Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([OH:14])=[CH:9][C:8]=1[N:15]1[C:20](=[O:21])[N:19]([CH3:22])[C:18](=[O:23])[CH:17]=[N:16]1.C(N(CC)CC)C>O1CCCC1.O>[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:9][C:8]=1[N:15]1[C:20](=[O:21])[N:19]([CH3:22])[C:18](=[O:23])[CH:17]=[N:16]1
Reactant: CS(=O)(=O)Cl
Reactant: Cn1c(=O)cnn(-c2cc(O)c(Cl)cc2Cl)c1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(=O)cnn(-c2cc(OS(C)(=O)=O)c(Cl)cc2Cl)c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 79 %

Procedure:
A solution of 0.35 g (0.0031 mole) of methanesulfonyl chloride in 5 mL of tetrahydrofuran was added to a stirred solution of 0.8 g (0.0028 mole) of 2-(2,4-dichloro-5-hydroxyphenyl)-4-methyl-1,2,4-triazine-3,5-(2H,4H)-dione (Compound 9, Example III H) and 0.30 g (0.0031 mole) of triethylamine in 10 mL of tetrahydrofuran. The reaction mixture was stirred at room temperature for approximately 18 hours, then diluted with water. The resultant mixture was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. The dried extract was filtered, and the filtrate was evaporated under reduced pressure to give 0.81 g of 2-(2,4-dichloro-5-methylsulfonyloxyphenyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione as a solid, Compound 23 in the tables.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:41])=[C:13]([C:15]([N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[C:27](=[O:28])[C:26]([CH3:30])([CH3:29])[C:25]([C:31]4[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=4)=[N:24]3)[CH2:19][CH2:18]2)=[O:16])[CH:14]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd].CC(=O)OCC>[CH3:40][O:39][C:33]1[CH:32]=[C:31]([C:25]2[C:26]([CH3:30])([CH3:29])[C:27](=[O:28])[N:23]([CH:20]3[CH2:21][CH2:22][N:17]([C:15]([C:13]4[CH:14]=[C:9]([OH:8])[CH:10]=[CH:11][C:12]=4[CH3:41])=[O:16])[CH2:18][CH2:19]3)[N:24]=2)[CH:36]=[CH:35][C:34]=1[O:37][CH3:38]
Reactant: COc1ccc(C2=NN(C3CCN(C(=O)c4cc(OCc5ccccc5)ccc4C)CC3)C(=O)C2(C)C)cc1OC
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cc(O)ccc4C)CC3)C(=O)C2(C)C)cc1OC

Procedure:
Under a blanket of nitrogen 4.0 g of 2-(1-{[5-(benzyloxy)-2-methylphenyl]carbonyl}piperidin-4-yl)-5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound described in example 84) are dissolved in 80 ml of methanol and 0.4 g palladium on charcoal (10%) and 2.25 g ammonium formiate are added. The reaction mixture is heated to reflux or 20 min until the starting material is consumed according to TLC analysis. The mixture is filtered over a plug of celite, and the solvent is removed under reduced pressure resulting in the crude product, which is taken up in EA and washed twice with water and with brine. Crystallization from EA and PE results in the title compound.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]1(N)[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1N.C([O:16][C:17](=[O:21])[CH2:18][C:19]#N)C.C(C1C=CC(O)=CC=1N(OCCC)OCCC)=O>>[O:21]1[C:7]2[C:6](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:19]=[CH:18][C:17]1=[O:16]
Reactant: CCOC(=O)CC#N
Reactant: Nc1ccccc1N
Agent: CCCON(OCCC)c1cc(O)ccc1C=O
Agent: O=S(=O)(O)O
Product: O=c1ccc2ccccc2o1
Temperature: 92.5 °C

