Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[CH3:11][C:12]([CH3:19])([CH3:18])[C:13](=O)[CH2:14][C:15]#[N:16].Cl>CCO.CCCC(C)C>[C:12]([C:13]1[CH:14]=[C:15]([NH2:16])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:10])=[CH:3][CH:4]=2)[N:9]=1)([CH3:19])([CH3:18])[CH3:11]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Solvent: CCCC(C)C
Solvent: CCO
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Temperature: 25 °C
Yield: 53 %

Procedure:
To a stirred solution of p-tolylhydrazine hydrochloride (100 g, 630 mmol) in EtOH (1251 mL) was added 4,4-dimethyl-3-oxopentanenitrile (88 g, 699 mmol) and HCl (62.5 mL, 750 mmol). The resulting mixture was stirred at reflux overnight. The reaction mixture was cooled to room temperature and concentrated in vacuo to c.a. ⅓ of the original volume. The reaction mixture was then cooled in an ice-bath and taken to c.a. pH 8-9 with 6M aq NaOH. The reaction mixture was extracted with diethyl ether (500 mL) and the organic phase washed with water (2×300 mL) before being dried over magnesium sulphate and concentrated in vacuo to afford an orange solid. The solid was suspended in iso-hexane and stirred at reflux for 2.5 h before being cooled and filtered whilst still hot to yield the subtitle product 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-amine as a pale brown solid (76.5 g, 52%); Rt 1.31 min (Method 1); m/z 230 (M+H)+ (ES+); 1H NMR δ: 1.20 (9H, s), 2.32 (3H, s), 5.10 (2H, br s), 5.35 (1H, s), 7.24 (2H, d), 7.42 (2H, m).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH:6]1[CH2:9][NH:8][CH2:7]1.[CH3:16][N:17]=[C:18]=[O:19]>>[CH3:16][NH:17][C:18]([N:8]1[CH2:9][CH:6]([O:5][C:4]2[CH:10]=[CH:11][CH:12]=[CH:13][C:3]=2[C:2]([F:1])([F:14])[F:15])[CH2:7]1)=[O:19]
Reactant: CN=C=O
Reactant: FC(F)(F)c1ccccc1OC1CNC1
Product: CNC(=O)N1CC(Oc2ccccc2C(F)(F)F)C1

Procedure:
The compound was prepared from 3-[2-(trifluoromethyl)phenoxy]azetidine and methylisocyanate as described in Example 5 of U.S. Pat. No. 4,226,861, m.p. 134°-136° C.
Reaction SMILES: [C:1]1([C:13](Cl)=[O:14])[CH:6]=[C:5]([C:7](Cl)=[O:8])[CH:4]=[C:3]([C:10](Cl)=[O:11])[CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].ClCCl.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:13]([C:1]2[CH:6]=[C:5]([C:7]([C:27]3[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=3)=[O:8])[CH:4]=[C:3]([C:10](=[O:11])[C:27]3[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=3)[CH:2]=2)=[O:14])=[CH:26][CH:25]=1
Reactant: Fc1ccccc1
Reactant: O=C(Cl)c1cc(C(=O)Cl)cc(C(=O)Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: O=C(c1ccc(F)cc1)c1cc(C(=O)c2ccc(F)cc2)cc(C(=O)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
5 g of 1,3,5-benzenetricarbonyltrichloride (18.8 mol), 6.7 g of aluminum chloride (50.0 mmol) and 50 mL of distilled dichloromethane (DCM) were put in a 250 mL round flask, which was stirred for 30 minutes at 25° C. for reaction in the presence of nitrogen. 20 mL of dichloromethane and 4.5 g of fluorobenzene (48.8 mmol) were added in 100 mL of Dropping funnel, and the fluorobenzene solution was dropped in the round flask drop by drop. The reaction mixture was stirred for 4 hours in the presence of nitrogen, to which 20 mL of distilled water was added. The reaction mixture was stirred further for more than 12 hours. The organic layer of the reaction mixture was extracted by using dichloromethane, and the organic solvent was eliminated, resulting in a crude product. The crude product was re-crystallized using ethanol to give white brancher [3,5-bis(4-fluorobenzoyl)phenyl](4-fluorophenyl) methanone (yield: 70%). The structure of the [3,5-bis(4-fluorobenzoyl)phenyl](4-fluorophenyl)methanone was confirmed by 1H-NMR, 13C-NMR spectrometry and elemental analysis.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]2[O:11][C:12]3[N:13]=[C:14]([S:20][CH3:21])[N:15]=[C:16]([OH:19])[C:17]=3[N:18]=2)=[CH:5][C:4]=1[CH3:22].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH3:32].O>CN(C)C=O>[CH3:1][O:2][C:3]1[C:4]([CH3:22])=[CH:5][C:6]([C:10]2[O:11][C:12]3[N:13]=[C:14]([S:20][CH3:21])[N:15]=[C:16]([O:19][CH2:30][CH2:31][CH3:32])[C:17]=3[N:18]=2)=[CH:7][C:8]=1[CH3:9]
Reactant: COc1c(C)cc(-c2nc3c(O)nc(SC)nc3o2)cc1C
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1nc(SC)nc2oc(-c3cc(C)c(OC)c(C)c3)nc12
Temperature: 60 °C
Reaction time: 5 h
Yield: 37.4 %

