Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH:15][C:16](=[O:32])[CH2:17][CH2:18][C:19]#[C:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]([F:31])([F:30])[F:29])[CH:22]=3)[CH:13]=2)[CH:8]=[CH:7]1)C.[H-].[Na+].CI.[C:38](OCC)(=O)C>O1CCCC1>[CH3:38][N:15]([C:16](=[O:32])[CH2:17][CH2:18][C:19]#[C:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]([F:30])([F:29])[F:31])[CH:22]=1)[C:12]1[CH:13]=[C:14]2[C:9]([CH:8]=[CH:7][N:6]2[CH2:5][C:4]([OH:3])=[O:33])=[CH:10][CH:11]=1
Reactant: CCOC(=O)Cn1ccc2ccc(NC(=O)CCC#Cc3cccc(OC(F)(F)F)c3)cc21
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CN(C(=O)CCC#Cc1cccc(OC(F)(F)F)c1)c1ccc2ccn(CC(=O)O)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
{6-[5-(3-Trifluoromethoxy-phenyl)-pent-4-ynoylamino]-indol-1-yl}-acetic acid ethyl ester (50 mg, 0.11 mmol) was added to a suspension of sodium hydride (9 mg, 0.22 mmol) in tetrahydrofuran (1.5 ml) at 0° C. The mixture was stirred for 30 min at 0° C., methyl iodide (30 μl, 0.44 mmol) was added and stirring was continued for 14 h at ambient temperature. The suspension was cooled to 0° C., sodium hydride (13 mg, 0.33 mmol) and methyl iodide (45 μl, 0.66 mmol) were added and the mixture was stirred for 4 h at ambient temperature. Ethyl acetate was added, the solution was successively washed with brine, 1 N HCl/ice water 1/1 and brine and dried over sodium sulfate. The solvent was removed under reduced pressure to give 42 mg (0.09 mmol, 82%) of the title compound as yellow solid.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[CH3:22][O:23][C:24]1[C:29]([O:30][CH3:31])=[CH:28][C:27]([CH:32]([C:34]2[CH:39]=[C:38]([O:40][CH3:41])[C:37]([O:42][CH3:43])=[C:36]([O:44][CH3:45])[CH:35]=2)[OH:33])=[C:26]([N+:46]([O-:48])=[O:47])[CH:25]=1.C(Cl)Cl>CCOCC>[CH3:22][O:23][C:24]1[C:29]([O:30][CH3:31])=[CH:28][C:27]([C:32]([C:34]2[CH:35]=[C:36]([O:44][CH3:45])[C:37]([O:42][CH3:43])=[C:38]([O:40][CH3:41])[CH:39]=2)=[O:33])=[C:26]([N+:46]([O-:48])=[O:47])[CH:25]=1
Reactant: COc1cc(C(O)c2cc(OC)c(OC)c(OC)c2)c([N+](=O)[O-])cc1OC
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: COc1cc(C(=O)c2cc(OC)c(OC)c(OC)c2)c([N+](=O)[O-])cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 38 %

Procedure:
Powdered 4 Å molecular sieves (583 mg) and pyridinium dichromate (2.17 g, 5.77 mmol) were successively added to a stirred solution of intermediate 241 (1.46 g, 3.84 mmol) in of anhydrous DCM (38.5 mL) at 0° C. The mixture was stirred at rt for 15 h. More PDC (290 mg, 0.770 mmol) was added and the mixture was stirred for another 4 h, The diluted with ether and filtered through a celite pad. The filtrate was concentrated and the brown solid was purified by flash chromatography using EtOAc/DCM (7:93) affording the title compound 242 (551 mg, 41%) as a yellow solid. 1H NMR (CDCl3) δ (ppm): 7.72 (s, 1H), 6.99 (s, 2H), 6.86 (s, 1H), 4.06 (s, 3H), 4.00 (s, 3H), 3.93 (s, 3H), 3.84 (s, 6H). m/z: 378.4 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[S:7](=[O:9])(=[O:8])[CH:6]2[CH2:10][CH2:11][O:12][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:14]=3[C:5]2([CH3:22])[N:4]=[C:3]1[NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27]>CCOC(C)=O.CCO.[Pd]>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]2[O:12][CH2:11][CH2:10][CH:6]3[S:7](=[O:8])(=[O:9])[C:2]([CH3:31])([CH3:1])[C:3]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[N:4][C:5]3([CH3:22])[C:14]=2[CH:15]=1
Reactant: CC(C)(C)OC(=O)NC1=NC2(C)c3cc([N+](=O)[O-])ccc3OCCC2S(=O)(=O)C1(C)C
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1=NC2(C)c3cc(N)ccc3OCCC2S(=O)(=O)C1(C)C
Yield: 74.7 %

