Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH3:27])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]([CH3:18])=[N:14][O:15][C:16]=2[CH3:17])=[C:8]([C:19]#[C:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:7]=1)=[O:4].[CH3:28][C:29](=O)[CH3:30].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:18][C:13]1[C:12]([C:9]2[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[CH:2]([NH:1][CH:29]([CH3:30])[CH3:28])[CH3:27])=[N:7][C:8]=2[C:19]#[C:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[C:16]([CH3:17])[O:15][N:14]=1
Reactant: Cc1noc(C)c1-c1ccc(NC(=O)C(C)N)nc1C#Cc1ccccc1
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1noc(C)c1-c1ccc(NC(=O)C(C)NC(C)C)nc1C#Cc1ccccc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-amino-N-[5-(3,5-dimethyl-1,2-oxazol-4-yl)-6-(2-phenylethynyl)pyridin-2-yl]propanamide (example 165, 20 mg, 0.06 mmol), propan-2-one (16.2 ml, 0.28 mmol), acetic acid (4 μl, 0.07 mmol), MeOH (0.5 ml) and sodium cyanoborohydride (5.5 mg, 0.08 mmol) is stirred at 50° C. for 30 minutes. The reaction mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 11 mg (48%). HPLC-MS: M+H=403; tR=1.52 min (*Method—1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:56][C:57]1[CH:58]=[C:59]2[C:64](=[CH:65][CH:66]=1)[CH:63]=[C:62]([C:67]([O:69][CH3:70])=[O:68])[CH:61]=[CH:60]2.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:70][O:69][C:67]([C:62]1[CH:61]=[CH:60][C:59]2[C:64](=[CH:65][CH:66]=[C:57]([NH:56][C:28]([C@H:9]3[C@H:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=4[F:31])[C@:12]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[NH:10]3)=[O:29])[CH:58]=2)[CH:63]=1)=[O:68]
Reactant: COC(=O)c1ccc2cc(N)ccc2c1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc2cc(NC(=O)[C@@H]3N[C@@H](CC(C)(C)C)[C@](C#N)(c4ccc(Cl)cc4F)[C@H]3c3cccc(Cl)c3F)ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid (233.5 mg, 0.50 mmol), HATU (190 mg, 0.50 mmol), methyl 6-amino-2-naphthoate (208 mg, 1 mmol) and DIPEA (0.2 mL) were combined with methylene chloride (10 ml) and the mixture was stirred at rt overnight.
Reaction SMILES: [NH:1]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl-:16].[Mn+2:17].[Cl-:18]>CO>[Cl:16][CH:2]1[CH2:3][NH:4][CH2:5][CH2:6][NH:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][N:1]1[Cl:18].[Mn+2:17]
Reactant: C1CNCCNCCNCCNCCN1
Reactant: [Cl-]
Agent: [Mn+2]
Solvent: CO
Product: ClC1CNCCNCCNCCNCCN1Cl
Yield: 88 %

Procedure:
A solution of 1,4,7,10,13-pentaazacyclopentadecane prepared as in Example 1E (2.0 g, 9.3 mmole) and anhydrous manganese(II) chloride (1.2 g, 9.3 mmole) in anhydrous methanol (50 ml) was refluxed under a dry nitrogen atmosphere for 3 h. The solution was filtered and the solvent removed in vacuo. The resulting solid was recrystallized from ethanol-ethyl ether to give 2.79 g (88% yield) of the product as an off-white crystalline solid: FAB mass spectrum (NBA) m/z (relative intensity) 340 (M+, 2), 305/307 ((M-Cl)+ 100/45)); Anal. Calcd. for C10H25Cl2MnN5 : C, 35.17; H, 7.38; Cl, 20.76; N 20.60. Found: C, 34.95; H, 7.31; Cl, 20.49; N, 20.22.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[O:10])[CH:4]=1.CN(C)C=O.[CH3:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31]Br>C(#N)C>[CH3:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20](=[O:21])[C:11]([C:9]([C:5]2[CH:4]=[N:3][CH:8]=[CH:7][CH:6]=2)=[O:10])=[CH:12]1
Reactant: O=C(c1cccnc1)c1c[nH]c2ccccc2c1=O
Reactant: Cc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cc1cccc(Cn2cc(C(=O)c3cccnc3)c(=O)c3ccccc32)c1

