Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.[CH3:18][C:19]([CH3:24])([CH3:23])[C:20]([NH2:22])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cu]I>[CH3:18][C:19]([CH3:24])([CH3:23])[C:20]([NH:22][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1)=[O:21]
Reactant: Cc1cc(N2CCCC2)c2ccc(I)cc2n1
Reactant: CC(C)(C)C(N)=O
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(N2CCCC2)c2ccc(NC(=O)C(C)(C)C)cc2n1
Temperature: 150 °C
Yield: 56.2 %

Procedure:
A suspension of 0.338 mg (1 mmol) of 7-iodo-2-methyl-4-pyrrolidin-1-yl-quinoline, 0.81 g (8 mmol) of trimethylacetamide, 0.414 g (3 mmol) of potassium carbonate (water free) and 20 mg (0.1 mmol) of copper (I) iodide in DMF (10 ml) was heated at 150° C. (oil bath temperature) under an argon atmosphere for 20 h. The reaction mixture was partitioned between EtOAc and water, the layers were separated, the organic layer washed twice with water dried over sodium sulphate and concentrated in vacuo. The residue was applied to silica gel column with CH2Cl2/MeOH/NH4OH (20:1:0.2) as eluent. Combination of the purified fractions and concentration in vacuo gave 175 mg (50.4%) of the desired 2,2-dimethyl-N-(2-methyl-4-pyrrolidin-1-yl-quinolin-7-yl)-propionamide as light brown solid. ISP mass spectrum, m/e: 312.3 (M+1 calculated for C19H25N3O: 312).
Reaction SMILES: [Cl:1][CH2:2][C:3]1(O)[CH2:7][S:6][C:5]([CH2:8][N:9]([CH3:11])[CH3:10])=[N:4]1.S(Cl)(Cl)=O>ClCCCl>[ClH:1].[Cl:1][CH2:2][C:3]1[N:4]=[C:5]([CH2:8][N:9]([CH3:11])[CH3:10])[S:6][CH:7]=1
Reactant: CN(C)CC1=NC(O)(CCl)CS1
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Product: CN(C)Cc1nc(CCl)cs1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ten g. of 4-chloromethyl-4-hydroxy-2-dimethylaminomethyl-2-thiazoline was dissolved in 50 ml. of 1,2-dichloroethane, and to it was added 8.6 g. of thionyl chloride dissolved in 30 ml. of 1,2-dichloroethane. The mixture was stirred at ambient temperature overnight, and then was stirred at 35° for 35 minutes and then for 1 hour at 50°. The mixture was cooled to 5° and filtered, and the solids were washed with 1,2-dichloroethane, and then were slurried in 20 ml. of methanol and 50 ml. of ethyl acetate. The crystals were then recovered by filtration and dried to obtain 6.4 g. of relatively pure product, m.p. 137°-140°. The product was identified by nmr analysis in DMSO-D6, on a 60 mHz instrument, which analysis showed characteristic features at δ3.05 (s, 6H); 4.85 (s, 2H); 4.90 (s, 2H); 7.85 (s, 1H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([OH:8])=[C:6]([C:9]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)S[CH2:16][CH2:15][C:14]3=[O:21])=[O:10])[CH:5]=[N:4]1)[CH3:2].OO.C(O)(=O)C.[S:28]([O-:31])(O)=[O:29].[Na+]>O>[CH2:1]([N:3]1[C:7]([OH:8])=[C:6]([C:9]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[S:28](=[O:31])(=[O:29])[CH2:16][CH2:15][C:14]3=[O:21])=[O:10])[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc(C(=O)c2ccc3c(c2)C(=O)CCS3)c1O
Reactant: O=S([O-])O
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCn1ncc(C(=O)c2ccc3c(c2)C(=O)CCS3(=O)=O)c1O
Temperature: 60 °C