Procedure:
100 parts of 50% sulfuric acid were charged to a reactor vessel to which 10.8 parts of o-phenylenediamine and 11.4 parts of ethylcyanoacetate were then subsequently added. This mixture was heated to a reflux until all of the o-phenylenediamine disappeared from the system. To this mixture was then added 25.4 parts of the p-formyl-N,N-dipropoxy-m-aminophenol produced in parts B above and the resultant composition was maintained at a temperature of about 90-95° C. for 1 hour. Hydrolysis with aqueous NAOH resulted in a bright yellow coumarin colorant represented by Formula (VII): ##STR8##
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].C(OC(C1C(C(OCC)=O)=CC(C)=C(COC)N=1)=O)C.NC(C)(C(C)C)C(N)=O.[K].[CH:37]([C:40]1([CH3:57])[NH:44][C:43]([C:45]2[C:50]([C:51]([OH:53])=[O:52])=[CH:49][C:48]([CH2:54]C)=[CH:47][N:46]=2)=[N:42][C:41]1=[O:56])([CH3:39])[CH3:38]>C1(C)C=CC=CC=1>[CH3:2][O:4][C:47]1[N:46]=[C:45]([C:43]2[NH:44][C:40]([CH:37]([CH3:39])[CH3:38])([CH3:57])[C:41](=[O:56])[N:42]=2)[C:50]([C:51]([OH:53])=[O:52])=[CH:49][C:48]=1[CH3:54]
Reactant: CCc1cnc(C2=NC(=O)C(C)(C(C)C)N2)c(C(=O)O)c1
Reactant: CC(C)(C)[O-]
Agent: CC(C)C(C)(N)C(N)=O
Agent: CCOC(=O)c1cc(C)c(COC)nc1C(=O)OCC
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1nc(C2=NC(=O)C(C)(C(C)C)N2)c(C(=O)O)cc1C
Temperature: 25 °C

Procedure:
5 g of potassium tert.-butoxide are added in portions at a temperature of 80° C. to a solution of 5.7 g of 6-methoxymethyl-5-methylpyridine-2,3-dicarboxylic acid diethyl ester and 2.6 g of 2-amino-2,3-dimethylbutyramide in 200 ml of dry toluene while stirring. Once the addition of the potassium tert.-butoxide is complete, the resulting red solution is stirred for 2 hours at 80° C., the potassium salt of 2-(5-isopropyl-5-methyl-4-oxoimidazolin-2-yl)-5-ethylpyridine-3-carboxylic acid being deposited in the form of a thick crystalline slurry. The mixture is cooled to room temperature and filtered with suction, and the crystals are dried and then dissolved in 50 ml of saturated sodium chloride solution. The solution is adjusted to pH 4 with concentrated hydrochloric acid and then extracted three times with 100 ml of ethyl acetate each time. The organic phase is dried over magnesium sulphate, filtered off with suction and concentrated by evaporation. The residue crystallises from ether/hexane 1:2 yielding 2.8 g of the above acid, which has a melting point of 151°-153° C.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][C:7]1[O:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[CH:11]=1.[C:21](Cl)(=[O:30])[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1>>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([C:21]([C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[O:8][C:7]=2[CH2:6][C:5]2[CH:16]=[CH:17][CH:18]=[C:3]([C:2]([F:1])([F:19])[F:20])[CH:4]=2)=[O:30])=[CH:23][CH:24]=1
Reactant: FC(F)(F)c1cccc(Cc2cc3ccccc3o2)c1
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)c2c(Cc3cccc(C(F)(F)F)c3)oc3ccccc23)cc1

