl ether was added and the mixture was washed with 10% NH4Cl, water and brine. The organic phase was dried (MgSO4), concentrated under reduced pressure and purified by flash-chromatography (10%-20% EtOAc in hexane). This gave tert-butyl (4-formylphenoxy)acetate (17.4 g, 73.4 mmol, 90% yield) as an colourless oil. This intermediate was dissolved in dry toluene (120 ml) and 4-chloroaniline (9.37 g, 73.4 mmol) was added. The mixture was refluxed in a Dean-Stark apparatus for 20 h, cooled and concentrated under reduced pressure. Hexane was added and the formed precipitate was filtered, washed twice with cold hexane and dried. This afforded 20.0 g (79%) of the title compound as a yellow solid. 1H-NMR (CDCl3, 200 MHz): δ 1.5 (s, 9H), 4.6 (s, 2H), 7.0 (d, 2H), 7.2 (d, 2H), 7.4 (d, 2H), 7.8 (d, 2H), 8.4 (s, 1H). MS (CI) M/z: 368.0 (M++Na, 100), 369.0 (20), 370.0 (30), 371.0 (10).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=O.[CH:13]([NH2:16])([CH3:15])[CH3:14]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH:13]([NH:16][CH:7]1[C:8]2[C:4](=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][CH:9]=2)[CH2:5][CH2:6]1)([CH3:15])[CH3:14]
Reactant: CC(C)N
Reactant: COc1cccc2c1CCC2=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cccc2c1CCC2NC(C)C
Reaction time: 3 h

Procedure:
To a solution of 4-methoxy-1-indanone (0.71 g) and iso-propylamine (8 ml) in dichloromethane (10 ml) was added 1M solution of titanium(IV) chloride in dichloromethane (11 ml) at −60° C. for 15 minutes. The reaction mixture was stirred for 3 hours at the same temperature. Methanol (15 ml) wash added to the reaction mixture. After being stirred for 2 hours at room temperature, the solution was evaporated in vacuo. The residue was partitioned between ethyl acetate and 1N aqueous NaOH solution. The insoluble material was filtered off by zeolite. The organic layer was washed with brine. The dried solvent was evaporated in vacuo to give 1-isopropylamino-2,3-dihydro-4-methoxy-1H-indene (0.89 g).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15](=[O:50])/[C:16](/[N:21]2[CH:24]([S:25]S(C3C=CC([N+]([O-])=O)=CC=3)(=O)=O)[CH:23]([NH:38][C:39](=[O:48])[CH2:40][O:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:22]2=[O:49])=[C:17](\[O:19][CH3:20])/[CH3:18])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)/C=C\C.N12CCCCC1C=NCCC2>O1CCCC1.C1C=CC=CC=1>[C:8]1([CH:7]([O:14][C:15]([CH:16]2[N:21]3[C:22](=[O:49])[C@@H:23]([NH:38][C:39](=[O:48])[CH2:40][O:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[C@H:24]3[S:25][CH:18]=[C:17]2[O:19][CH3:20])=[O:50])[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CO/C(C)=C(\C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: C/C=C\C(=O)O
Agent: C1=NCCCN2CCCCC12
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: COC1=CS[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1

