Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](N(OC)C)=[O:13])[C:9]([N:18]2[CH2:22][CH2:21][CH2:20][C@@H:19]2[CH2:23][O:24][CH3:25])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:26][Mg]Br>O1CCCC1>[Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:13])[CH3:26])[C:9]([N:18]2[CH2:22][CH2:21][CH2:20][C@@H:19]2[CH2:23][O:24][CH3:25])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: COC[C@H]1CCCN1c1c(C(=O)N(C)OC)cc(Cl)c2cccnc12
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: COC[C@H]1CCCN1c1c(C(C)=O)cc(Cl)c2cccnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 12 %

Procedure:
To a mixture of 5-chloro-N-methoxy-8-[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]-N-methylquinoline-7-carboxamide (132 mg, 0.363 mmol) in tetrahydrofuran (0.5 mL) was added 1.40 M methylmagnesium bromide in tetrahydrofuran (1.6 mL, 2.2 mmol). The reaction was stirred at room temperature overnight, quenched with saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, then concentrated to dryness under reduced pressure. The resultant residue was purified on silica gel, eluting with 0 to 10% methanol in dichloromethane, to give the desired product (14 mg, 12%). LCMS calculated for C17H20ClN2O2(M+H)+: m/z=319.1; found: 319.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH:9](OC)[O:10]C)[CH:6]=1.Cl>O1CCCC1>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH:9]=[O:10])[CH:6]=1
Reactant: COC(CC(c1ccccc1)n1cc(Br)cn1)OC
Agent: Cl
Solvent: C1CCOC1
Product: O=CCC(c1ccccc1)n1cc(Br)cn1

Procedure:
A solution of EXAMPLE 77B (0.34 g) and hydrochloric acid (2 mL) in tetrahydrofuran (3.5 mL) was stirred at room temperature for 16 hours. The reaction mixture was concentrated, redissolved in dichloromethane, dried over magnesium sulfate, filtered, and used in the next step without purification.
Reaction SMILES: [CH2:1]([N:3](CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:21])[CH2:16][CH2:17][C:18](O)=[O:19])=[CH:11][C:10]=1[S:22]([Cl:25])(=[O:24])=[O:23].ClC(OCC)=O.CN>O1CCCC1.O>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([OH:21])[N:3]([CH3:1])[C:18](=[O:19])[CH2:17][CH2:16]2)=[CH:11][C:10]=1[S:22]([Cl:25])(=[O:24])=[O:23]
Reactant: CCN(CC)CC
Reactant: O=C(O)CCC(=O)c1ccc(Cl)c(S(=O)(=O)Cl)c1
Agent: CCOC(=O)Cl
Agent: CN
Solvent: C1CCOC1
Solvent: O
Product: CN1C(=O)CCC1(O)c1ccc(Cl)c(S(=O)(=O)Cl)c1
Reaction time: 0.12 h

Procedure:
2.1 g of triethylamine are rapidly added dropwise to a mixture of 6.2 g 4-(4-chloro-3-chlorosulfonylphenyl)-4-oxobutanoic acid and 2.2 g of ethyl chloroformate in 20 ml of absolute tetrahydrofurane at a rate such that the internal temperature is maintained between -5° and -10° C. The mixture is stirred for about 5 to 10 minutes at -5° to 0° C. and 1.55 ml of a 4% strength solution of gaseous methylamine in tetrahydrofurane is rapidly added dropwise. Stirring is continued for 15 to 20 minutes at 10°-15° C., the reaction mixture is poured into water and extracted twice, each time with 80 ml of ethyl acetate. The organic phase is washed once with 50 ml of 0.01 N hydrochloric acid at 0° C. and once with cold bicarbonate solution, dried for one hour over Na2SO4 at 0°-10° C. while stirring with a magnetic stirrer and concentrated on a rotavapor (bath temperature ≤30° C.). The 5-(4-chloro-3-chlorosulfonylphenyl)-5-hydroxy-1-methyl-2-oxo-pyrrolidine is mostly obtained in the form of an amorphous residue. After addition of 20 ml of 40% strength aqueous methylamine solution (cooling) the mixture is stirred overnight at room temperature, concentrated and allowed to crystallize under water. Colorless crystals, melting point 112°-114° C. (from ethanol).
Reaction SMILES: [NH2:1][C:2]1[C:30]([Cl:31])=[CH:29][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:32][CH3:33])[CH:3]=1.[CH:34](=O)[CH2:35][CH3:36].C([BH3-])#N.[Na+]>>[NH2:1][C:2]1[C:30]([Cl:31])=[CH:29][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:34][CH2:35][CH3:36])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:32][CH3:33])[CH:3]=1
Reactant: CCC=O
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNCc2ccccc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCCN(CCCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)CC1)Cc1ccccc1