Procedure:
Acylation of 2-(3-trifluoromethylbenzyl)benzofuran with p-anisoyl chloride is carried out as outlined in the procedure of Example 1 to give 3-(4-methoxybenzoyl)-2-(3-trifluoromethylbenzyl)benzofuran.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[CH:22][CH:21]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[C:16][CH2:17][O:18][CH3:19])[CH:10]=2)[N:3]=1>C(O)C.N1C2C(=CC=CC=2)C=CC=1.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH:27]([F:29])[F:28])=[CH:24][CH:25]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[C:11](/[CH:15]=[CH:16]\[CH2:17][O:18][CH3:19])[CH:10]=2)[N:3]=1
Reactant: COCC#Cc1cccc(C2(c3ccc(OC(F)F)cc3)N=C(N)N(C)C2=O)c1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: c1ccc2ncccc2c1
Solvent: CCO
Product: COC/C=C\c1cccc(C2(c3ccc(OC(F)F)cc3)N=C(N)N(C)C2=O)c1
Reaction time: 16 h
Yield: 50 %

Procedure:
A mixture of a solution of 2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-methoxyprop-1-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one (0.1 g, 0.25 mmol) in ethanol (1.5 mL), quinoline (1 drop) and Lindlar catalyst (24 mg. 10% mol) was placed under a hydrogen filled balloon, stirred for 16 hr filtered through celite. The filtrate was concentrated in vacuo. The resultant residue was purified by flash chromatography on silica ge,l ethyl acetate as eluent, to afford the title compound as a white solid, 0.05 g (50% yield), mp 41-44° C.; 1H NMR (DMSO-d6) δ 2.95 (s, 3H); 3.2 (s, 3H); 4.0 (d, 2H); 5.7 (q, 1H) 6.5 (d, 1H); 6.6 (b, 2H); 7.1 (m, 3H); 7.3 (m, 4H); 7.4 (d, 2H); MS [(+)ESI] m/z=402 [M−H]+.
Reaction SMILES: C([N-]C1CCCCC1)(C)C.[Li+].[CH3:12][C:13]([CH3:32])=[CH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=1)=[O:16].[Br:33]Br.Cl>C1COCC1.CCOCC.CN(P(N(C)C)(N(C)C)=O)C>[Br:33][CH:14]([C:13]([CH3:32])=[CH2:12])[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=1)=[O:16]
Reactant: BrBr
Reactant: CC(C)=CC(=O)OCc1cccc(Oc2ccccc2)c1
Agent: CC(C)[N-]C1CCCCC1
Agent: Cl
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=C(C)C(Br)C(=O)OCc1cccc(Oc2ccccc2)c1
Reaction time: 1 h

Procedure:
A 100 ml flask is flushed with nitrogen and to it is added 25 ml of a 1 M THF solution of lithium N-isopropylcyclohexylamide (0.025 mole) followed by HMPT (5 ml). The flask is cooled to -78° and 7.1 g (0.025 mole) of m-phenoxybenzyl 3-methyl-2-butenoate in THF (25 ml) is added dropwise over 5 minutes. After the addition the mixture is stirred at -20° for 1 hour. This cold solution is then added dropwise to 1.1 equivalent of bromine in THF at -78°. After a further 1 hour at -78°, 5 ml of concentrated hydrochloric acid is added and the mixture allowed to come to RT and poured into ether plus cold aqueous hydrochloric acid. The ether layer is washed with water and brine and dried over calcium sulfate. Removal of the solvent gives m-phenoxybenzyl 2-bromo-3-methyl-3-butenoate, which is reacted with p-methylaniline by the process of Example 5 to give m-phenoxybenzyl ester of 2-(p-methylphenylamino)-3-methyl-3-butenoate.
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([NH:8]N)=[CH:4][CH:3]=1.Cl.[CH2:12]([N:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1)[CH3:13]>C(O)C>[CH2:12]([N:14]1[CH2:19][CH2:18][C:17]2[NH:8][C:5]3[CH:4]=[CH:3][C:2]([CH3:10])=[CH:7][C:6]=3[C:16]=2[CH2:15]1)[CH3:13]
Reactant: CCN1CCC(=O)CC1
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Solvent: CCO
Product: CCN1CCc2[nH]c3ccc(C)cc3c2C1
Temperature: 80 °C
Yield: 91.4 %