Procedure:
5.9 g of 2-(4-methoxy-3,5-dimethylphenyl)-5-methylsulfanyloxazolo[5,4-d]pyrimidin-7-ol were dissolved in 150 ml of N,N-dimethylformamide, and 7.7 g of potassium carbonate and then 2.7 g of 1-bromopropane were added. The solution was stirred at 60° C. for 5 h and then, after cooling, poured into 150 ml of water. The precipitate was filtered off with suction. The regioisomer mixture obtained was purified by silica gel chromatography (50 g silicon dioxide solute cartridge, heptane/ethyl acetate 9/1). In addition to 1.4 g of 2-(4-methoxy-3,5-dimethylphenyl)-5-methylsulfanyl-6-propyl-6H-oxazolo[5,4-d]pyrimidin-7-one (LC/MS (Method LC1): Rt=1.43 min; m/z=360.13 [M+H]+), 2.5 g of the title compound were obtained.
Reaction SMILES: [CH2:1]([N:4]1[C:8](=[O:9])[CH:7]([C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:6][C:5]1=[S:18])[CH:2]=[CH2:3].[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CC(C)([O-])C.[K+]>O1CCCC1.C(OCC)(=O)C>[C:11]1([C:10]([O:17][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:7]2[NH:6][C:5](=[S:18])[N:4]([CH2:1][CH:2]=[CH2:3])[C:8]2=[O:9])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C=CCN1C(=O)C(C(=O)c2ccccc2)NC1=S
Reactant: ClCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCN1C(=O)C(=C(OCc2ccccc2)c2ccccc2)NC1=S
Temperature: 25 °C
Yield: 123.7 %

Procedure:
To a solution of 3-allyl-5-benzoyl-2-thiohydantoin (0.098 g, 0.0003 mol) and benzyl chloride (0.042 g, 0.00033 mol) in tetrahydrofuran (2 mL) was added a solution of 1M potassium tert-butoxide in tetrahydrofuran (0.33 mL, 0.00033 mol) under argon. A cherry solid was formed in the reaction mixture. The resulting mixture was heated at reflux for 1 hr and then cooled to room temperature. The reaction mixture was diluted with ethyl acetate (40 mL), washed with 3M HCl (2×20 mL) and brine (1×20 mL), filtered through 1 PS filter paper and concentrated under reduced pressure to give 0.13 g of a brown oil which solidified on standing. This solid was triturated with hexane (5 mL) once and then was dried under high vacuum. NMR (CDCl3) δ (10.9 s br, 1H), 8.6-8.9 (m, 2H), 7.3-7.9 (m, 8H), 4.7 (S, 2H), 4.4 (d, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C[N:15](C)C=O.S(Cl)(Cl)=O>O1CCCC1>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:15])=[O:5]
Reactant: Nc1c(C(=O)O)cccc1[N+](=O)[O-]
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: NC(=O)c1cccc([N+](=O)[O-])c1N
Temperature: 25 °C
Yield: 68 %