Procedure:
4-Amino-N-((1-(5-benzylaminopentyl)piperidin-4-yl)methyl)-5-chloro-2-methoxybenzamide (2.0 g) as starting compound, propionaldehyde (0.13 ml) and sodium cyanoborohydride (0.35 g) were reacted and treated in the same manner as in Example 136 to give 1.05 g of 4-amino-5-chloro-2-methoxy-N-((1-(5-(N-n-propyl-N-benzylamino)pentyl)piperidin-4-yl)methyl)-benzamide.
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[O:7])[CH2:2][CH2:3][CH3:4].[CH3:8][N:9]1[C:13](=[CH2:14])[C:12]2([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[O:11][C:10]1=[O:20]>C(#N)C>[CH2:1]([NH:5][C:6]([N:17]1[CH2:18][CH2:19][C:12]2([O:11][C:10](=[O:20])[N:9]([CH3:8])[C:13]2=[CH2:14])[CH2:15][CH2:16]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN=C=O
Reactant: C=C1N(C)C(=O)OC12CCNCC2
Solvent: CC#N
Product: C=C1N(C)C(=O)OC12CCN(C(=O)NCCCC)CC2
Yield: 91.3 %

Procedure:
2.25 ml of n-butyl isocyanate are dropped to a suspension of 3.64 g of 3-methyl-4-methylene-2-oxo-1-oxa-3,8-diazaspiro[4,5]decane in 18 ml of acetonitrile while stirring under argon. Since the reaction is exothermic, the temperature is maintained at 25° to 30° C. by cooling. After 15 minutes the reaction mixture is evaporated under reduced pressure. The white solid evaporation residue is recrystallized from ethyl acetate to obtain the title compound in 91.3% yield, m.p.: 129°-130° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[N:18]([C:19](=[O:37])[N:20]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]=[CH2:36])[CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[CH2:17][CH:16]([O:38]C(=O)C3C=CC([N+]([O-])=O)=CC=3)[CH2:15]2)=[O:13])[CH2:8][CH:7]1C=C)=[O:5])[CH3:2]>ClCCCl>[CH2:1]([O:3][C:4]([C:6]12[CH2:8][CH:7]1[CH:36]=[CH:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][N:20]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)[C:19](=[O:37])[N:18]1[CH:14]([CH2:15][CH:16]([OH:38])[CH2:17]1)[C:12](=[O:13])[NH:11]2)=[O:5])[CH3:2]
Reactant: C=CCCCCCN(Cc1ccc(OC)cc1)C(=O)N1CC(OC(=O)c2ccc([N+](=O)[O-])cc2)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Solvent: ClCCCl
Product: CCOC(=O)C12CC1C=CCCCCCN(Cc1ccc(OC)cc1)C(=O)N1CC(O)CC1C(=O)N2
Temperature: 0 °C
Reaction time: 4 h
Yield: 60.9 %

Procedure:
Compound 2a (1 g, 1.48 mmol) was dissolved in 1,2-dichloroethane (2 l). The mixture was degassed for 15 min using a stream of argon. Hoveyda-Grubbs catalyst (II) (50 mg, 5 mol %) was added and the mixture was refluxed for 4 h. The solvent was evaporated and the crude ester was dissolved in THF (100 ml), methanol (50 ml) and water (50 ml). The mixture was cooled to 0° C. on an ice-bath. Aqueous lithium hydroxide (20 ml, 1M) was added and the mixture was stirred at 0° C. for 4 h. The volume was then doubled by addition of water and the mixture was acidified with acetic acid. Extraction (dichloromethane) followed by flash column chromatography (methanol 1→5% in ether) gave pure title compound (450 mg, 61%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:29]=[N:28][C:13]3[N:14]([CH2:26][CH3:27])[C:15]4[N:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:16]=4[N:17]([CH3:20])[C:18](=[O:19])[C:12]=3[CH:11]=2)[CH:5]=[CH:6][CH:7]=1.N([O-])=O.[Na+].[N-:34]=[N+:35]=[N-].[Na+]>Cl.O>[N:1]([C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:29]=[N:28][C:13]3[N:14]([CH2:26][CH3:27])[C:15]4[N:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:16]=4[N:17]([CH3:20])[C:18](=[O:19])[C:12]=3[CH:11]=2)[CH:5]=[CH:6][CH:7]=1)=[N+:34]=[N-:35]
Reactant: CCN1c2ncc(CCc3cccc(N)c3)cc2C(=O)N(C)c2ccc(Cl)nc21
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCN1c2ncc(CCc3cccc(N=[N+]=[N-])c3)cc2C(=O)N(C)c2ccc(Cl)nc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 72.6 %