Procedure:
A solution of tert-butyl ((4aRS,11bRS)-3,3,11b-trimethyl-10-nitro-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate (100 mg, 0.221 mmol) in EtOAc (2 ml) and EtOH (2 ml) was hydrogenated under hydrogen balloon in the presence of palladium, 10% wt. on activated carbon (50 mg, 0.047 mmol) for 30 min. The mixture was filtered through the plug of Celite, filter cake was washed with ethyl acetate. The combined filtrate was concentrated ton afford crude tert-butyl ((4aRS,11bRS)-10-amino-3,3,11b-trimethyl-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate (70 mg, 0.165 mmol, 75.0% yield) which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.ClC1N=CN=C(C(NC2C=CC(O)=CC=2)=O)C=1.[C:28]([O:32][C:33](=[O:43])[NH:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=1)([CH3:31])([CH3:30])[CH3:29].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:42][C:39]2[CH:40]=[CH:41][C:36]([CH2:35][NH:34][C:33](=[O:43])[O:32][C:28]([CH3:30])([CH3:31])[CH3:29])=[CH:37][CH:38]=2)=[O:9])[CH:3]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Reactant: O=C(Cl)c1cc(Cl)ncn1
Agent: O=C(Nc1ccc(O)cc1)c1cc(Cl)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1ccc(NC(=O)c2cc(Cl)ncn2)cc1

Procedure:
To a cooled (0° C.) solution of 6-chloropyrimidine-4-carbonyl chloride in DCM (30 mL), obtained as described above for Intermediate 7, step 1 (1.43 g; 8.10 mmol) was added dropwise, during a period of 15 minutes, a solution of (4-amino-benzyl)-carbamic acid tert-butyl ester (Astatech, 1.50 g; 6.75 mmol) and DIEA (2.33 ml; 13.5 mmol) in DCM (5 mL). At the end of addition the reaction mixture was concentrated in vacuo, diluted with water and extracted with EtOAc. The resulting precipitate was filtered and dried under vacuum. The mother liquors were dried on MgSO4, concentrated under vacuum to give a residue, which was precipitated from cyclohexane. The two solids were combined to give the title compound as a brown solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:24][C:23]3[C:18](=[N:19][CH:20]=[C:21]([C:39]#[N:40])[C:22]=3[NH:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:28][CH:27]=3)[CH:17]=2)=[CH:12][CH:11]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CN(C)C=O.C(O)(=O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[S:24][C:23]4[C:18](=[N:19][CH:20]=[C:21]([C:39]#[N:40])[C:22]=4[NH:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)=[CH:28][CH:27]=4)[CH:17]=3)=[CH:14][CH:15]=2)[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: N#Cc1cnc2cc(-c3ccc(C=O)cc3)sc2c1Nc1ccc(Oc2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CN1CCN(Cc2ccc(-c3cc4ncc(C#N)c(Nc5ccc(Oc6ccccc6)cc5)c4s3)cc2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 57.7 %