Procedure:
To a solution of 100 g (0.55 mol) of acid 5 in 600 ml of tetrahydrofuran (THF) and 1 ml of N,N-dimethylformamide (DMF) 131 g (1.1 mol) of thionyl chloride were added. The mixture was stirred under reflux for 4 h and at room temperature for 12 h. The mixture was concentrated to 300 ml and added to a mixture of 1500 g of ice and 1500 ml of ammonia. The mixture was stirred for 3 h at 5° C. The resulting crystals were isolated at 10° C., washed with water, 100 ml of iso-propanol, and 100 ml of MTBE and dried in a vacuum oven at 50° C. Recrystallisation from toluene/MTBE (3/1). Yield: 68%.
Reaction SMILES: [Br:1][CH:2]1[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]([NH:7][C:8](=[O:9])[CH:3]12)=[O:6].N1C=CC=CC=1.[Br:20][C:21]1[C:29]([Br:30])=[CH:28][C:27]([Br:31])=[CH:26][C:22]=1[C:23](Cl)=[O:24]>C1C=CC=CC=1>[Br:20][C:21]1[C:29]([Br:30])=[CH:28][C:27]([Br:31])=[CH:26][C:22]=1[C:23]([N:7]1[C:8](=[O:9])[CH:3]2[CH:2]([Br:1])[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]1=[O:6])=[O:24]
Reactant: O=C(Cl)c1cc(Br)cc(Br)c1Br
Reactant: O=C1NC(=O)C2C1CCC(Br)C2Br
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: O=C(c1cc(Br)cc(Br)c1Br)N1C(=O)C2CCC(Br)C(Br)C2C1=O
Temperature: 25 °C

Procedure:
3,4-Dibromohexahydrophthalimide (0.10 mole), benzene (300 ml) and pyridine (0.11 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,3,5-Tribromobenzoyl chloride (0.10 mole) is then added dropwise to the flask with stirring at room temperature. After the addition is completed the reaction mixture is heated at reflux with continued stirring for a period of about 1 hour. After this time the reaction mixture is filtered and the filtrate is washed with water. The washed filtrate is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(2,3,5-tribromobenzoyl)-3,4-dibromohexahydrophthalimide.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[C:12]([N:20]=[C:21]=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:12]([NH:20][C:21]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:7]=[CH:8][CH:9]=[CH:10][N:11]=1)=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: NCCSCc1ncccn1
Product: O=C(NC(=S)NCCSCc1ncccn1)c1ccccc1

Procedure:
By the procedure of Example 18, 2-[(2-aminoethyl)thiomethyl]pyrimidine is reacted with benzoyl isothiocyanate to give N-benzoyl-N'-[2-(2-pyrimidylmethylthio)ethyl]thiourea. Removing the benzoyl group by the procedure of Example 18 gives N-[2-(2-pyrimidylmethylthio)ethyl]thiourea.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]([NH:18]S(C(C)(C)C)=O)[CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15].Cl.O1CCOCC1>CO>[NH2:18][CH:11]([C:4]1[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)CCC(NS(=O)C(C)(C)C)c1c(OC)cccc1OC
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)CCC(N)c1c(OC)cccc1OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A cooled (0° C.) solution of methyl 4-(2,6-dimethoxyphenyl)-4-(1,1-dimethylethylsulfinamido)butanoate (7.750 g; 21.68 mmol) in MeOH (70 ml) was treated dropwise with a solution of 4 M HCl in 1,4-dioxane (10.9 ml; 43.60 mmol). The resulting yellow mixture was further stirred at 0° C., under nitrogen, for 10 min., and then at rt for 1 h. The reaction mixture was then concentrated to dryness under reduced pressure and the yellow oily residue was further dried under HV to give the chlorhydrate salt of methyl 4-amino-4-(2,6-dimethoxyphenyl)butanoate as a dark-yellow/brown oil. LC-MS (conditions A): tR=0.45 min.; [M+H]+: 254.40 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:29])[C:7]([CH2:18][NH:19][C:20]([NH:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[O:21])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:29])[C:7]([CH2:18][NH:19][C:20]([NH:22][CH:23]3[CH2:28][CH2:27][N:26]([S:31]([CH3:30])(=[O:33])=[O:32])[CH2:25][CH2:24]3)=[O:21])=[CH:8][N:9]2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)NC1CCNCC1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)N1CCC(NC(=O)NCc2cn(-c3ccccc3)c3cc(Cl)ccc3c2=O)CC1