Procedure:
Compound 4hh was prepared following the procedure outlined in Step 3 of Example 1 using 16 mg (0.40 mmol) of sodium hydride (60%), 75 mg (0.30 mmol) of 3-(pyridine-3-carbonyl)-1H-quinolin-4-one, 3 mL of anhydrous dimethylformamide, and 74.0 mg (0.4 mmol) of 3-methylbenzylbromide. The crude product was purified by flash chromatography to yield 35 mg of 4hh as a colorless solid: LC-MSD, m/z for C23H18N2O2, [M+H]+=355.4, [M+2H]+=356.4; Reverse phase HPLC (gradient acetonitrile 0.1% TFA 20-95% in 4 min) retention time=1.710 min; 1H NMR (400 MHz, CDCl3/HCl): δ 2.36 (s, 3H), 5.41 (s, 2H), 7.00 (d, 2H), 7.12-7.28 (m, 2H), 7.34-7.45 (m, 3H), 7.60 (m, 1H), 8.09 (m, 1H), 8.42-8.46 (m, 2H), 8.71 (m, 2H), 8.99 (s, 1H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]=1[CH3:13].CNCC1C=CC2C(=CC=CC=2)C=1CCC.[ClH:30].[N:31]1([CH2:37][CH2:38][N:39]2[CH2:45][C:44]3[CH:46]=[C:47](/[CH:50]=[CH:51]/[C:52](O)=[O:53])[CH:48]=[N:49][C:43]=3[NH:42][C:41](=[O:55])[CH2:40]2)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1>>[ClH:30].[CH3:1][N:2]([CH2:3][C:4]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]=1[CH3:13])[C:52](=[O:53])/[CH:51]=[CH:50]/[C:47]1[CH:48]=[N:49][C:43]2[NH:42][C:41](=[O:55])[CH2:40][N:39]([CH2:38][CH2:37][N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)[CH2:45][C:44]=2[CH:46]=1
Reactant: CNCc1sc2ccccc2c1C
Reactant: O=C(O)/C=C/c1cnc2c(c1)CN(CCN1CCOCC1)CC(=O)N2
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CN(CCN2CCOCC2)CC(=O)N3)sc2ccccc12
Yield: 74 %

Procedure:
According to the procedure of Example 1, except substituting methyl-(3-methyl-benzo[b]thiophen-2-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-[4-(2-morpholin-4-yl-ethyl)-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl]acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (90 mg, 74%) was prepared as a tan solid: 1H NMR (300 MHz, DMSO-d6) δ 10.58 (br s, 2H), 8.62 (s, 1H), 8.27-8.25 (m, 1H), 7.88-7.86 (m, 1H), 7.75-7.72 (m, 1H), 7.61-7.53 (m, 1H), 7.42-7.29 (m, 3H), 5.15-4.89 (m, 2H), 4.03-3.65 (m, 12H), 3.28-3.17 (m, 4H), 3.01-2.64 (m, 3H), 2.42 (s, 3H); MS (ESI) m/e 520 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[C:5]2[CH2:6][N:7]([C:10](=[O:12])[CH3:11])[CH2:8][CH2:9][N:4]2[N:3]=1.Br[C:15]1[C:16](=[O:23])[N:17]([CH3:22])[CH:18]=[C:19]([Br:21])[CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.CO.CCOCC.CCOC(C)=O.O>[C:10]([N:7]1[CH2:8][CH2:9][N:4]2[N:3]=[C:2]([NH:1][C:15]3[C:16](=[O:23])[N:17]([CH3:22])[CH:18]=[C:19]([Br:21])[CH:20]=3)[CH:13]=[C:5]2[CH2:6]1)(=[O:12])[CH3:11]
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: CC(=O)N1CCn2nc(N)cc2C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(=O)N1CCn2nc(Nc3cc(Br)cn(C)c3=O)cc2C1
Temperature: 100 °C
Yield: 41 %