Procedure:
A solution of 367 mg (0.5 mM) of a mixture consisting of 2-[4-(p-nitrobenzenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-crotonic acid diphenylmethyl ester and the corresponding isocrotonic acid dihenylmethyl ester, and 152 mg (1.0 mM) of 1,5-diazabicyclo[5.4.0]undec- 5-ene in 10 ml of dry tetrahydrofurane is stirred for 40 minutes at room temperature. The reaction mixture is diluted with benzene, washed successively with dilute hydrochloric acid, water and dilute aqueous sodium bicarbonate solution, dried over sodium sulphate and freed from the solvent in vacuo. The residue is chromatographed on acid-washed silica gel, using toluene/ethyl acetate, 7:1, as the running agent, whereby pure 7β-phenoxyacetamido-3-methoxy-ceph-2-em-4-carboxylic acid diphenylmethyl ester is obtained. Subsequent elution with toluene/ethyl acetate, 2:1, results in the isolation of a mixture which in addition to 7β-phenoxyacetamido-3-methoxy-ceph-2-em-4-carboxylic acid diphenylmethyl ester also contains 7βphenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester.
Reaction SMILES: FC1C=C(C2N=C(SC)N=C(N3CCOC[C@@H]3C)C=2)C=NC=1.Cl[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]2[CH3:36])[N:25]=1.[CH2:37]([NH:39][C:40](=[O:57])[NH:41][C:42]1[CH:47]=[CH:46][C:45](B2OC(C)(C)C(C)(C)O2)=[CH:44][CH:43]=1)[CH3:38]>>[CH2:37]([NH:39][C:40]([NH:41][C:42]1[CH:47]=[CH:46][C:45]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]3[CH3:36])[N:25]=2)=[CH:44][CH:43]=1)=[O:57])[CH3:38]
Reactant: CCNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: C[C@H]1COCCN1c1nccc(Cl)n1
Agent: CSc1nc(-c2cncc(F)c2)cc(N2CCOC[C@@H]2C)n1
Product: CCNC(=O)Nc1ccc(-c2ccnc(N3CCOC[C@@H]3C)n2)cc1

Procedure:
Method as described for intermediate 5 using (S)-4-(4-chloropyrimidin-2-yl)-3-methylmorpholine (intermediate 15) and 4-(3-ethylureido)phenyl boronic acid pinacol ester. Material was purified by prep HPLC (low pH) to afford a brown solid, (77 mg, 40%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10]([C@H:12]1[C@H:17]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:16][C:15](=O)[N:14]([CH3:26])[C:13]1=O)=O)C.C1(C)C=CC=CC=1.[OH-].[Na+]>C1(C)C=CC=CC=1.C1COCC1.C1COCC1.O>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C@@H:17]2[CH2:16][CH2:15][N:14]([CH3:26])[CH2:13][C@H:12]2[CH2:10][OH:9])=[CH:19][CH:20]=1
Reactant: CCOC(=O)[C@@H]1C(=O)N(C)C(=O)C[C@H]1c1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CN1CC[C@@H](c2ccc(F)cc2)[C@H](CO)C1
Temperature: 25 °C

Procedure:
To a cooled solution of LiAlH4 (0.22 mol) in toluene/THF under argon was added (+/−) trans-3-ethoxycarbonyl-4-(4′-fluorophenyl)-N-methyl-piperidine-2,6-dione (0.083 mol) in THF holding the temperature below 15° C. After addition was complete, the reaction was allowed to warm to room temperature. After 30 minutes at room temperature reaction was heated to >40° C. for 2 hr. Reaction was then cooled to <5° C. and toluene (50 ml) was added. Water (9 ml) was then added slowly holding the temperature below 15° C. Additional H2O or aqueous NaOH was used as necessary. The solid inorganic salts were removed by filtration. These solids were washed with additional THF or toluene. The filtered solution was then concentrated to give (+/−) trans-4-(4′-fluorophenyl)-3-hydroxymethyl-N-methylpiperidine in higher yield (but similar impurity profile) as with NaAlH4 as shown by HPLC analysis. The product can be recovered by standard procedures such as trituration with a less polar solvent.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[O:28][C:29]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([F:39])[CH:30]=1)[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15][N:11]2[C:12](=[O:14])[N:13]=1)#[N:2]>CN(C=O)C>[F:39][C:31]1[CH:30]=[C:29]([CH:34]=[C:33]([C:35]([F:36])([F:38])[F:37])[CH:32]=1)[O:28][C:27]1[CH:26]=[CH:25][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]3[NH:17][CH2:16][CH2:15][N:11]3[C:12](=[O:14])[N:13]=2)=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1ccc(Oc3cc(F)cc(C(F)(F)F)c3)c(C#N)c1)nc2=O
Solvent: CN(C)C=O
Product: N#Cc1cc(COc2cc3n(c(=O)n2)CCN3)ccc1Oc1cc(F)cc(C(F)(F)F)c1