Procedure:
1-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-3-(1-methanesulfonyl-piperidin-4-yl)-urea was prepared starting from intermediate N and methanesulfonyl chloride. MS calcd. for C23H26ClN4O4S [(M+H)+] 489.1, obsd. 489.1.
Reaction SMILES: C([O:5][C:6](=[O:27])[CH:7]=[C:8]([CH3:26])[CH:9]=[CH:10][CH:11]=[C:12]([CH3:25])[CH:13]=[CH:14][C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[C:17]([CH3:23])[C:16]=1[CH3:24])CCC.[Cl-].CC1C(C)=C(C)C=C(C)C=1C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OC(=O)C=C(C)C=CC=C(C=O)C)CCC>>[CH3:24][C:16]1[C:17]([CH3:23])=[C:18]([CH3:22])[CH:19]=[C:20]([CH3:21])[C:15]=1[CH:14]=[CH:13][C:12]([CH3:25])=[CH:11][CH:10]=[CH:9][C:8]([CH3:26])=[CH:7][C:6]([OH:27])=[O:5]
Reactant: CCCCOC(=O)C=C(C)C=CC=C(C)C=Cc1c(C)cc(C)c(C)c1C
Agent: CCCCOC(=O)C=C(C)C=CC=C(C)C=O
Agent: Cc1cc(C)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(C)c1C
Agent: [Cl-]
Product: CC(C=Cc1c(C)cc(C)c(C)c1C)=CC=CC(C)=CC(=O)O

Procedure:
By the procedure of Example 14, 9-(2,3,4,6-tetramethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid butyl ester is manufactured from 2,3,4,6-tetramethyl-benzyltriphenylphosphonium chloride by reaction with 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid butyl ester. From this product, there is produced by the procedure of Example 15 9-(2,3,4,6-tetra-methyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid of melting point 201°-202° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2]1.[Cl:15][C:16]1[C:17](F)=[C:18]2[C:24]([NH2:25])=[CH:23][NH:22][C:19]2=[N:20][CH:21]=1.C(N(C(C)C)C(C)C)C>CN1C(=O)CCC1>[NH2:25][C:24]1[C:18]2[C:19](=[N:20][CH:21]=[C:16]([Cl:15])[C:17]=2[N:1]2[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:2]2)[NH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: Nc1c[nH]c2ncc(Cl)c(F)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Cl)cnc3[nH]cc(N)c23)C1
Temperature: 120 °C
Reaction time: 24 h