Procedure:
1.0 Gram (3.31 mmol) of 6-(1-ethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-4-one and 0.83 g (7.28 mmol) of a 30 wt % hydrogen peroxide aqueous solution were added to 3 ml of glacial acetic acid, and then stirred under heat of 60° C. for 2.5 hours. While the reaction mixture was cooled in an ice bath after allowed to cool, a 1 wt % sodium hydrogensulfite aqueous solution was added to decompose excess hydrogen peroxide, and then the reaction mixture was diluted with water. A precipitated solid was extracted with ethyl acetate. An organic layer was washed with water and then with a saturated sodium chloride aqueous solution once, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 1.11 g (yield: quantitative) of the titled compound. Table 24 shows the physical property data of the titled compound.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[N:6]=1.Cl.[NH:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]1.C(N(CC)CC)C.O>CN(C=O)C>[Br:7][C:5]1[N:6]=[C:2]([N:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]2)[S:3][CH:4]=1
Reactant: Brc1csc(Br)n1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CCN(c2nc(Br)cs2)CC1
Temperature: 80 °C
Reaction time: 72 h

Procedure:
1 g (4.12 mmol) of 2,4-dibromothiazole was dissolved in 10 ml of DMF, 1.06 g (7.82 mmol) of piperidin-4-one hydrochloride and 2.3 ml (16.47 mmol) of triethylamine were added, and the mixture was stirred at 80° C. for 3 days. The reaction mixture was stirred into 300 ml of water and extracted by shaking with EA. The organic phase was dried over sodium sulfate, filtered and evaporated. The purification was carried out by means of flash chromatography on silica gel.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1OC.[CH2:10]([CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22]C#N)[CH2:16][CH2:15]1)[CH2:11][CH2:12][CH3:13].S(=O)(=O)(O)O.[OH-].[Na+].CC[O:34][CH2:35][CH3:36]>C(Cl)Cl.CO.C1COCC1>[CH2:10]([CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][C:35]([C:36]2[CH:2]=[CH:7][CH:6]=[CH:5][C:4]=2[CH3:3])=[O:34])[CH2:16][CH2:15]1)[CH2:11][CH2:12][CH3:13]
Reactant: COc1ccccc1I
Reactant: CCCCC1CCN(CCCC#N)CC1
Reactant: CCOCC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: CCCCC1CCN(CCCC(=O)c2ccccc2C)CC1
Reaction time: 1 h
Yield: 26 %

Procedure:
In a 25 mL oven-dried flask was charged Mg turnings (125 mg, 5.2 mmol) which were activated by the use of a heat-gun. Under inert atmosphere was added a suspension of 2-iodoanisole (1.13 g, 5.2 mmol) in Et2O (4 mL) and the reaction mixture was allowed to stand at rt for 1 hour. Compound 4 (720 mg, 3.4 mmol) dissolved in Et2O (4 mL) was added and the mixture was refluxed over-night. THF (15 mL) and sulfuric acid (4 mL, 2 M) was added and the reaction mixture was stirred for 4 h, followed by addition of NaOH (6 mL, 2 M). The reaction mixture was extracted with ethyl acetate (3×50 mL), and the combined organic phases were evaporated to dryness to produce 1.2 g of crude 5. The crude product was subjected to CC [eluent: CH2Cl2:CH3OH (99:1)] to give pure 5 (0.42 g, 26%). 1H NMR (CDCl3) δ0.83 (t, 3H), 1.20-1.42 (m, 9H), 1.65-1.73 (d, 2H), 1.96-2.20 (m, 4H), 2.53 (t, 2H), 3.02-3.17 (m, 4H), 3.89 (s, 3H), 6.95-7.01 (m, 2H), 7.44 (t, 1H), 7.65 (d, 1H).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH:10]1[CH:11]=[CH:12][C:13]2[N:20]=[CH:19][NH:18][C:16](=[O:17])[C:14]=2[CH:15]=1.N.[CH3:22]O.[CH:24]([Cl:27])([Cl:26])[Cl:25].C[C:29]([N:31](C)C)=[O:30]>>[CH3:29][O:30][C:10]1[C:15]([S:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)=[C:14]2[C:13](=[CH:12][CH:11]=1)[N:20]=[C:19]([CH3:22])[NH:18][C:16]2=[O:17].[NH3:31].[CH3:16][OH:17].[CH:24]([Cl:27])([Cl:26])[Cl:25]
Reactant: CC(=O)N(C)C
Reactant: O=c1[nH]cnc2ccccc12
Reactant: Sc1ccncc1
Agent: N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc2nc(C)[nH]c(=O)c2c1Sc1ccncc1
Temperature: 135 °C