Procedure:
To a solution of p-tolylhydrazine hydrochloride (5.0 g, 31.5 mmol) in Ethanol (150 mL) was added 1-ethylpiperidin-4-one hydrochloride (4.0 g, 24.5 mmol) and heated at 80° C. for 16 h. After completion of the reaction (monitored by LCMS). The reaction mixture was concentrated to dryness and basified with aq. saturated NaHCO3, extracted with EtOAc, the organic layer was separated dried over sodium sulfate and concentrated under vacuum to obtain 4.8 g (Yield 71.0%) of 2-ethyl-8-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CDCl3, free base) δ (ppm) 7.7 (bs, 1H), 7.2-7.1 (m, 2H), 6.9 (d, 1H), 3.8 (s, 2H), 2.9 (s, 4H), 2.7 (q, 2H), 2.4 (s, 3H), 1.2 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:29])[N:9]([C:13]3[CH:18]=[CH:17][C:16]([C@H:19]4[CH2:24][CH2:23][C@H:22]([CH2:25][C:26]([NH2:28])=O)[CH2:21][CH2:20]4)=[CH:15][CH:14]=3)[CH2:10][CH2:11][O:12][C:6]=2[N:5]=[CH:4][N:3]=1.CN(C=O)C.C(Cl)(=O)C(Cl)=O>C1COCC1>[NH2:1][C:2]1[C:7]2[C:8](=[O:29])[N:9]([C:13]3[CH:14]=[CH:15][C:16]([C@H:19]4[CH2:20][CH2:21][C@H:22]([CH2:25][C:26]#[N:28])[CH2:23][CH2:24]4)=[CH:17][CH:18]=3)[CH2:10][CH2:11][O:12][C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: NC(=O)C[C@H]1CC[C@H](c2ccc(N3CCOc4ncnc(N)c4C3=O)cc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: N#CC[C@H]1CC[C@H](c2ccc(N3CCOc4ncnc(N)c4C3=O)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred slurry of 2-{trans-4-[4-(4-amino-5-oxo-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-6(5H)-yl)phenyl]cyclohexyl}acetamide (45 mg, 0.11 mmol), from Example 30, in THF (1 mL) was added DMF (0.002 mL) and oxalyl chloride (0.05 mL, 0.6 mmol). After two hours of stirring at room temperature, the reaction was quenched with aqueous sodium bicarbonate and extracted with EtOAc. The organic layer was washed with water, dried over sodium sulfate and concentrated in vacuo to afford the title compound as a light-yellow colored solid, 34 mg. 1H NMR (400 MHz, DMSO-d6): δ 8.17 (s, 1H), 7.63 (br s, 2H) 7.22 (m, 4H), 4.57 (m, 2H), 3.90 (m, 2H), 2.43 (m, 3H), 1.78 (m, 4H), 1.63 (m, 1H), 1.43 (m, 2H), 1.08 (m, 2H). m/z=378.3 (M+1). IC50 64.3 nM (range 51.2-91.1 nM).
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=2)[N:4]([CH3:18])[C:3]=1[C:19]([N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[CH2:31][CH2:30][CH2:29][C@H:28]2[CH2:32][O:33]C(=O)C2C=CC=CC=2)[CH2:23][CH2:22]1)=[O:20].BrC1N=C(C2C=CC=C(OC(F)(F)F)C=2)N(C)C=1C(O)=O.N1CCC(N2CCC[C@H]2COC(=O)C2C=CC=CC=2)CC1.[Li+].[OH-].Cl>C1COCC1.CO>[Br:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=2)[N:4]([CH3:18])[C:3]=1[C:19]([N:21]1[CH2:22][CH2:23][CH:24]([N:27]2[CH2:31][CH2:30][CH2:29][C@H:28]2[CH2:32][OH:33])[CH2:25][CH2:26]1)=[O:20]
Reactant: Cn1c(-c2cccc(OC(F)(F)F)c2)nc(Br)c1C(=O)N1CCC(N2CCC[C@H]2COC(=O)c2ccccc2)CC1
Agent: Cl
Agent: Cn1c(-c2cccc(OC(F)(F)F)c2)nc(Br)c1C(=O)O
Agent: O=C(OC[C@@H]1CCCN1C1CCNCC1)c1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: Cn1c(-c2cccc(OC(F)(F)F)c2)nc(Br)c1C(=O)N1CCC(N2CCC[C@H]2CO)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 0.15 g (0.24 mmol) of benzoic acid (S)-1-{1-[5-bromo-3-methyl-2-(3-trifluoromethoxy-phenyl)-3H-imidazole-4-carbonyl]-piperidin-4-yl}-pyrrolidin-2-ylmethyl ester [prepared in analogy to the procedure described for example 2 from 5-bromo-3-methyl-2-(3-trifluoromethoxy-phenyl)-3H-imidazole-4-carboxylic acid (example 72) and benzoic acid (S)-1-piperidin-4-yl-pyrrolidin-2-ylmethyl ester (intermediate 6C)] in 10 ml of THF/MeOH 1:1 was treated with 0.59 ml (0.59 mmol) of a LiOH solution (1.0 molar in H2O) and the mixture was stirred for 20 hours at RT. It was then poured into crashed ice, acidified with HCl (1.0 N) and extracted twice with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 98:2 to 4:1) to give 0.128 g (quant.) of the title compound as colorless amorphous solid. MS: 531.0 (MH+, 1Br).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]#[N:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:23][CH2:22]1.C(N(CC)C(C)C)(C)C>CN1C(=O)CCC1>[C:11]([C:10]1[C:3]2[C:2]([N:21]3[CH2:26][CH2:25][CH:24]([NH:27][C:28](=[O:35])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:23][CH2:22]3)=[N:7][CH:6]=[N:5][C:4]=2[N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:9]=1)#[N:12]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)c2c(Cl)ncnc21
Reactant: O=C(NC1CCNCC1)c1ccccc1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1cc(C#N)c2c(N3CCC(NC(=O)c4ccccc4)CC3)ncnc21
Reaction time: 0.75 h