Procedure:
(R)-tert-Butyl piperidin-3-ylcarbamate (1619 mg, 8.08 mmol) was added to a mixture of 5-chloro-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (500 mg, 2.69 mmol; Example 8, Step D) and N-ethyl-N-isopropylpropan-2-amine (1408 μL, 8.08 mmol) in NMP (6.75 mL). N2 was bubbled through the mixture for 5 minutes, and the reaction was stirred at 120° C. under N2 for 24 hours. The mixture was allowed to cool, was diluted with 20% EtOAc/Et2O (200 mL) and washed with water (5×50 mL). The organic layer was then dried over MgSO4, filtered, and concentrated in vacuo to provide the crude (R)-tert-butyl 1-(3-amino-5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate. LCMS (APCI+) m/z 366 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:54]=[CH:53][C:6]2[N:7]=[C:8]([S:10]([C:13]3[CH:35]=[CH:34][C:16]([O:17][CH2:18][C:19]([O:21][CH2:22][CH2:23][S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])=[O:20])=[C:15]([O:36][CH2:37][C:38]([O:40][CH2:41][CH2:42][S:43]([C:46]4[CH:51]=[CH:50][C:49]([CH3:52])=[CH:48][CH:47]=4)(=[O:45])=[O:44])=[O:39])[CH:14]=3)(=[O:12])=[O:11])[NH:9][C:5]=2[C:4]=1[S:55][CH2:56][C:57]1[C:62]([CH3:63])=[C:61]([O:64][CH3:65])[C:60]([CH3:66])=[CH:59][N:58]=1.ClC1C=C(C=CC=1)C(OO)=[O:72].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].C(OCC)(=O)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:54]=[CH:53][C:6]2[N:7]=[C:8]([S:10]([C:13]3[CH:35]=[CH:34][C:16]([O:17][CH2:18][C:19]([O:21][CH2:22][CH2:23][S:24]([C:27]4[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=4)(=[O:25])=[O:26])=[O:20])=[C:15]([O:36][CH2:37][C:38]([O:40][CH2:41][CH2:42][S:43]([C:46]4[CH:51]=[CH:50][C:49]([CH3:52])=[CH:48][CH:47]=4)(=[O:44])=[O:45])=[O:39])[CH:14]=3)(=[O:12])=[O:11])[NH:9][C:5]=2[C:4]=1[S:55]([CH2:56][C:57]1[C:62]([CH3:63])=[C:61]([O:64][CH3:65])[C:60]([CH3:66])=[CH:59][N:58]=1)=[O:72]
Reactant: COc1ccc2nc(S(=O)(=O)c3ccc(OCC(=O)OCCS(=O)(=O)c4ccc(C)cc4)c(OCC(=O)OCCS(=O)(=O)c4ccc(C)cc4)c3)[nH]c2c1SCc1ncc(C)c(OC)c1C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2nc(S(=O)(=O)c3ccc(OCC(=O)OCCS(=O)(=O)c4ccc(C)cc4)c(OCC(=O)OCCS(=O)(=O)c4ccc(C)cc4)c3)[nH]c2c1S(=O)Cc1ncc(C)c(OC)c1C
Reaction time: 0.67 h
Yield: 37.1 %

Procedure:
2-(4-Tolylsulfonyl)ethyl 4-[{5-methoxy-([4-methoxy-3,5-dimethyl(2-pyridyl)]methylthio)benzimidazolyl}sulfonyl]-2-(2-[4-tolylsulfonyl]ethoxycarbonylmethoxy)phenoxyacetate (Intermediate A20, 4.8 g, 0.0054 mol) was dissolved in 20 mL of tetrahydrofuran, and the solution was left in a freezer for 40 min. A solution of 3-chloroperoxybenzoic acid (1.3 g, 0.0075 mol) in 6 mL of tetrahydrofuran was cooled for 30 min. The two were combined and left in the freezer for 16 hr. The mixture was then poured into a rapidly stirring mixture of 5% aqueous sodium metabisulfite and ethyl acetate. The layers were separated, and the organic layer was washed with 2 portions of 2.5% aqueous sodium bicarbonate and with saturated aqueous sodium chloride. The solution was filtered through 1PS paper and concentrated at aspirator pressure. The residue was separated on a column of flash silica gel (2:1 ethyl acetate:hexanes→ethyl acetate) to yield 2.0 g (41%) of the title compound.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([OH:6])[CH2:4][CH3:5].[H-].[Na+].Cl[C:10]1[C:11]2[CH:21]=[CH:20][N:19]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=3[CH3:29])[C:12]=2[C:13](=[O:18])[N:14]([CH2:16][CH3:17])[N:15]=1>CN(C=O)C.O>[CH3:29][C:23]1[CH:24]=[C:25]([CH3:28])[CH:26]=[CH:27][C:22]=1[N:19]1[C:12]2[C:13](=[O:18])[N:14]([CH2:16][CH3:17])[N:15]=[C:10]([O:6][CH:3]([CH2:4][CH3:5])[CH2:2][CH3:1])[C:11]=2[CH:21]=[CH:20]1
Reactant: CCC(O)CC
Reactant: CCn1nc(Cl)c2ccn(-c3ccc(C)cc3C)c2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(CC)Oc1nn(CC)c(=O)c2c1ccn2-c1ccc(C)cc1C
Temperature: 60 °C
Reaction time: 4 h
Yield: 75.4 %