Procedure:
8-[2-(3-Aminophenyl)ethyl]-2-chloro-5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.22 g, 0.54 mmol) was dissolved in 0.55 mL of concentrated hydrochloric acid. Water (2.8 mL) was added and the solution was cooled to 0° C. producing a precipitate. A solution of sodium nitrite (0.19 g, 2.75 mmol) in 8 mL of water was added dropwise. After 20 min, a solution of sodium azide (0.27 g, 4.15 mmol) in 3 mL of water was added in the dark. After 15 min, the product was extracted with ethyl acetate. Purification by flash chromatography, eluting with ethyl acetate/hexanes, and recrystallization (ether/petroleum ether) afforded 0.17 g of the title compound, m.p. 104°-105° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH:5]([N:9]([CH:23]1[CH2:25][CH2:24]1)[C:10](=O)[C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=1)[C:6](=O)[CH3:7])[CH3:2].FC(F)(F)C([O-])=O.[NH4+:34]>CO>[CH2:1]([O:3][C:4]([C:5]1[N:9]([CH:23]2[CH2:25][CH2:24]2)[C:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)=[N:34][C:6]=1[CH3:7])=[O:26])[CH3:2]
Reactant: CCOC(=O)C(C(C)=O)N(C(=O)c1ccc(OC(F)(F)F)cc1)C1CC1
Reactant: [NH4+]
Agent: O=C([O-])C(F)(F)F
Solvent: CO
Product: CCOC(=O)c1c(C)nc(-c2ccc(OC(F)(F)F)cc2)n1C1CC1
Temperature: 110 °C
Yield: 70.6 %

Procedure:
To 0.15 g (0.4 mmol) of 2-[cyclopropyl-(4-trifluoromethoxy-benzoyl)-amino]-3-oxo-butyric acid ethyl ester in 5 ml of MeOH was added 0.2 g (1.5 mmol) of ammonium trifluoroacetate. The MeOH was evaporated and the residue heated to 110° C. for 4 h. The cooled residue was partitioned between saturated sodium hydrogen carbonate solution and CH2Cl2. The organic phase was dried with sodium sulfate and concentrated. Purification by flash column chromatography [n-heptane/EtOAc 3:7 to 1:1] afforded 0.1 g (73%) of the title compound as a colorless solid. MS: 355.2 (MH+).
Reaction SMILES: [Cl:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[C:22]3[C:21](=[O:23])[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([N+:24]([O-:26])=[O:25])[CH:19]=4)[C:14](=[O:27])[C:13]=3[C:12](Br)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[CH2:29]([NH2:33])[CH2:30][CH2:31][CH3:32].C([O-])(=O)C.[Cl-]>COCCO.[Cu]>[Cl:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[C:22]3[C:21](=[O:23])[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([N+:24]([O-:26])=[O:25])[CH:19]=4)[C:14](=[O:27])[C:13]=3[C:12]([NH:33][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: O=C1c2ccc([N+](=O)[O-])cc2C(=O)c2c(NC3CCC(Cl)CC3)ccc(Br)c21
Reactant: CCCCN
Agent: [Cu]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: COCCO
Product: CCCCNc1ccc(NC2CCC(Cl)CC2)c2c1C(=O)c1ccc([N+](=O)[O-])cc1C2=O