Procedure:
Prepared in a manner similar to that described for E71 using tert-butyl 7-((3-cyano-4-(3-fluoro-5-(trifluoromethyl)phenoxy)benzyl)oxy)-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimi-dine-1 (5H)-carboxylate (50 mg, 0.091 mmol) in DMF (2 mL) and silica gel.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([S:19]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)(=[O:21])=[O:20])[CH2:15][CH2:14]2)=[CH:8][CH:7]=1)=O.[OH-].[Li+]>CO.O>[N:22]1([S:19]([N:16]2[CH2:15][CH2:14][CH:13]([CH2:12][C:9]3[CH:10]=[CH:11][C:6]([NH2:5])=[CH:7][CH:8]=3)[CH2:18][CH2:17]2)(=[O:21])=[O:20])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: O=C(Nc1ccc(CC2CCN(S(=O)(=O)N3CCCCC3)CC2)cc1)C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Nc1ccc(CC2CCN(S(=O)(=O)N3CCCCC3)CC2)cc1
Temperature: 60 °C
Yield: 80.1 %

Procedure:
A mixture of 2,2,2-trifluoro-N-[4-(1-piperidinesulfonylpiperidin-4-ylmethyl)-phenyl]acetamide (0.48 g, 1.11 mmol) and lithium hydroxide (0.23 g, 5.54 mmol) in methanol (10 mL) and water (1 mL) was heated at 60° C. for about 2 hours. The reaction mixture was concentrated in vacuo, diluted with water, and extracted with dichloromethane. The organic extracts were washed with water and brine, and dried (Na2SO4). The residue was crystallized from ethyl acetate/hexanes, to give 4-(1-piperidinesulfonylpiperidin-4-ylmethyl)-phenylamine (0.30 g) as a white solid, m.p. 144–145° C.; Analysis for C17H27N3O2S: Calc.: C, 60.50; H, 8.06; N, 12.45; Found: C, 60.76; H, 8.07; N, 12.56.
Reaction SMILES: [Br:1]Br.N[C:4]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]([CH3:11])[CH:5]=1.N([O-])=O.[Na+]>Br.O>[Br:1][C:4]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]([CH3:11])[CH:5]=1
Reactant: Cc1cc(N)cc(C)n1
Reactant: BrBr
Agent: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(Br)cc(C)n1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
Bromine (4 g) is added, with stirring over 10 minutes, to a mixture of 4-amino-2,6-lutidine (22, 1 g, approximately 6.5 mmol) in 48% HBr (12 ml) at −10° C., followed by cooling to −20° C. A solution of sodium nitrite (1.4 g) in water (4 ml) is added slowly. The mixture is stirred at −20° C. for 1 hour, and then warmed and left at room temperature for 3 hours. The mixture is distilled. The oil fraction of the distillate is extracted with chloroform (3×10 ml). The combined extracts are dried over magnesium sulfate. After filtration, the filtrate is neutralized in an ice-bath using 2M butyl lithium in hexanes until the pH reaches 7. A large amount of salt forms. After filtration, the filtrate is concentrated and dried, yielding 4-bromo-2,6-lutidine (23) oil. 1H NMR (300 MHz, CDCl3) δ 2.82 (s, 6H), 7.5 (s, 2H). MS, m/z 186 and 188 (M+1).
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2O)[CH:3]=[CH:2]1.P(Cl)(Cl)([Cl:13])=O.[OH-].[Na+]>C(OCC)(=O)C>[Cl:13][C:8]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:3]=[CH:2][S:1][C:9]=12
Reactant: Oc1ccnc2ccsc12
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Clc1ccnc2ccsc12
Temperature: 105 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
A mixture of thieno[3,2-b]pyridin-7-ol (3.8 g, 25 mmol) and phosphorus oxychloride (18 g, 120 mmol) was stirred at 105° C. for 2 hr. The reaction mixture was added to ice water, and basified with 8N aqueous sodium hydroxide solution. Ethyl acetate was added, the insoluble material was filtered off, and the filtrate was extracted with ethyl acetate. The collected organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→30/70), and the obtained solution was concentrated under reduced pressure to give the title compound (2.8 g, 66%) as a pale-yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:18][C:6]2=[C:7]([C:13]3[CH:17]=[CH:16][NH:15][N:14]=3)[S:8][C:9](S(C)=O)=[C:5]2[C:4](=[O:19])[CH2:3]1.[CH3:21][O-:22].[Na+]>CO>[CH3:1][C:2]1([CH3:20])[CH2:18][C:6]2=[C:7]([C:13]3[CH:17]=[CH:16][NH:15][N:14]=3)[S:8][C:9]([O:22][CH3:21])=[C:5]2[C:4](=[O:19])[CH2:3]1
Reactant: CS(=O)c1sc(-c2cc[nH]n2)c2c1C(=O)CC(C)(C)C2
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1sc(-c2cc[nH]n2)c2c1C(=O)CC(C)(C)C2
Temperature: 70 °C
Yield: 15 %