Procedure:
1-Methylpiperazine (65 μL, 0.59 mmol) is added to a suspension of 2-(4-formylphenyl)-7-[(4-phenoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile (200 mg, 0.45 mmol) in 4 mL of dichloromethane and 1 mL of N,N-dimethylformamide. The reaction mixture is cooled to 0° C. and sodium triacetoxyborohydride (474 mg, 2.24 mmol) is added. After stirring at 0° C. for 10 minutes, 3 drops of acetic acid are added and the reaction mixture is allowed to warm to room temperature and stirred for 4 hours. The reaction is quenched by the addition of water and then partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic layer is washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 5% methanol in dichloromethane to provide 138 mg of 2-[4-(4-methylpiperazin-1-ylmethyl)phenyl]-7-[(4-phenoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile as white crystals, mp 199-201° C.; 1H NMR (DMSO-d6) δ 2.17 (s, 3H), 2.37 (br s, 8H), 3.50 (s, 2H), 7.05-7.18 (m, 5H), 7.35-7.44 (m, 6H), 7.66 (d, J=8 Hz, 2H), 7.86 (s, 1H), 8.59 (s, 1H), 9.58 (s, 1H); MS 532.3 (M+H)+.
Reaction SMILES: [CH3:1][Si:2]([CH3:51])([CH3:50])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][C:23]([F:27])=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH:28]([NH:30][C:31]([C:33]2([CH3:41])[CH2:38][O:37][C:36]([CH3:40])([CH3:39])[O:35][CH2:34]2)=[O:32])[CH3:29])[CH:9]=1.[Br:52]N1C(=O)CCC1=O>C(O)(=O)C>[CH3:51][Si:2]([CH3:1])([CH3:50])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:47])([CH3:48])[CH3:49])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][C:23]([F:27])=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH:28]([NH:30][C:31]([C:33]2([CH3:41])[CH2:38][O:37][C:36]([CH3:40])([CH3:39])[O:35][CH2:34]2)=[O:32])[CH3:29])[C:9]=1[Br:52]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(NC(=O)C1(C)COC(C)(C)OC1)c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n2ncc(-c3cnc4ccc(F)cc4c3)c2n1
Solvent: CC(=O)O
Product: CC(NC(=O)C1(C)COC(C)(C)OC1)c1nc2c(-c3cnc4ccc(F)cc4c3)cnn2c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c1Br
Reaction time: 0.17 h

Procedure:
N-{1-[7-(bis{[2-(trimethylsilyl)ethoxy]methyl}amino)-3-(6-fluoroquinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl]ethyl}-2,2,5-trimethyl-1,3-dioxane-5-carboxamide (370 mg, 0.501 mmol) was dissolved in acetic acid (13 mL). and N-bromosuccinimide (104 mg, 0.585 mmol) was added in a single portion, and the reaction was stirred for 10 min before being quenched with 20% aq. Na2S2O3 (20 mL) and saturated aq. NaHCO3 (60 mL) and EtOAc (50 mL). Solid NaHCO3 was added until the pH was above 5. The layers were separated, and the aqueous was extracted with EtOAc (2×50 mL). The combined organics were washed with brine (50 mL), dried with MgSO4, filtered, and concentrated in vacuo to give N-{1-[7-(bis{[2-(trimethylsilyl)ethoxy]methyl}amino)-6-bromo-3-(6-fluoroquinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl]ethyl}-2,2,5-trimethyl-1,3-dioxane-5-carboxamide, which was used without further purification.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:29])[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:27]=[CH:26][C:13]([O:14][CH:15]3[CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]3)=[CH:12][C:11]=2[CH3:28])[CH2:5][CH2:4]1.C(O)(C(F)(F)F)=O.O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[NH:17]1[CH2:18][CH:15]([O:14][C:13]2[CH:26]=[CH:27][C:10]([CH2:9][N:6]3[CH2:7][CH2:8][C:3]([CH2:2][OH:1])([CH3:29])[CH2:4][CH2:5]3)=[C:11]([CH3:28])[CH:12]=2)[CH2:16]1
Reactant: Cc1cc(OC2CN(C(=O)OC(C)(C)C)C2)ccc1CN1CCC(C)(CO)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(OC2CNC2)ccc1CN1CCC(C)(CO)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.8 %