Procedure:
4-chloro-7-({[2-(trimethylsilyl)ethyl]oxy}methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile D43 (100 mg) and N-4-piperidinylbenzamide (86 mg, 0.42 mmol, commercially available from e.g. Fluorochem, Alfa Aesar and Apollo) were dissolved in NMP and then N,N-diisopropylethylamine was added dropwise. The reaction mixture was carried out in the microwave at 120° C. for 45 minutes. The reaction mixture was poured onto water extracted with EtOAc (2×60 ml). Organic layers were washed water (3×20 ml), brine (30 ml), dried (MgSO4), filtered and solvent removed. Crude product obtained was purified by flash chromatography on silica gel eluting with Pet Eth/EtOAc 3/1-2/1 to give the desired product D44 in 69 mg. LCMS [MH+] 477.2@1.80 min (5 min run)
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH3:19])[C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:10][CH:11]=1)=[O:4].CN(C)CCN(C)C.C([Li])CCC.[I:34]I.C(=O)=O.O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1.CCCCCC.O.C(OCC)C>[I:34][C:11]1[CH:10]=[C:9]([N:12]2[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]2)[N:8]=[CH:7][C:6]=1[NH:5][C:3](=[O:4])[C:2]([CH3:20])([CH3:19])[CH3:1]
Reactant: II
Reactant: CN1CCN(c2ccc(NC(=O)C(C)(C)C)cn2)CC1
Agent: CN(C)CCN(C)C
Agent: O=C=O
Agent: O=S([O-])([O-])=S
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CN1CCN(c2cc(I)c(NC(=O)C(C)(C)C)cn2)CC1
Temperature: -30 °C
Yield: 42.6 %