Procedure:
A sealed tube was equipped with a magnetic stirrer and charged with 125f (860 mg, 4.8 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (1.8 g, 6.7 mmol), and cesium carbonate (3.4 g, 10.5 mmol) in 1,4-dioxane (67 mL). After bubbling nitrogen through the solution for 30 min, Xantphos (330 mg, 0.6 mmol) and tris(dibenzylideneacetone) dipalladium(0) (300 mg, 0.3 mmol) were added, and the reaction mixture was heated to 100° C. for 16 h. After this time, H2O (50 mL) and EtOAc (50 mL) were added. The aqueous layer was separated and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine (100 mL) and dried over sodium sulfate. The resulting residue was purified by column chromatography eluting with a gradient of CH2Cl2— 60:35:5 CH2Cl2:Et2O:MeOH to afford a 41% yield of 125g (720 mg).
Reaction SMILES: [N:1]#[N:2].[CH2:3]([O:10][C:11]([C@@:13]1([C:23]([NH2:25])=[O:24])[CH2:17][C@H:16]([OH:18])[CH2:15][N:14]1[C:19]([CH3:22])([CH3:21])[CH3:20])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28].O>N1C=CC=CC=1>[N:1]#[N:2].[CH2:3]([O:10][C:11]([C@@:13]1([C:23]([NH2:25])=[O:24])[CH2:17][C@H:16]([O:18][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:15][N:14]1[C:19]([CH3:21])([CH3:22])[CH3:20])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)N1C[C@@H](O)C[C@]1(C(N)=O)C(=O)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: N#N
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)N1C[C@@H](OS(C)(=O)=O)C[C@]1(C(N)=O)C(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
0.32 g of N2 -(benzyloxycarbonyl)-N1 -tert.butyl-4(S)-hydroxy-L-prolinamide was dissolved in 5 ml of dry pyridine while stirring, cooled to 0° C. and treated dropwise with 0.82 ml of methanesulphonyl chloride. The solution was stirred at 0° C. for a further 2 hours. The mixture was poured into a mixture of ice and water which was then extracted with ethyl acetate. The combined organic extracts were washed with 2M hydrochloric acid and then with saturated sodium bicarbonate solution and subsequently dried over anhydrous sodium sulphate. After evaporation there was obtained 0.5 g of N2 -(benzyloxycarbonyl)-N1 -tert.butyl-4(S)-(methanesulphonyloxy)-L-prolinamide as an oil which was used without further purification.
Reaction SMILES: [C:1](=[N:9]O)([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11](=[S:13])=[S:12].C[O-].[Na+]>C(O)C>[SH:13][C:11]1[S:12][N:9]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:8]=1
Reactant: S=C=S
Reactant: NC(=NO)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: Sc1nc(-c2ccccc2)ns1
Yield: 39 %