Procedure:
To a solution of 69B (3.10 g, 7.66 mmol) in DCM (100 mL) was added TFA (30 mL) and the reaction mixture was stirred at RT for 2 h. The mixture was transferred to a reparatory funnel and water was added. The aqueous phase was carefully basified with Na2CO3. The organic layer was separated and the basic aqueous layer was extracted ten times with. The combined organic layers were filtered through a phase separator and the solvent was removed by evaporation. The residue was dissolved in a mixture of THF (30 mL) and an aqueous solution of NaOH (1M, 40 mL). The mixture was stirred at RT for 4 h and then the solution was concentrated using a rotavapor. The aqueous residue was extracted several times with DCM. The aqueous layer was diluted with a saturated solution of NaHCO3 and the mixture was further extracted with DCM. The combined organic layers were filtered through a phase separator and the solvent was removed by evaporation. There was obtained 1.65 g (71%) of 69C as an oil. 1H NMR (500 MHz, CDCl3): δ 0.95 (s, 3H), 1.32 (m, 2H), 1.54 (m, 2H), 2.32 (m, 2H), 2.54 (m, 2H), 3.38 (s, 2H), 3.42 (s, 2H), 3.83 (m, 2H), 3.95 (m, 2H), 4.97 (m, 1H), 6.50 (dd, 1H), 6.57 (s, 1H), 7.16 (d, 1H), MS (APCI+) m/z 305 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][CH:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=4)[CH2:16][NH:15][CH2:14]3)[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:30]([O:34][C:35]([NH:37][C:38]([CH3:43])([C:40](O)=[O:41])[CH3:39])=[O:36])([CH3:33])([CH3:32])[CH3:31]>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][CH:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:27])[F:28])=[CH:21][CH:20]=4)[CH2:16][N:15]([C:40](=[O:41])[C:38]([NH:37][C:35](=[O:36])[O:34][C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:43])[CH3:39])[CH2:14]3)[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: Fc1cccc(-c2noc(C3CNCC(c4ccc(OC(F)(F)F)cc4)C3)n2)c1
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3cccc(F)c3)no2)C1

Procedure:
150 mg (0.30 mmol) of the compound from Example 178A and 66 mg (0.32 mmol) of N-(tert-butoxycarbonyl)-2-methylalanine were reacted according to the General Method 7. Yield: 117 mg (64% of theory)
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.P(Cl)(Cl)(Cl)=O.C(N(CC)CC)C.[CH:18]1([C:24]2[N:32]3[C:27](C=NC=N3)=[C:26]([I:33])[N:25]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(#N)C>[CH:18]1([C:24]2[N:32]3[C:27]([C:5]([NH2:1])=[N:4][CH:3]=[N:2]3)=[C:26]([I:33])[N:25]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: c1nc[nH]n1
Reactant: Ic1nc(C2CCCCC2)n2ncncc12
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Nc1ncnn2c(C3CCCCC3)nc(I)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 1H-1,2,4-triazole (1 g, 0.02 mol) in acetonitrile (23 mL) was added dropwise phosphoryl chloride (0.6 mL, 0.007 mol) and triethylamine (3 mL, 0.02 mol) at 0° C. To this mixture was added 7-cyclohexyl-5-iodoimidazo[5,1-f][1,2,4]triazin-4(3H-one (77 mg, 0.224 mmol) and the resulting mixture refluxed overnight. The cooled mixture was then quenched with excess NH3 in iPrOH (pH 8) stirred at rt for 30 min. then filtered and the isolated solid washed with DCM. The filtrate was concentrated in vacuo and purified by chromatography over silica gel eluting with 2% MeOH in DCM to afford the 7-cyclohexyl-5-iodoimidazo[5,1-f][1,2,4]triazin-4-amine. 1H NMR (400 MHz-DMSO-d6) δ 1.14-1.91 (m, 10H), 3.11-3.18 (m, 1H), 6.75 (br.s, 1H), 7.84 (s, 1H) 8.42 (bs, 1H); MS (ES+): m/z: 344.01 (100) [MH+]. HPLC: tR=3.10 min (OpenLynx: polar—5 min).
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[C:3]#[CH:4].CCCCCC.C([Li])CCC.[CH:18]([CH:20]=[CH2:21])=[O:19]>O1CCCC1>[OH:19][CH:18]([C:4]#[C:3][C:2]([CH3:6])([CH3:5])[CH3:1])[CH:20]=[CH2:21]
Reactant: C=CC=O
Reactant: C#CC(C)(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CC(O)C#CC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 741.3 %