Procedure:
A solution of 30 g (108 mmol) 2,2-dimethyl-N-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-propionamide and 58 ml (380 mmol) N,N,N′,N′-tetramethylethylenediamine under argon in 650 ml tetrahydrofuran was cooled in a dry ice bath to −78° C. Within lh, 239 ml (380 mmol) of a 1.6 N n-butyllithium solution in hexane were added dropwise. The reaction mixture was allowed to warm up to −30° C. overnight. After cooling again to −78° C., 43.6 g (170 mmol) iodine dissolved in 60 ml tetrahydrofuran were added dropwise during 15 min. The dry ice bath was replaced by an ice bath and a solution of 90 g (363 mmol) sodium thiosulfate pentahydrate in 250 ml water were added within 10 min when the temperature of the reaction mixture had reached 0° C. Then, 1000 ml diethyl ether were added and the organic layer was separated. The aqueous layer was extracted twice with 500 ml dichloromethane and the combined organic layers were dried (magnesium sulfate) and evaporated. Flash chromatography gave 18.5 g (42%) of the title compound as a light brown oil which crystallized upon standing at room temperature.
Reaction SMILES: Cl.[NH2:2]O.CN([CH2:7][CH:8]=[N:9][C:10](=[O:20])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18])C>[OH-].[Na+].O>[CH3:7][C:8]1[N:9]=[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])[O:20][N:2]=1
Reactant: CN(C)CC=NC(=O)c1ccccc1[N+](=O)[O-]
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1noc(-c2ccccc2[N+](=O)[O-])n1
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 81.6 %

Procedure:
To a solution of hydroxylamine hydrochloride (1.37 g, 20.1 mmol) in 5N aqueous sodium hydroxide (3.9 mL) was added N-[(dimethylamino)ethylidene]-2-nitrobenzamide (3.7 g, 15.7 mmol) portionwise. After stirring 20 minutes, the reaction was diluted with water (30 mL) and placed in a −23° C. freezer for 1 hour. The yellow crystals were collected by filtration. This material was dissolved in glacial acetic acid and heated to 110° C. for 14 hours. Toluene (30 mL) was added and the reaction fitted with a Dean-Stark Trap. The toluene was removed by distillation over a 2 hour period, and after cooling, water was added to the reaction mixture. After 2 hours in a −23° C. freezer, the precipitate was collected by filtration and rinsed with water to give 3-methyl-5-(2-nitrophenyl)-1,2,4-oxadiazole (2.63 g).
Reaction SMILES: OC(C(F)(F)F)=O.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([C@H:18]1[CH2:22][CH2:21][NH:20][CH2:19]1)(=[O:17])=[O:16].[Cl:23][C:24]1[N:29]=[C:28](Cl)[CH:27]=[CH:26][N:25]=1.[F-].[K+]>C(#N)C>[Cl:23][C:24]1[N:29]=[C:28]([N:20]2[CH2:21][CH2:22][C@H:18]([S:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[Cl:8])(=[O:16])=[O:17])[CH2:19]2)[CH:27]=[CH:26][N:25]=1
Reactant: O=S(=O)(c1ccccc1Cl)[C@H]1CCNC1
Reactant: Clc1ccnc(Cl)n1
Agent: [F-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: O=S(=O)(c1ccccc1Cl)[C@H]1CCN(c2ccnc(Cl)n2)C1
Temperature: 150 °C
Reaction time: 2 h
Yield: 36.6 %

Procedure:
(S)-3-(2-Chloro-benzenesulfonyl)-pyrrolidine TFA salt (250 mg) was dissolved in ACN (3.0 mL). 2,4-Dichloropyrimidine (155 mg), TEA (0.39 mL) and KF (4 mg) were added to the solution. The reaction mixture was stirred at 150° C. in the microwave oven for 2 h. The reaction mixture was evaporated to dryness and purified with preparative HPLC to yield 2-Chloro-4-[(S)-3-(2-chloro-benzenesulfonyl)-pyrrolidin-1-yl]-pyrimidine (91 mg, 36%) as a light yellow solid. MS: m/z=358.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:16])=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5]([Cl:16])=[O:6]
Reactant: COc1cccc(OC)c1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1cccc(OC)c1C(=O)Cl
Temperature: 25 °C