Procedure:
A mixture of benzamidoxime (270 parts) carbon disulphide (152 parts), 5-normal sodium methoxide (40 parts) and ethanol (200 parts) were heated at reflux for 16 hours. The solution was evaporated to dryness and the residue washed with 3-normal hydrochloric acid to give 5-mercapto-3-phenyl-1,2,4-thiadiazole (152 parts, 39% yield), melting point 147°-148° C.
Reaction SMILES: [CH3:1][N:2]([C@H:9]1[CH2:14][CH2:13][CH2:12][C@@H:11]([O:15][C:16]2[C:17]([CH3:31])=[C:18]3[C:22](=[CH:23][CH:24]=2)[N:21](C2CCCCO2)[N:20]=[CH:19]3)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.O1CCOCC1>C(O)(C)C>[CH3:1][N:2]([C@H:9]1[CH2:14][CH2:13][CH2:12][C@@H:11]([O:15][C:16]2[C:17]([CH3:31])=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][N:20]=[CH:19]3)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1c(O[C@@H]2CCC[C@H](N(C)c3ccccc3)C2)ccc2c1cnn2C1CCCCO1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: Cc1c(O[C@@H]2CCC[C@H](N(C)c3ccccc3)C2)ccc2[nH]ncc12
Yield: 87.2 %

Procedure:
Under nitrogen, N-methyl-N-[cis-3-[(4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)oxy]cyclohexyl]-N-phenylamine (89 mg, 0.212 mmol) was dissolved in isopropyl alcohol (4 ml), followed by adding thereto a 4N-hydrochloric acid/1,4-dioxane solution (4 ml), and the resulting mixture was stirred at room temperature for 22 hours. The solvent was distilled off under reduced pressure, and the residue was neutralized with aqueous ammonia and concentrated to dryness under reduced pressure. The resulting concentration residue was purified by a silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1) to obtain N-methyl-N-[cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl]-N-phenylamine (62 mg, yield 87.1%) as a white amorphous substance.
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N+:4]([O-:8])[CH:3]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH3:26][CH:27]1[CH2:32][CH2:31][CH2:30][N:29]([CH2:33][C:34]2[CH:35]=[C:36]([CH:42]=[CH:43][CH:44]=2)[O:37][CH2:38][CH2:39][CH2:40][NH2:41])[CH2:28]1>C(Cl)Cl>[CH3:26][CH:27]1[CH2:32][CH2:31][CH2:30][N:29]([CH2:33][C:34]2[CH:35]=[C:36]([CH:42]=[CH:43][CH:44]=2)[O:37][CH2:38][CH2:39][CH2:40][NH:41][C:1]([C:2]2[CH:3]=[N+:4]([O-:8])[CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:28]1
Reactant: CC1CCCN(Cc2cccc(OCCCN)c2)C1
Reactant: O=C(O)c1ccc[n+]([O-])c1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CCCN(Cc2cccc(OCCCNC(=O)c3ccc[n+]([O-])c3)c2)C1
Reaction time: 0.5 h

Procedure:
To a solution of 0.03 mol of nicotinic acid 1-oxide in 40 ml of methylene chloride containing 10 ml of triethylamine, is added, at the temperature of from 0° to 5° C. and within about 10 minutes, 0.03 mol of isobutyl chloroformate dissolved in 15 ml of methylene chloride, then the mixture is stirred 30 minutes at the same temperature. To the same mixture and at the same temperature there is added 0.03 mol of 3-[3-(3-methylpiperidinomethyl)phenoxy]propylamine dissolved in 15 ml of methylene chloride, then, after a 2 hours stirring at room temperature, the reaction mixture is washed with 10 ml of water. The organic phase is filtered, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue is purified by chromatography on silica as described in Example 7 to yield the N-[3-[3-(3-methylpiperidinomethyl)phenoxy]propyl]-3-pyridinecarboxamide 1-oxide, identical to the product of Example 8.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=1.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1B(O)O.C([O-])([O-])=O.[K+].[K+]>C1(C)C(CO)=CC=CC=1>[C:7]1([N:5]2[CH:6]=[C:2]([C:14]3[S:13][CH:17]=[CH:16][CH:15]=3)[CH:3]=[N:4]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Brc1cnn(-c2ccccc2)c1
Reactant: OB(O)c1cccs1
Agent: Cc1ccccc1CO
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccc(-n2cc(-c3cccs3)cn2)cc1
Temperature: 80 °C
Yield: 27.6 %