Procedure:
Ten grams (0.122 mole) of 3,3-dimethyl-1-butyne was dissolved in 100 ml of anhydrous tetrahydrofuran, and the resulting solution was cooled to -40° C. or less in a dry ice-acetone bath. Under a stream of a nitrogen gas, 81.13 ml (0.122 mole) of a 1.5 M hexane solution of n-butyllithium was added dropwise at -40° C. or less with stirring. After aging the reaction solution at -50° C. for 30 minutes, 6.84 g (0.122 mole) of acrolein was added dropwise at -50° C. or less. After the reaction solution was allowed to stand overnight at room temperature, it was poured into 200 ml of ice water and extracted with two 100-ml portions of ethyl acetate. The organic layers were combined, washed once with 100 ml of a saturated aqueous sodium chloride solution and concentrated under reduced pressure. The resulting oily product was distilled under reduced pressure to obtain 125 g of 3-hydroxy-6,6-dimethylhept-1 -ene-4-yne (bp20, 80° C.).
Reaction SMILES: [N+:1]([C:4]1[C:5]([OH:15])=[C:6]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[C:16]([NH:20][OH:21])([CH3:19])([CH3:18])[CH3:17]>>[N+:1]([C:4]1[C:5]([OH:15])=[C:6]([CH:7]=[N+:20]([C:16]([CH3:19])([CH3:18])[CH3:17])[O-:21])[CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)NO
Reactant: O=Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1O
Product: CC(C)(C)[N+]([O-])=Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1O

Procedure:
The title compound was prepared according to the procedure described in Example 13 using 3,5-dinitro-2-hydroxybenzaldehyde and N-tert-butylhydroxylamine. The title compound was isolated in 4.4% yield as a yellow crystalline solid, m.p. 200.3° C. (Rf=0.15 on a silica gel plate using 10:1 EtOAc/MeOH as an eluant).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=O.[CH3:9][O:10][C:11]1[C:12](OC)=[C:13]([O:17][CH3:18])[CH:14]=[CH:15][CH:16]=1.[C:21](O)(=[O:23])C>>[CH3:1][N:2]1[CH2:7][CH:6]=[CH:5][CH:4]([C:12]2[C:13]([O:17][CH3:18])=[CH:14][C:15]([O:23][CH3:21])=[CH:16][C:11]=2[O:10][CH3:9])[CH2:3]1
Reactant: CC(=O)O
Reactant: CN1CCCCC1=O
Reactant: COc1cccc(OC)c1OC
Product: COc1cc(OC)c(C2C=CCN(C)C2)c(OC)c1

Procedure:
N-methylpiperidone (2.8 mol) is added with stirring to a solution of trimethoxybenzene (2.38 mol) in glacial acetic acid (750 ml), the temperature of the reaction mixture being maintained below 25° C. After the addition has ended, hydrogen chloride is bubbled through the reaction mixture, which is heated for 3 hours to 95°-100° C. and then concentrated, and the residue is diluted with water. The aqueous solution is extracted with ether, the ether is separated off and the aqueous layer is rendered alkaline with concentrated sodium hydroxide solution. The precipitate thus obtained is filtered off, washed with water and dried. Recrystallization from petroleum ether (60°-80° C.) gives 500 g of 1-methyl-3-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine of melting point 118°-122° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1([C:13]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)=[O:14])SCCCS1.ClN1C(=[O:34])CCC1=O>C(#N)C.C(OCC)(=O)C.[N+]([O-])([O-])=O.[Ag+]>[O:34]=[C:7]([C:2]1[N:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:13]([CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=[O:14]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)C2(c3ncccn3)SCCCS2)CC1
Reactant: O=C1CCC(=O)N1Cl
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)C(=O)c2ncccn2)CC1
Reaction time: 0.17 h