Procedure:
To 78 mg (0.7 mmol) of 4-Mercaptopyridine was added 34 mg (0.5 mmol) of solid NaOH in 1 ml of dry DNA. To the resulting solution, 134 mg (0.5 mmol) of quinazolinone (16) dissolved in 2 ml dry DMA was added. The mixture was kept under N2, and a finely ground catalyst mixture containing 44 mg CuBr and 22 mg Cu2O was added. The mixture was stirred magnetically and heated to 135° C., until the reaction was complete as judged by TLC (anh. NH3 /MeOH/CHCl3 ; 0.5:4.5:9.5). The solvent was removed under high vacuum through a cryogenic trap cooled to -78° C. The desired product was isolated by flash chromatography (anh. NH3 /MeOH/CHCl3 ; 0.5:4.5:9.5) on silica, yielding 130 mg (89%) of (17) as a white powder. M.P. 248°-249° C. (dec.). IR (KBr) 3358, 3073, 2933, 1682, 1634, 1574, 1475, 1462, 1318, 1277, 1059, 835, 710 cm-1 ; 1H NMR (CDCl3) δ 2.36 (s, 3H), 3.84 (s, 3H), 6.90 (d, 2H, J=5.1 Hz), 7.48 (d, 1H, J=9.1 Hz), 7.79 (d, 1H, J=9.1 Hz), 8.28 (d, 2H, J=5.1 Hz), 10.86 (s, 1H). Anal. Calcd. for C15H13N3O2S: C, 60.18; H, 4.38; N, 14.04; S, 10.71. Found: C, 60.28; H, 4.43; N, 14.07; S, 10.63. HRMS Calcd. for C15H13N3O2S: 299.0730. Found: 299.0718.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10](=O)[NH:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1.S(Cl)([Cl:19])=O>CN(C=O)C>[ClH:19].[Cl:19][C:10]1[C:9]2[C:14](=[CH:15][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:7][CH:8]=2)[N:13]=[CH:12][N:11]=1
Reactant: O=S(Cl)Cl
Reactant: COCCOc1ccc2c(=O)[nH]cnc2c1
Solvent: CN(C)C=O
Product: COCCOc1ccc2c(Cl)ncnc2c1
Product: Cl
Yield: 83 %

Procedure:
A solution of 7-(2-methoxyethoxy)-3,4-dihydroquinazolin-4-one (500 mg, 2.2 mmol) in thionyl chloride (15 ml) and DMF (0.1 ml) was heated at reflux for 3 hours. The volatiles were removed by evaporation to give 4-chloro-7-(2-methoxyethoxy)quinazoline hydrochloride as a cream solid (520 mg, 83%).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[CH3:17]I>CN(C=O)C>[CH3:17][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CI
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccccc2n1C
Reaction time: 0.25 h
Yield: 99.8 %

Procedure:
NaH (60% dispersion in mineral oil, 8.02 g, 200.49 mmole) was washed with hexanes, then was suspended in dry DMF (530 mL). Solid ethyl indole-2-carboxylate (25.29 g, 133.66 mmole) was added portionwise over 5-10 min, allowing gas evolution to subside between additions. When the addition was complete, the yellow mixture was stirred for 15 min, then methyl iodide (42 mL, 668.3 mmole) was added all at once. The reaction was exothermic, and the internal temperature rose to 40-45° C. After 1 hr, the reaction was quenched with 10% NH4Cl (100 mL) and concentrated on the rotavap (high vacuum). The residue was partitioned between Et2O (500 mL) and H2O (100 mL), and the layers were separated. The Et2O layer was washed with H2O (100 mL), dried (MgSO4), and concentrated to leave the title compound (27.10 g, quantitative) as a light yellow solid. This was used without further purification: TLC (10% EtOAc/hexanes) Rf=0.39.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[F:23])[CH2:12][N:11]([CH2:24][C:25]([F:28])([F:27])[F:26])[C:10]1=[S:29].[O:30]=[C:31]1[NH:39][C:34]2=[N:35][CH:36]=[CH:37][CH:38]=[C:33]2[N:32]1[CH:40]1[CH2:45][CH2:44][N:43]([C:46](Cl)=[O:47])[CH2:42][CH2:41]1.O>ClCCl>[F:23][C:17]1[C:18]([F:22])=[CH:19][CH:20]=[CH:21][C:16]=1[C@H:13]1[CH2:12][N:11]([CH2:24][C:25]([F:27])([F:28])[F:26])[C:10](=[S:29])[C@H:9]([NH:8][C:46]([N:43]2[CH2:42][CH2:41][CH:40]([N:32]3[C:33]4[C:34](=[N:35][CH:36]=[CH:37][CH:38]=4)[NH:39][C:31]3=[O:30])[CH2:45][CH2:44]2)=[O:47])[CH2:15][CH2:14]1
Reactant: N[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(CC(F)(F)F)C1=S
Reactant: O=C(Cl)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(CC(F)(F)F)C1=S)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.8 %