Procedure:
4-Bromo-1-phenyl-1H-pyrazole (150 mg, 0.672 mmol), thiophen-2-ylboronic acid (296 mg, 2.31 mmol), PEPPSI-iPr (13.6 mg, 0.062 mmol), and K2CO3 (480 mg, 3.48 mmol) were combined in toluene-methanol (1:1) (2 ml). The reaction mixture was heated under microwave at 80° C. for 10 minutes. The reaction mixture was then filtered and washed with toluene-methanol (5 ml), and the filtrate was concentrated. The crude mixture was then column purified using 15-20% ethyl acetate/hexane to yield 1-phenyl-4-(thiophen-2-yl)-1H-pyrazole (42 mg, yield 27%). The HPLC purity of the final product was 99.32%. LC-MS [M+H] 227 (C13H10N2S+H expected 227.06). The 1H-NMR spectra was in accordance with the chemical structure.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:28][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[C:21]([CH3:26])[C:20]([CH3:27])=[N:19]4)(=O)=O)=CC=1.[NH:29]1[CH2:34][CH:33]=[C:32]([C:35]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[NH:37][CH:36]=2)[CH2:31][CH2:30]1>CS(C)=O.C(OCC)(=O)C>[NH:37]1[C:38]2[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:35]([C:32]2[CH2:33][CH2:34][N:29]([CH2:12][CH:13]3[O:28][C:17]4=[C:18]5[C:23](=[CH:24][CH:25]=[C:16]4[O:15][CH2:14]3)[N:22]=[C:21]([CH3:26])[C:20]([CH3:27])=[N:19]5)[CH2:30][CH:31]=2)=[CH:36]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nc(C)c(C)nc4c3O2)cc1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1nc2ccc3c(c2nc1C)OC(CN1CC=C(c2c[nH]c4ccccc24)CC1)CO3
Temperature: 80 °C

Procedure:
To a solution of [(2R)-8,9-dimethyl-2,3-dihydro[1,4]dioxino[2,3-f]-quinoxalin-2-yl]methyl 4-methylbenzenesulfonate (0.400 g, 1.000 mmole) in methyl sulfoxide (20 mL) was added 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.495 g, 2.497 mmole) and the reaction mixture was heated to 80° C. for 12 hours. The reaction mixture was allowed to cool to room temperature and was diluted with ethyl acetate (250 mL), washed with water (2×100 mL), aqueous sodium chloride (100 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, methanol:ethyl acetate 1:9) followed by recrystallization from ethanol provided 0.262 g (62%) of the (S)-enantiomer of the title compound as a pale yellow solid. Rf=0.32 (silica, methanol:ethyl acetate 1:9); mp 153–155° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:7](=[O:14])[NH:6][C:5]2=[O:15].N1C=CN=C1.[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24]N.CCOCC>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:7](=[O:14])[N:6]([CH2:24][CH2:23][N:22]([CH3:26])[CH3:21])[C:5]2=[O:15]
Reactant: CN(C)CCN
Reactant: Nc1cc2c(cc1[N+](=O)[O-])C(=O)NC2=O
Agent: c1c[nH]cn1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCOCC
Product: CN(C)CCN1C(=O)c2cc(N)c([N+](=O)[O-])cc2C1=O
Temperature: 150 °C
Yield: 95.2 %