Procedure:
10 g of 1-(p-chlorocyclohexylamino)-4-bromo-7-nitroanthraquinone, 60 ml of n-butylamine, 2.5 g of K acetate, 50 mg of copperI chloride and a trace of copper are heated under reflux until only a little starting material remains detectable in a sample. The mixture is diluted with 35 ml of ethylene glycol monomethyl ether and the product is filtered off and washed with methanol and water. 6.5 g of 1-(p-chlorocyclohexylamino)-4-butylamino-7-nitroanthraquinone are obtained.
Reaction SMILES: [CH:1]1[C:13]2[N:12]([C:14]3[CH:15]=[C:16](B(O)O)[CH:17]=[N:18][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:24]1[CH:25]=[C:26]([C:30]2[N:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:33]3[CH:41]=[CH:42][CH:43]=[CH:44][C:32]=3[N:31]=2)[CH:27]=[N:28][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:35]1([N:34]2[C:33]3[CH:41]=[CH:42][CH:43]=[CH:44][C:32]=3[N:31]=[C:30]2[C:26]2[CH:25]=[C:24]([C:16]3[CH:17]=[N:18][CH:19]=[C:14]([N:12]4[C:13]5[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=5[C:6]5[C:11]4=[CH:10][CH:9]=[CH:8][CH:7]=5)[CH:15]=3)[CH:29]=[N:28][CH:27]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Brc1cncc(-c2nc3ccccc3n2-c2ccccc2)c1
Reactant: OB(O)c1cncc(-n2c3ccccc3c3ccccc32)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: c1ccc(-n2c(-c3cncc(-c4cncc(-n5c6ccccc6c6ccccc65)c4)c3)nc3ccccc32)cc1
Temperature: 90 °C
Yield: 49 %

Procedure:
A mixture of (5-(9H-carbazol-9-yl)pyridin-3-yl)boronic acid (2C) (0.90 g, 3.1 mmol), 2-(5-bromopyridin-3-yl)-1-phenyl-1H-benzo[d]imidazole (1F) (0.856 g, 3.1 mmol), Pd(PPh3)4 (0.18 g, 0.155 mmol) and potassium carbonate (1.07 g, 7.8 mmol) in dioxane/water (20 mL/5 mL) was degassed and heated at about 90° C. overnight under argon atmosphere. The whole was poured into ethyl acetate (100 mL), then washed with brine (50 mL). The organic phase was collected and dried over Na2SO4, absorbed on silica gel, then purified by flash column (dichloromethane/methanol 40:1) to give a light yellow solid (0.78 g), which was purified again by flash column (silica gel, dichloromethane/methanol 50:1) followed by recrystallization in dichloromethane/methanol to give HTH-2, a light yellow solid (0.60 g, 38% yield).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH:26][CH:27]1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H:28]1O>>[OH:26][CH:27]([C:23]1[CH:24]=[CH:25][C:20]([N:14]2[CH:15]=[C:16]([C:17]([NH2:19])=[O:18])[C:12]([NH:11][C:8]3[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=3)=[N:13]2)=[CH:21][CH:22]=1)[CH3:28]
Reactant: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O
Reactant: CS(=O)(=O)c1ccc(Nc2nn(-c3ccccc3)cc2C(N)=O)cc1
Product: CC(O)c1ccc(-n2cc(C(N)=O)c(Nc3ccc(S(C)(=O)=O)cc3)n2)cc1

Procedure:
As a specific embodiment of this invention, 100 mg of 3-{[4-(methylsulfonyl)phenyl]amino}-1-phenyl-1H-pyrazole-4-carboxamide is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0, hard-gelatin capsule.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:11][CH3:12])[O:9][CH3:10])=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1.CC([O-])(C)C.[K+].[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:10][O:9][CH:8]([O:11][CH3:12])[C:5]1[CH:6]=[CH:7][C:2]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:3][C:4]=1[C:13]([F:16])([F:15])[F:14]
Reactant: COC(OC)c1ccc(Cl)cc1C(F)(F)F
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COC(OC)c1ccc(N2CCOCC2)cc1C(F)(F)F
Temperature: 25 °C
Yield: 10.4 %

Procedure:
A mixture of 4-chloro-1-(dimethoxymethyl)-2-(trifluoromethyl)benzene (18; 3.20 g, 12.6 mmol), Pd2(dba)3 (0.30 g, 0.33 mmol), t-BuOK (3.50 g, 31.2 mmol) and morpholine (48; 1.09 g, 12.6 mmol) in anhydrous toluene (50 mL) was stirred under reflux for 12 h under an inert atmosphere of nitrogen. Upon cooling to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by chromatography (petroleum ether:ethyl acetate=10:1) to give 4-(4-(dimethoxymethyl)-3-(trifluoromethyl)phenyl)morpholine 19 (0.40 g, 10.4%).
Reaction SMILES: [C:1]1([S:7]([N@:10]2[CH2:12][CH:11]2[C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[CH3:28])[CH2:17][CH2:16]2)=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[Na+].[F:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1>>[C:1]1([S:7]([N:10]2[CH2:12][C@@H:11]([C:13]([N:15]3[CH2:16][CH2:17][N:18]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[CH3:28])[CH2:19][CH2:20]3)=[O:14])[N:38]([C:35]3[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=3)[C:39]2=[O:40])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3C[N@@]3S(=O)(=O)c3ccccc3)CC2)c1
Agent: [I-]
Agent: [Na+]
Product: Cc1ccc(C)c(N2CCN(C(=O)[C@@H]3CN(S(=O)(=O)c4ccccc4)C(=O)N3c3ccc(F)cc3)CC2)c1