Procedure:
To a stirred solution of 6,6-dimethyl-3-methanesulphinyl-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (80 mg, 0.26 mmol) in methanol (3 mL) was added a solution of sodium methoxide in methanol (1.0 mL of a 0.5M solution, 0.5 mmol). The solution was heated at 70° C. for 24 h. after which time the mixture was cooled to room temperature and partitioned between EtOAc (2×20 mL) and water (20 mL). The combined organic layers were dried (Na2SO4) and evaporated. The residue was chromatographed on silica gel, eluting with CH2Cl2:MeOH (95:5), to give the title compound (11 mg, 15%) as a pale yellow solid. mp 202-204° C. Found: C, 60.24; H, 5.66; N, 10.06%. C14H16N2O2S.0.1 (H2O) requires: C, 60.45; H, 5.87; N, 10.07%. 1HNMR (360 MHz, d6-DMSO)δ 0.98 (6H, s), 2.27 (2H, s), 2.79 (2H, s), 4.03 (3H, s), 6.54 (1H, br s), 7.81 (1H, br s), 12.92 (1H, br s). MS (ES+) 277 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([C:21]=1[CH3:22])[C:7]([C:9]1[C:14]([CH3:15])=[CH:13][C:12]([O:16][CH3:17])=[C:11]([OH:18])[C:10]=1[O:19][CH3:20])=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH2:31](OS(OCC)(=O)=O)[CH3:32].C(#N)C>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([C:21]=1[CH3:22])[C:7]([C:9]1[C:14]([CH3:15])=[CH:13][C:12]([O:16][CH3:17])=[C:11]([O:18][CH2:31][CH3:32])[C:10]=1[O:19][CH3:20])=[O:8]
Reactant: CCOS(=O)(=O)OCC
Reactant: COc1cc(C)c(C(=O)c2c(OC)ccc(Cl)c2C)c(OC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOc1c(OC)cc(C)c(C(=O)c2c(OC)ccc(Cl)c2C)c1OC

Procedure:
A mixture of 66B (1.15 g), potassium carbonate (1.0 g), diethylsulfate (0.54 g) and acetonitrile (20 ml) is heated to reflux for 3 hours. Upon cooling to room temperature water is added. The solid material is collected and the residue is re-crystallized from methanol yielding white crystals, 1.07 g (85.6% ), mp 131-132° C.
Reaction SMILES: [NH2:1][C:2]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH2:7][C:8]#[N:9])=[O:5].[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([Cl:23])=[CH:18][N:17]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[Cl-].[NH4+]>>[C:8]([CH2:7][NH:6][C:4](=[O:5])[C:3]1[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:2]=1[NH:1][C:18]1[C:19]([Cl:23])=[CH:20][N:21]=[C:16]([Cl:15])[N:17]=1)#[N:9]
Reactant: Cc1cccc(C(=O)NCC#N)c1N
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(C(=O)NCC#N)c1Nc1nc(Cl)ncc1Cl
Temperature: 85 °C
Reaction time: 8 h
Yield: 13.5 %