Procedure:
A 8.5 Kg portion of 2,6-dimethoxybenzoic acid was dissolved in 60 liters of toluene and the solution was stirred at ambient temperature while 6.8 liters of thionyl chloride was added dropwise over forty-five minutes. Following the addition, the reaction mixture next was cooled to room temperature and the solvent was removed by evaporation under reduced pressure, washed with 25 liters of Pet. ether cooled and filtered to provide a crude solid product. The product was stirred for one hour with 25 liters of fresh Pet. ether, and then cooled to 10° C. and filtered to provide 8.94 Kg of 2,6-dimethoxybenzoyl chloride.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]([OH:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)([OH:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH2:21]([O:2][C:1]([C:4]1[CH:13]=[C:12]([O:14][CH2:12][C:11]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)=[O:3])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1cc(O)c2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cc(OCc2ccccc2)c2ccccc2n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 186.4 %

Procedure:
2-carboxy-4-hydroxyquinoline (5 g, 1.0 eq) was dissolved in 50 mL DMF. Cesium carbonate (20 g, 2.3 eq) was added to the solution and the resulting reaction mixture was heated at 50° C. for 20 minutes. Benzyl bromide (10 g, 2.1 eq) was added. The resulting reaction mixture was stirred at 50° C. for 1 hour. Then the reaction mixture was poured into 500 mL ice-water, the precipitate was collected by filtration, and dried in vacuo to afford 2-benzyloxycarbonyl-4-benzyloxyquinoline (9.1 g). 2-benzyloxycarbonyl-4-benzyloxyquinoline (9.0 g) was dissolved in 50 mL THF, and 2 N LiOH solution (20 mL) was added, and the resulting reaction mixture was stirred at ambient temperature for 2 hours. The solvent was then removed in vacuo, and the residue acidified by the addition of 2N NaHSO4 to pH 3–4. The white precipitate was collected to afford 2-carboxy-4-benzyloxyquinoline (7.2 g), which was used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:18])[CH2:11][CH:12]([CH3:17])[CH2:13][C:14]([OH:16])=O)=[CH:5][CH:4]=1)#[N:2].[CH2:19]([N:21]1[C:33]2[CH2:32][CH2:31][CH2:30][CH2:29][C:28]=2[C:27]2[C:22]1=[CH:23][CH:24]=[C:25]([NH2:34])[CH:26]=2)[CH3:20].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:18])[CH2:11][CH:12]([CH3:17])[CH2:13][C:14]([NH:34][C:25]2[CH:26]=[C:27]3[C:22](=[CH:23][CH:24]=2)[N:21]([CH2:19][CH3:20])[C:33]2[CH2:32][CH2:31][CH2:30][CH2:29][C:28]3=2)=[O:16])=[CH:7][CH:8]=1)#[N:2]
Reactant: CC(CC(=O)O)CC(=O)Nc1ccc(C#N)cc1
Reactant: CCn1c2c(c3cc(N)ccc31)CCCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1c2c(c3cc(NC(=O)CC(C)CC(=O)Nc4ccc(C#N)cc4)ccc31)CCCC2
Temperature: 25 °C
Reaction time: 14 h
Yield: 57.7 %

Procedure:
To a solution of 5-(4-cyanophenylamino)-3-methyl-5-oxopentanoic acid (172 mg, 0.70 mmol), 9-ethyl-2,3,4,9-tetrahydro-1H-carbazol-6-amine (150 mg, 0.70 mmol) and DIEA (0.367 mL, 2.10 mmol) in DMF (8 mL) was added HATU (399 mg, 1.05 mmol), and the mixture was stirred at room temperature for 14 hr. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10 to 100% ethyl acetate/hexane) to give the title compound (179 mg, 0.404 mmol, 57.8%) as a white powder.