Procedure:
To a suspension of 5-Amino-6-nitroisoindoline-1,3-dione (5.0 g, 24.15 mmol) in Dowtherm (75 mL) were added imidazole (1.64 g, 24.15 mmol) and N′,N′-dimethylethane-1,2-diamine (3.16 mL, 24.15 mmol) and the resulting mixture was heated at 150° C. for overnight. The reaction mixture was cooled to RT, was added ether (100 mL). The yellow precipitate was collected by filtration and washed with ether (2×50 mL) and dried to afford 5-Amino-2-(2-(dimethylamino)ethyl)-6-nitroisoindoline-1,3-dione (6.4 g, 95%) as a yellow solid.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH:4]=[C:3]([C:7]([O-:9])=[O:8])[CH2:2]1.B(O[O-])=O.[Na+].O.[OH-].[Na+].[C:18](O)(=O)C>>[S:1]1[CH2:6][CH2:5][CH:4]=[C:3]([C:7]([O:9][CH3:18])=[O:8])[CH2:2]1
Reactant: CC(=O)O
Reactant: O=C([O-])C1=CCCSC1
Agent: O=BO[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)C1=CCCSC1
Temperature: 55 °C
Reaction time: 19 h
Yield: 76 %

Procedure:
To a solution of 0.934 gm (5.75 mmol) of 5,6-dihydro-2H-thiopyran-3-carboxylate from part C in glacial acetic acid (40 mL) was added 1.98 gm (12.88 mmole) sodium perborate. The reaction mixture was stirred at 55° C. under N2 for 19 hrs. whereupon the solution was poured into H2O (50 mL) and neutralized with 50% NaOH to pH=7. The solution was extracted three times with methylene chloride. The combined organic layers were washed once with saturated sodium bicarbonate and once with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated in vacuo to give 0.832 gm (76%) of methyl 5,6-dihydro-2H-thiopyran-3-carboxylate, 1,1 dioxide as a white solid; mass spectrum m/e=190 (EI, M+)
Reaction SMILES: [CH3:1][C:2]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4].[Cl:10]N1C(=O)CCC1=O>CC#N>[Cl:10][C:7]1[CH:6]=[CH:5][C:3]([OH:4])=[C:2]([CH3:1])[C:8]=1[OH:9]
Reactant: Cc1c(O)cccc1O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: Cc1c(O)ccc(Cl)c1O

Procedure:
To a solution of 2-methyl resorcinol (1 eq) in MeCN (5 ml) was added N-chlorosuccinimide (1 eq) and refluxed under nitrogen overnight. The yellow solution was concentrated in vacuo and purified by flash chromatography to give 4-chloro-2-methyl-benzene-1,3-diol as a solid.
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4]O.[C:7]([O-:13])([O-])([O:9][CH2:10][CH3:11])[CH3:8]>C1(C=CC(O)=CC=1)O>[CH3:1][C:2]([CH3:6])([CH:3]=[CH2:4])[CH2:8][C:7]([O:9][CH2:10][CH3:11])=[O:13]
Reactant: CCOC(C)([O-])[O-]
Reactant: CC(C)=CCO
Agent: Oc1ccc(O)cc1
Product: C=CC(C)(C)CC(=O)OCC
Yield: 75.1 %

Procedure:
A mixture of 12.9 g (0.15 mole) of 3-methyl-2-buten-1-ol, 48.6 g (0.3 mole) of ethyl orthoacetate and 0.5 g of hydroquinone was heated at 140° for 20 hours with stirring. Ethanol was removed by distillation during the heating. At the end of 20 hours, the mixture was distilled under reduced pressure to give, after removal of unreacted ethyl orthoacetate, 17.6 g (75% yield) of ethyl 3,3-dimethyl-4-pentenoate, b.p. 74°-78°/55 mm.
Reaction SMILES: [Li]CCCC.[C:6](#[N:8])[CH3:7].[CH3:9][O:10][C:11]1[CH:27]=[CH:26][C:14]([CH2:15][N:16]2[CH:20]=[C:19]([C:21]([O:23]CC)=O)[CH:18]=[N:17]2)=[CH:13][CH:12]=1>C1COCC1>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][N:16]2[CH:20]=[C:19]([C:21](=[O:23])[CH2:7][C:6]#[N:8])[CH:18]=[N:17]2)=[CH:26][CH:27]=1
Reactant: CC#N
Reactant: CCOC(=O)c1cnn(Cc2ccc(OC)cc2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(Cn2cc(C(=O)CC#N)cn2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 68.2 %