Procedure:
2-Amino-N-cyanomethyl-3-methyl-benzamide (0.624 g, 0.00330 mol), 2,4,5-Trichloro-pyrimidine (0.605 g, 0.00330 mol) and Potassium carbonate (0.456 g, 0.00330 mol) were dissolved in N,N-Dimethylformamide (10.00 mL, 0.1291 mol) and the reaction was heated at 85° C. and was allowed to stir overnight. The reaction mixture was poured over saturated ammonium chloride, and organics were extracted with ethyl acetate/dichloromethane. Combined organics were dried over sodium sulfate, filtered and reduced en vacuo. The crude mixture was purified by Isco flash column chromatography (Hexane/Ethyl Acetate). Combined fractions were reduced en vacuo to afford 150 mg (14%) of N-Cyanomethyl-2-(2,5-dichloro-pyrimidin-4-ylamino)-3-methyl-benzamide. LC/MS (ESI): 336.07.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1.[NH2:16][C@@H:17]([CH2:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[F:38])[CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29].FC1C=CC=C(F)C=1C[C@@H](C(O)=O)N.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[F:38][C:32]1[CH:33]=[CH:34][C:35]([F:37])=[CH:36][C:31]=1[CH2:30][C@H:17]([NH:16][C:7]([C:5]1[S:6][C:2]([CH3:1])=[C:3]([C:10]2[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=2)[CH:4]=1)=[O:9])[CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29]
Reactant: Cc1sc(C(=O)O)cc1-c1ccnn1C
Reactant: N[C@@H](Cc1cc(F)ccc1F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: N[C@@H](Cc1c(F)cccc1F)C(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1sc(C(=O)N[C@@H](Cc2cc(F)ccc2F)CN2C(=O)c3ccccc3C2=O)cc1-c1ccnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
To a 50 mL round-bottomed flask was added 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (171 mg, 0.77 mmol) [prepared according to the procedure of Example 151], 2-[(2S)-2-amino-3-(2,5-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (270 mg, 0.77 mmol) [prepared according to the procedure of Preparation 18 except substituting 2,5-difluoro-L-phenylalanine (3.02 g, 15.0 mmol) for 2,6-difluoro-L-phenylalanine] and PyBrop (436 mg, 0.93 mmol) in chloroform (7.5 mL). DIEA (680 μL, 3.89 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (246 mg, 0.44 mmol, 52%): LC-MS (ES) m/z=521 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:22][CH2:21][C:12]2=[C:13](Cl)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH2:32]1[CH2:38][O:37][CH2:36][CH2:35][NH:34][CH2:33]1.Cl.O>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:22][CH2:21][C:12]2=[C:13]([N:34]3[CH2:33][CH2:32][CH2:38][O:37][CH2:36][CH2:35]3)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CNCCOC1
Reactant: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(Cl)c2CC1
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(N3CCCOCC3)c2CC1
Temperature: 80 °C

Procedure:
To 0.1 g (0.31 mmol) 10-chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester, in a sealed tube in 4 mL ethanol, was added 0.2 mL (1.12 mmol) DIPEA followed by 47 mg (0.34 mmol) homomorpholine hydrochloride, and the reaction was heated at 80° C. for 16 hours. 5 mL of H2O was added and the mixture was extracted with EtOAc (2×10 mL), the organic layers were combined and dried with MgSO4. After filtration and evaporation of the solvent the product was purified by column chromatography (silica, hexane/EtOAc 10:0 to 6:4).