Procedure:
To a solution of 3-pentanol (0.079 ml, 0.73 mmol) in DMF (1 ml) was added sodium hydride (60% in oil, 29 mg, 0.73 mmol). The mixture was stirred for 10 min before addition of 4-chloro-1-(2,4-dimethylphenyl)-6-ethyl-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (55 mg, 0.18 mmol). The mixture was stirred at 60° C. for 4 hours, then diluted with water (30 ml) and extracted with ethyl acetate (50 ml). The extract were combined, washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (10:1) to give 48 mg (48%) of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][N:15]3[CH2:21][C:22]2[C:30]3[C:25](=[N:26][CH:27]=[CH:28][CH:29]=3)[N:24](C(OC(C)(C)C)=O)[N:23]=2)[CH:9]=1)[C:5]#[N:6].CN(C=O)C.Cl>CC(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][N:15]3[CH2:21][C:22]2[C:30]3[C:25](=[N:26][CH:27]=[CH:28][CH:29]=3)[NH:24][N:23]=2)[CH:9]=1)[C:5]#[N:6]
Reactant: CC(C)(C)OC(=O)n1nc(Cn2ncc3c(Oc4cc(Cl)cc(C#N)c4)c(Cl)ccc32)c2cccnc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3c2cnn3Cc2n[nH]c3ncccc23)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A jacketed reaction vessel (30 L) equipped with a thermocouple was charged with 3-chloro-5-{[5-chloro-1-(1-t-butyloxycarbonyl-1H-pyrazolo[3,4-b]pyridin-3-ylmethyl)-1H-indazol-4-yl]oxy}benzonitrile (1.338 kg; 2.499 moles; 1.0 eq.) and then with DMF (10.7 L) and IPA (2.68 L). Concentrated HCl (2.68 L) was then charged to the vessel during which time the internal temperature rose from 16° C. to 44° C. The mixture was then heated to 60° C. After 1 hour at 60° C., the suspension became a clear solution. Conversion was complete after 1.75 hours as determined by HPLC, at which point the reaction mixture was transferred into a 4-necked round bottom flask (75 L) at 55° C.-60° C. via an in-line filter. The reaction vessel was rinsed with IPA (2 L×2), and the rinse transferred to the flask via the in-line filter. Filtered water (16 L) was then added to the mixture via an additional funnel while maintaining the temperature at 55° C.-60° C., during which crystallization of the title product began. Upon completion of the water addition, the mixture was stirred at 55° C. for 40 minutes, then cooled to room temperature and filtered with a filter pot. The wet cake was rinsed with filtered IPA:water (3:7, 10 L), and then with filtered water (7 L×6), and then dried in a vacuum oven at 40° C. for two days to afford the title product.
Reaction SMILES: C(O[C:4](=[O:17])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:6])C.C(N(CC)CC)C.[NH2:25][C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[N:27]=1>C1(C)C=CC=CC=1>[CH3:32][C:30]1[CH:29]=[C:28]([CH3:33])[N:27]=[C:26]([NH:25][C:4](=[O:17])[C:5]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)=[O:6])[CH:31]=1
Reactant: CCOC(=O)C(=O)Nc1ccc([N+](=O)[O-])cc1
Reactant: Cc1cc(C)nc(N)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1cc(C)nc(NC(=O)C(=O)Nc2ccc([N+](=O)[O-])cc2)c1
Temperature: 0 °C
Yield: 74.5 %