Procedure:
Triethylamine (100 μL, 0.720 mmol) was added to a solution of the bis hydrochloride salt of (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepane-2-thione (90 mg, 0.240 mmol) and 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carbonyl chloride (74 mg, 0.264 mmol) in dichloromethane (10 mL) and the mixture heated to reflux. After 18 h, the reaction was allowed to cool to ambient temperature, water was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography (100% dichloromethane→95% dichloromethane/methanol) gave the title compound (78 mg). MS 583.2 (M+1).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[C:5]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)[N:4]=1.Cl.[Cl:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH:27]=[C:26]([S:31]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)(=[O:33])=[O:32])[CH:25]=[CH:24]2>>[ClH:20].[Cl:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH:27]=[C:26]([S:31]([N:34]1[CH2:35][CH2:36][N:37]([C:14](=[O:16])[C:13]3[CH:12]=[CH:11][C:10]([C:5]4[N:4]=[C:3]([NH2:2])[N:8]=[C:7]([NH2:9])[CH:6]=4)=[CH:18][CH:17]=3)[CH2:38][CH2:39]1)(=[O:32])=[O:33])[CH:25]=[CH:24]2
Reactant: Nc1cc(-c2ccc(C(=O)O)cc2)nc(N)n1
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Agent: Cl
Product: Nc1cc(-c2ccc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2)nc(N)n1

Procedure:
In the same manner as in Example A-4, a reaction was conducted using 4-(2,4-diamino-6-pyrimidyl)benzoic acid hydrochloride and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride as starting materials, whereby the title compound was obtained.
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([B:19]2[O:27][C:24]([CH3:26])([CH3:25])[C:21]([CH3:23])([CH3:22])[O:20]2)=[CH:15][CH:14]=1.C(=O)([O-])[O-:29].[K+].[K+]>CN(C=O)C>[CH3:22][C:21]1([CH3:23])[C:24]([CH3:26])([CH3:25])[O:27][B:19]([C:16]2[CH:17]=[CH:18][C:13]([CH2:12][O:29][C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[C:3](=[O:4])[CH3:2])=[CH:14][CH:15]=2)[O:20]1
Reactant: O=C([O-])[O-]
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Reactant: O=C(CO)c1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccccc1OCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 110 °C
Yield: 63.6 %

Procedure:
A mixture of 2-hydroxy-acetophenone (0.3 g, 2.2 mmol), 4-bromomethylphenylboronic acid pinacol ester (0.8 g, 2.7 mmol) and potassium carbonate (0.3 g, 2.2 mmol) in DMF (5 ml) was heated up to 110° C. for 24 h. The reaction mixture composition was determined by TLC and 4-bromomethylphenylboronic acid pinacol ester (0.3 g, 1.0 mmol) was added. The reaction mixture was heated to 110° C. for additional 24 h. The solvent was removed in vacuo. The crude product was purified by column chromatography on silica (CH2Cl2 to 4% MeOH) to give the desired product as an oil (0.51 g, 1.4 mmol, 64%). δH (CDCl3, 400 MHz): 1.24 (12H, s, CH3), 2.59 (3H, s, COCH3), 6.98 (1H, dd, 3J=9.2, 4J=1.6), 7.00 (1H, dd, 3J=8.4, 4J=0.8), 7.41 (1H, dd, 4J=4), 7.43 (2H, d, 3J=8.4), 7.74 (1H, dd, 3J=7.6, 4J=1.6), 7.83 (2H, d). δC (CDCl3, 125 MHz): 24.91 (CH3), 32.15 (COCH3), 70.62 (Cqart), 83.95 (CH2), 112.80 (CAr), 120.93 (CAr), 126.78 (CAr), 128.72 (CAr), 130.52 (CAr), 133.62 (CAr), 135.16 (CAr), 139.23 (CAr), 158.00 (CAr), 199.93 (CO). m/z (ES+) 391.1 [M+K]+ calc for C21H25BKO4391.2.
Reaction SMILES: O[C:2]1([CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:10]=[C:9]2[CH2:11][NH:12][CH:13]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:16])[CH2:14][N:7]3[C:8]2=[C:4]([CH:5]=[CH:6]3)[CH:3]1[C:24]([F:27])([F:26])[F:25].S(Cl)(Cl)=O>N1C=CC=CC=1>[CH2:28]([C:2]1[C:3]([C:24]([F:26])([F:27])[F:25])=[C:4]2[C:8]3=[C:9]([CH2:11][NH:12][CH:13]([C:15]([NH:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[O:16])[CH2:14][N:7]3[CH:6]=[CH:5]2)[CH:10]=1)[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(Nc1ccccc1)C1Cn2ccc3c2C(=CC(O)(CCc2ccccc2)C3C(F)(F)F)CN1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: O=C(Nc1ccccc1)C1Cn2ccc3c(C(F)(F)F)c(CCc4ccccc4)cc(c32)CN1