Procedure:
A solution of tert-butyl 4-{[2-(pyrimidin-2-yl)-1,3-dithian-2-yl]carbonyl}piperidine-1-carboxylate (0.51 g, 1.24 mmol) in acetonitrile (10 ml) was added quickly to a well stirred solution of N-chlorosuccinimide (1.10 g, 8.24 mmol) and silver nitrate (1.54 g, 9.06 mmol) in aqueous 80% acetonitrile (30 ml) at room temperature. The mixture was stirred 10 min, then diluted with ethyl acetate, and washed successively with aqueous Na2S2O3 (2 N), 2 N sodium carbonate and brine. The organic layer was separated, dried (MgSO4) and concentrated. The resulting residue was purified on a silica gel column (ethyl acetate/hexane) to give the title compound. LC-MS m/e 320.15 [M+1]+.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[S:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[O:20]=[CH:21][C:22]1[CH:30]=[CH:29][C:27]([OH:28])=[C:24]([O:25][CH3:26])[CH:23]=1.CN(C)C=O>O>[CH3:26][O:25][C:24]1[CH:23]=[C:22]([CH:30]=[CH:29][C:27]=1[O:28][CH2:2][C:3]1[N:4]=[C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[S:6][CH:7]=1)[CH:21]=[O:20]
Reactant: COc1cc(C=O)ccc1O
Reactant: ClCc1csc(N2CCCCC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)ccc1OCc1csc(N2CCCCC2)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
A mixture of 1-(4-chloromethyl-1,3-thiazol-2-yl)piperidine (1.00 g), potassium carbonate (0.64 g), vanillin (0.70 g) and N,N-dimethylformamide (30 mL) was stirred at 80° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 3-methoxy-4-[(2-piperidin-1-yl-1,3-thiazol-4-yl)methoxy]benzaldehyde as colorless crystals (1.34 g, 88%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 129-130° C.
Reaction SMILES: Cl.[CH3:2][N:3](C)[OH:4].Cl[CH2:7]Cl.[CH3:9][N:10]([CH3:14])[C:11](Cl)=[O:12]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH3:7][O:4][N:3]([CH3:2])[C:11]([N:10]([CH3:14])[CH3:9])=[O:12]
Reactant: ClCCl
Reactant: CN(C)C(=O)Cl
Reactant: CN(C)O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CON(C)C(=O)N(C)C
Temperature: -20 °C
Reaction time: 16 h
Yield: 69 %

Procedure:
A mixture of dimethylhydroxylamine hydrochloride (150.0 g, 1.54 mol), 4-dimethylaminopyridine (9.4 g, 0.076 mol), and dichloromethane (1.35 L) was chilled to −20° C., under argon. Dimethylcarbamyl chloride (135 ml, 1.46 mol) and pyridine (315 ml) were added consecutively over 25 minutes. The reaction was slowly warmed to room temperature over 2 hours, and agitated for about 16 hours. The reaction mixture was filtered to remove pyridine hydrochloride, and concentrated by rotary evaporator. The mixture was diluted with t-butyl methyl ether (500 ml), and the solids were removed by filtration. The filtrate was concentrated by rotary evaporation. Vacuum distillation provided the desired product (135.10 g, 69%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[C:23]=2[C:24]([OH:26])=O)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.C(Cl)(=O)C(Cl)=O>C1COCC1.CN(C=O)C>[ClH:1].[Cl:1][C:2]1[N:3]2[C:4](=[N:21][C:22]3[C:23]([C:24]2=[O:26])=[C:27]([F:32])[CH:28]=[C:29]([F:31])[CH:30]=3)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cc(F)cc(F)c4C(=O)O)nc(Cl)nc32)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c2nc(Cl)n2c(=O)c4c(F)cc(F)cc4nc32)cc1
Product: Cl
Reaction time: 1 h
Yield: 190 %

Procedure:
An opaque solution of 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-4,6-difluorobenzoic acid (5.3 g, 11.07 mmol) in THF (300 mL) was treated with a few drops of DMF, followed by oxalyl chloride (1M in CH2Cl2, 22.14 mL, 44.3 mmol). The reaction mixture was stirred for 1 h, then placed in an ice-bath for 2 h. The resulting slurry was filtered, the solid washed with CH2Cl2 to obtain 5-chloro-8,10-difluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one hydrogen chloride as a white solid (5.23 g, 95%). 1H NMR (400 MHz, THF-d6) δ ppm 2.41 (s, 3H), 6.97-7.12 (m, 2H), 7.12-7.24 (m, 1H), 7.44 (d, J=8.24 Hz, 2H), 7.68 (d, J=3.66 Hz, 1H), 8.11 (d, J=8.42 Hz, 2H); ESIMS (M+H)+=460.94.