Procedure:
A solution of N-(4-nitro-phenyl)-oxalamic acid ethyl ester (4.9 g, 20.5 mmol), triethylamine (4.2 g, 41 mmol) and 2-amino-4,6-dimethylpyridine (2.5 g, 20.5 mmol) in dry toluene (30 mL) was heated at reflux overnight. The mixture was cooled to 0° C., and a precipitate was filtered and washed with water. Drying under vacuum afforded N-(4,6-dimethyl-pyridin-2-yl)-N′-(4-nitro-phenyl)-oxalamide (4.8 g, 74%).
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][O:8][CH:9]1[CH2:12][NH:11][CH2:10]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.Cl.[CH2:44]([O:46][C:47](=[O:65])[CH2:48][N:49]1[CH2:54][C:53]2[CH:55]=[C:56](/[CH:59]=[CH:60]/[C:61](O)=[O:62])[CH:57]=[N:58][C:52]=2[NH:51][C:50]1=[O:64])[CH3:45]>CN(C)C=O>[O:64]=[C:50]1[NH:51][C:52]2[N:58]=[CH:57][C:56](/[CH:59]=[CH:60]/[C:61](=[O:62])[N:11]3[CH2:12][CH:9]([O:8][CH2:7][C:3]4[S:2][CH:6]=[CH:5][CH:4]=4)[CH2:10]3)=[CH:55][C:53]=2[CH2:54][N:49]1[CH2:48][C:47]([O:46][CH2:44][CH3:45])=[O:65]
Reactant: CCOC(=O)CN1Cc2cc(/C=C/C(=O)O)cnc2NC1=O
Reactant: c1csc(COC2CNC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN1Cc2cc(/C=C/C(=O)N3CC(OCc4cccs4)C3)cnc2NC1=O
Reaction time: 48 h

Procedure:
3-(Thiophen-2-ylmethoxy)-azetidine hydrochloride (243 mg, 1.18 mmol), EDCI (227 mg, 1.18 mmol), HOBt (160 mg, 0.6 mmol) and diisopropylethylamine (340 μL, 1.97 mmol) were successively added to a solution of (E)-3-(3-(2-ethoxy-2-oxoethyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-6-yl)acrylic acid hydrochloride (270 mg, 0.79 mmol) in dimethylformamide (15 mL) at room temperature. The reaction mixture was stirred for 2 days then partitioned between ethyl acetate (30 mL) and water (40 mL). The aqueous layer was separated and successively extracted with ethyl acetate (2×30 mL) and dichloromethane (2×30 mL). The combined organic phases were washed with a saturated solution of sodium chloride (3×40 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel using dichloromethane/methanol (10:0 to 98:2) as eluent. The title product was obtained as an off-white solid (215 mg, 60%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#N)=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.CO.[OH:21]S(O)(=O)=O>C1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]=[O:21])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: Cc1ccc2nc(-c3ccc(C#N)cc3)cn2c1
Reactant: O=S(=O)(O)O
Solvent: CO
Solvent: c1ccccc1
Product: Cc1ccc2nc(-c3ccc(C=O)cc3)cn2c1
Reaction time: 2.5 h

Procedure:
1.0 g of 6-methyl-2-(4'-cyanophenyl)imidazo[1,2-a]-pyridine in 20 ml dry benzene was treated with Dibal (5.5 ml of 1M solution). After stirring for 2-3 hrs, methanol 15 ml was added, followed by 10 ml of 10% H2SO4. The precipitate was filtered, dissolved in water and basified with 15% NaOH. The collected precipitate was recrystallized from ethanol. Yield 0.68 g (68%); mp 210°-211° C.