Procedure:
The 6-hydroxy-6-phenethyl-N-phenyl-7-(trifluoromethyl)-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi]indole-2(1H)-carboxamide was further processed with thionyl chloride and pyridine as described in Example 1, above to yield 6-phenethyl-N-phenyl-7-(trifluoromethyl)-3,4-dihydro-[1,4]diazepino[6,7,1-hi]indole-2(1H)-carboxamide (5 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[N:23]=[C:6]2[CH:7]=[C:8]([NH:11][C:12]([C:14]3[N:18]([CH3:19])[N:17]=[CH:16][C:15]=3[C:20](O)=[O:21])=[O:13])[CH:9]=[CH:10][N:5]2[N:4]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.CCCP(=O)=O.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH3:1][N:2]([CH3:24])[C:3]1[N:23]=[C:6]2[CH:7]=[C:8]([NH:11][C:12]([C:14]3[N:18]([CH3:19])[N:17]=[CH:16][C:15]=3[C:20]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:21])=[O:13])[CH:9]=[CH:10][N:5]2[N:4]=1
Reactant: CN(C)c1nc2cc(NC(=O)c3c(C(=O)O)cnn3C)ccn2n1
Reactant: C1CCNC1
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C)c1nc2cc(NC(=O)c3c(C(=O)N4CCCC4)cnn3C)ccn2n1
Temperature: 70 °C
Reaction time: 18 h
Yield: 89.1 %

Procedure:
A mixture of 5-(2-(dimethylamino)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (150 mg, 455 μmol), pyrrolidine (226 μl, 2.73 mmol), propylphosphonic anhydride (50% in ethyl acetate, 671 μl, 1.14 mmol) and diisopropylethylamine (239 μl, 1.37 mmol) in tetrahydrofurane (8 ml) is stirred for 18 hours at 70° C. under nitrogen atmosphere. The solvent is evaporated and the residue triturated with sat. aqueous sodium hydrogencarbonate solution. The precipitated solid is collected by filtration, washed with water and dried affording N-(2-(dimethylamino)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(pyrrolidine-1-carbonyl)-1H-pyrazole-5-carboxamide (155 mg, 89%) as a light brown solid. Mp.: 199-201° C. MS: m/z=383.4 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[C:5]([OH:10])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>C(OCC)(=O)C>[C:16]([O:15][C:13](=[O:14])[CH2:12][N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]1=[O:10])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=[N+]([O-])c1cccnc1O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Cn1cccc([N+](=O)[O-])c1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 74 %