Procedure:
In analogy to example 2, ((S)-1-benzenesulfonyl-aziridin-2-yl)-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-methanone (example 21, step 3) was reacted with sodium iodide and 4-fluorophenylisocyanate to give the title compound as a colorless solid. MS: 537.2 ([M+H]+)
Reaction SMILES: [C:1]([Si:5]([O:8]/[C:9](/[C:12]1[CH:17]=[CH:16][CH:15]=[C:14](Cl)[CH:13]=1)=[CH:10]\[CH3:11])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[F:19]CCC(C1C=CC=CC=1)=O.[Si](OS(C(F)(F)F)(=O)=O)(C(C)(C)C)(C)C.CCN(CC)CC>C(Cl)Cl>[C:1]([Si:5]([O:8]/[C:9](/[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:19])[CH:13]=1)=[CH:10]\[CH3:11])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: C/C=C(\O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Reactant: O=C(CCF)c1ccccc1
Agent: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C/C=C(\O[Si](C)(C)C(C)(C)C)c1cccc(F)c1
Yield: 93 %

Procedure:
Compound 9c was synthesized by a procedure similar to that described for 9a using commercially available 3-fluoropropiophenone (8c, 5.0 g, 0.033 mol), TBDMSOTf (8.3 mL, 36.1 mmol), and Et3N (7.3 mL) in CH2Cl2 (50 mL). After purification, 8.1 g (93%) of 9c was isolated as colorless oil: 1H NMR (CDCl3) δ 7.38-7.10 (m, 2H), 7.00-6.87 (m, 1H), 5.26 (q, 1H, J=6.9 Hz), 1.75 (d, 3H, J=6.9 Hz), 1.00 (s, 9H), −0.02 (s, 6H); 13C NMR (CDCl3) δ 164.5, 161.2, 149.2, 142.4, 129.4, 121.4, 114.3, 114.0, 112.8, 112.5, 107.1, 105.9, 26.0, 18.5, 11.9, −3.9. C15H23FOSi.
Reaction SMILES: [C:1]1([CH2:9][OH:10])[C:2]([CH2:7][OH:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[H-].[Na+].I[CH3:14].Cl>CN(C=O)C.O.CCOC(C)=O>[CH3:14][O:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH2:9][OH:10]
Reactant: CI
Reactant: OCc1ccccc1CO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCc1ccccc1CO
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1,2-benzenedimethanol (1.38 g, 10 mmol) in DMF (10 mL) cooled in an ice bath is added NaH (400 mg, 60% in mineral oil, 10 mmol) in portions. The mixture is stirred at 0° C. for 15 min then at RT for 30 min. To this is added iodomethane (1.45 g, 10.2 mmol) dropwise and the mixture is stirred at RT for 1 h. Ice, EtOAc and water is added and the mixture is acidified with 1N HCl. The organic phase is washed with water and brine then is dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue purified by column chromatography using a gradient of 0-100% EtOAc/hexane as eluent to give the title compound.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[C:11]([C:15]([O:17]C)=[O:16])[NH:12]2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[OH-].[Li+]>CO.O>[CH3:1][S:2]([NH:5][C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[C:11]([C:15]([OH:17])=[O:16])[NH:12]2)=[CH:8][CH:7]=1)(=[O:3])=[O:4]
Reactant: COC(=O)c1cc2ccc(NS(C)(=O)=O)cc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)Nc1ccc2cc(C(=O)O)[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
To 333 mg (1.24 mmol) of methyl 6-[(methylsulfonyl)amino]-1H-indole-2-carboxylate dissolved in 8 mL methanol was added 130 mg (3.10 mmol) lithium hydroxide dissolved in 2 mL water. The mixture was stirred at room temperature overnight, partitioned between ethyl acetate and 1 N hydrochloric acid, was dried over magnesium sulfate and concentrated to obtain 230 mg of 6-[(methylsulfonyl)amino]-1H-indole-2-carboxylic acid.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)=[N:8][C:9]=2[N:11]2[CH2:17][CH:16]3[O:18][CH:13]([CH2:14][CH2:15]3)[CH2:12]2)[N:4]([CH2:28][CH3:29])[N:3]=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+].[NH:82]1[CH2:86][CH2:85][CH2:84][CH2:83]1>C1(C)C=CC=CC=1>[CH2:28]([N:4]1[C:5]2=[N:6][C:7]([C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)=[N:8][C:9]([N:11]3[CH2:12][CH:13]4[O:18][CH:16]([CH2:15][CH2:14]4)[CH2:17]3)=[C:10]2[C:2]([N:82]2[CH2:86][CH2:85][CH2:84][CH2:83]2)=[N:3]1)[CH3:29]
Reactant: C1CCNC1
Reactant: CCn1nc(Br)c2c(N3CC4CCC(C3)O4)nc(-c3ccc([N+](=O)[O-])cc3)nc21
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CCn1nc(N2CCCC2)c2c(N3CC4CCC(C3)O4)nc(-c3ccc([N+](=O)[O-])cc3)nc21