Procedure:
According to Scheme 7, Step 1: At −78° C., BuLi (23 mmol, 9.2 mL, 2.5M) was added dropwise to a solution of acetonitrile (21.1 mmol, 0.87 g) in THF (25 mL). The resulting mixture was stirred at this temperature for 20 minutes and then ethyl 1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate (19.2 mmol, 5.00 g) in THF (25 mL) was added. The reaction mixture was stirred at −78° C. for 1 hour and then allowed to warm up to room temperature and stirred for another 1 hour. The reaction was quenched with saturated NH4Cl aqueous solution and extracted with EtOAc (50 mL×3). The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified on combi-flash EtOAc/PE (1:15 to ˜1:5) to give 3-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-3-oxopropanenitrile (13.1 mmol, 3.33 g, 68%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([F:19])=[CH:10][C:9]=1[N+:20]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([F:19])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(F)cc1[N+](=O)[O-]
Agent: [Pd]
Product: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(F)cc1N

Procedure:
The title compound was prepared from (4-fluoro-2-nitro-5-pyrrolidin-1-yl-phenyl)-carbamic acid tert.-butyl ester (Example C13) (6.37 g, 20 mmol) by hydrogenation with 10% Pd/C according to the general procedure J (method a). Obtained as a grey solid (5.92 g).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:9]2[CH:24]=[CH:23][C:12]([C:13]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:14])=[CH:11][N:10]=2)[C:6]=1[O:7][CH3:8].[CH3:25][C:26]1[CH:31]=[C:30](B(O)O)[CH:29]=[CH:28][N:27]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:8][O:7][C:6]1[N:5]([C:9]2[CH:24]=[CH:23][C:12]([C:13]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:14])=[CH:11][N:10]=2)[N:4]=[CH:3][C:2]=1[C:30]1[CH:29]=[CH:28][N:27]=[C:26]([CH3:25])[CH:31]=1
Reactant: Cc1cc(B(O)O)ccn1
Reactant: COc1c(Br)cnn1-c1ccc(C(=O)NCC2CCOCC2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1c(-c2ccnc(C)c2)cnn1-c1ccc(C(=O)NCC2CCOCC2)cn1
Temperature: 110 °C
Yield: 100.5 %

Procedure:
Combined 6-(4-bromo-5-methoxy-1H-pyrazol-1-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)nicotinamide (25 mg, 0.063 mmol), (2-methylpyridin-4-yl)boronic acid (26.0 mg, 0.190 mmol), sodium bicarbonate (26.6 mg, 0.316 mmol), and PdCl2(dppf)-CH2Cl2 adduct (2.58 mg, 3.16 μmol) in dioxane (0.2 mL) and water (0.05 mL) and purged with nitrogen. The mixture was heated in a microwave reactor on high absorbance for 1 hour at 110° C. Additional portions of (2-methylpyridin-4-yl)boronic acid (26.0 mg, 0.190 mmol), sodium bicarbonate (26.6 mg, 0.316 mmol), PdCl2(dppf)-CH2Cl2 Adduct (2.58 mg, 3.16 μmol), dioxane (0.1 mL), and water (0.025 mL) were added and the reaction mixture was heated again in a microwave reactor on high absorbance for 1 hour at 110° C., then cooled to 23° C. and diluted with water (1 mL) to give a residue which was extracted with EtOAc (2×1 mL), the organic layers were combined, washed with brine (0.5 mL), dried over Na2SO4, filtered through a Hydrophilic PTFE 0.45 um filter (Millipore Millex™-LCR), rinsed with EtOAc, and dried in vacuo to provide crude 6-(5-methoxy-4-(2-methylpyridin-4-yl)-1H-pyrazol-1-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)nicotinamide (25.8 mg, 100% yield) as a brown oil. MS m/z [M+H]+ 408.5.