Procedure:
To a solution of 3-bromo-1-ethyl-6-(4-nitrophenyl)-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidine (100 mg)(0.21 mmol) in toluene (2.0 mL) was added Pd(dba)3 (20 mg)(10 mol %), Binap (80 mg) (30 mol %), sodium tert butoxide (82 mg) and excess pyrrolidine. The mixture was purged under nitrogen for 5 minutes and then heated to 65 C overnight. Concentrated in vacuo to give an oil that was purified by silica gel chromatography (EtOAc/Hexanes) to afford 35 mg of the desired product as a yellow oil. MS m/z=450 (M+H)
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH2:12][C:13]#[CH:14])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][C:32]([O:34][CH3:35])=[O:33])[C:24]=1[CH2:25]Cl>CO>[CH3:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][C:32]([O:34][CH3:35])=[O:33])[C:24]=1[CH2:25][NH:1][C:2]1[C:3]2[N:4]([C:8]([CH2:12][C:13]#[CH:14])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C#CCc1c(C)nc2c(N)cccn12
Reactant: COC(=O)Nc1cccc(C)c1CCl
Solvent: CO
Solvent: CCN(CC)CC
Product: C#CCc1c(C)nc2c(NCc3c(C)cccc3NC(=O)OC)cccn12
Temperature: 25 °C
Reaction time: 17 h
Yield: 38.8 %

Procedure:
To a solution of 8-amino-3-(2-propynyl)-2-methylimidazo[1,2-a]pyridine (8.0 g) and triethylamine (4.8 g) in methanol (80 ml) was added 2-methyl-6-methoxycarbonylaminobenzyl chloride (10.15 g) and the mixture was stirred at room temperature for 17 hours. After methanol was evaporated in vacuo, the resultant residue was dissolved in methylene chloride (100 ml) and the mixture was washed with water and dried over magnesium sulfate. The solvent was evaporated in vacuo. The resultant residue was subjected to column chromatography on silica gel (240 g) and eluted with a mixture of chloroform and ethyl acetate (20:1) to give a crystalline product. The crystals were recrystallized from a mixture of ethyl acetate and n-hexane to give 8-(2-methyl-6-methoxycarbonylaminobenzylamino)-3-(2-propynyl)-2-methylimidazo[1,2-a]pyridine (6.08 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[NH:17][C:16](=O)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:28]([NH2:32])[CH2:29][CH2:30][CH3:31]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[N:17]=[C:16]([NH:32][CH2:28][CH2:29][CH2:30][CH3:31])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCN
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(=O)[nH]c3cc(Cl)ccc23)CC1
Agent: [H-]
Agent: [Na+]
Product: CCCCNc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c2ccc(Cl)cc2n1

Procedure:
4-[4-(tert-Butoxycarbonyl)piperazin-1-yl]-7-chloroquinol-2-one (150 mg, 0.41 mmol), sodium hydride (15 mg, 0.6 mmol), N-phenyl(trifluoromethylsulfon)imide (208 mg, 0.58 mmol), and n-butylamine (0.16 mL, 1.65 mmol) are treated according to method E yielding the title product.