Procedure:
Sodium hydride (1.57 g of a 60% dispersion in mineral oil, 0.039 mole) was washed with hexanes three times (10 mL each) and suspended in dimethylformamide (25 mL). The stirred suspension was cooled in an ice bath, then 3-nitro-2-hydroxypyridine (5.00 g, 0.036 mole) was added in small portions over a 25-minute period. After the addition was complete, the reaction was stirred at 0° C. for 10 minutes, then room temperature for 30 minutes. The reaction mixture was recooled in an ice bath. t-Butyl bromoacetate (5.25 mL, 0.036 mole) was added. The reaction was stirred at 0° C. for 1 hour, then 1.5 hours at room temperature. The reaction mixture was diluted with ethyl acetate (80 mL), and ice (80 g) was added. The aqueous layer was extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with water (4×100 mL), brine (100 mL), and dried over anhydrous sodium sulfate. The solvent was removed, and the resulting residue was chromatographed through silica gel using 10% ethyl acetate/dichloromethane as eluent. The pure fractions were combined, and the solvent was removed under vacuum to afford 6.77 g (75% yield) of the title compound as yellow solid. Rf=0.30 (silica gel, 20% ethyl acetate in dichloromethane).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[C:6]2[C:7](OC(=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8].[CH3:14][NH:15][CH3:16]>CN(C1C=CN=CC=1)C>[NH2:11][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:13][C:6]=1[C:7]([N:15]([CH3:16])[CH3:14])=[O:8]
Reactant: O=c1[nH]c2ccc(Br)cc2c(=O)o1
Reactant: CNC
Agent: CN(C)c1ccncc1
Product: CN(C)C(=O)c1cc(Br)ccc1N
Reaction time: 8 h
Yield: 106.1 %

Procedure:
Into an 15 mL high pressure glass vial (with Teflon screw cap) were added 5-bromoisatoic anhydride (0.401 g, 1.66 mmol), DMAP (20 mg, 0.16 mmol), and dimethylamine (2 M in THF; 5.0 mL, 10.0 mmol). The vial was sealed and placed in an oil bath at 70° C. for 8 h after which it was concentrated under vacuum. The crude product was dissolved in EtOAc and washed 2× with water followed by brine. The organic phase was dried (Na2SO4), filtered and concentrated to afford 0.428 g of 2-Amino-5-bromo-N,N-dimethyl-benzamide as a pink solid, which was used directly for the next step. 1H-NMR (500 MHz, d6-DMSO) δ=7.19 (dd, J=2.0, 8.5 Hz, 1H), 7.08 (d, J=2.0 Hz, 1H), 6.63 (d, J=8.5 Hz, 1H), 5.31 (br. s, 2H), 2.89 (br. s, 6H). MS: m/z 198/200 [C═O+].
Reaction SMILES: Br[CH2:2][C:3](Br)=[O:4].[CH2:6]([NH:8][CH2:9][CH3:10])[CH3:7].[C:11]([C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])(=[O:23])=[O:22])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12]>>[C:11]([C:15]1[CH:16]=[CH:17][C:18]([S:21]([N:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[CH2:2][C:3]([N:8]([CH2:9][CH3:10])[CH2:6][CH3:7])=[O:4])(=[O:22])=[O:23])=[CH:19][CH:20]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CCNCC
Reactant: O=C(Br)CBr
Reactant: COc1ccccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Product: CCN(CC)C(=O)CN(c1ccccc1OC)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of 2-bromoacetyl bromide with diethylamine and 4-tert-butyl-N-(2-methoxy-phenyl)-benzenesulfonamide
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:11]([Sn](CCC)(CCC)C=C)[CH2:12]C>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.C1(C)C=CC=CC=1>[N+:8]([C:7]1[C:2]([CH:11]=[CH2:12])=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: C=C[Sn](CCC)(CCC)CCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ncccc1[N+](=O)[O-]
Yield: 54 %

Procedure:
A mixture of 0.92 g (5.80 mmol) of 2-chloro-3-nitro-pyridine, 1.60 g (5.80 mmol) tripropyl-vinyl-stannane, 0.335 g (0.290 mmol) Pd(PPh3)4 and 10 mL of toluene were combined and refluxed under an inert atmosphere overnight. After routine aqueous workup the crude product was purified by chromatography on silica gel to give 0.470 g (54% yield) of 3-nitro-2-vinyl-pyridine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:34][Si:35]([C:38]#[CH:39])([CH3:37])[CH3:36]>[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.CN(C)C=O>[CH3:22][S:19]([C:16]1[CH:17]=[CH:18][C:13]([N:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([CH2:39][CH2:38][Si:35]([CH3:37])([CH3:36])[CH3:34])=[CH:3][CH:4]=3)=[CH:9][C:10]([C:23]([F:26])([F:25])[F:24])=[N:11]2)=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: C#C[Si](C)(C)C
Reactant: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(Br)cc2)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(S(C)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.4 %

Procedure:
To a mixture of 5-(4-bromophenyl)-1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole (670 mg, 1.5 mmol, from step 1), triethylamine (10 mL) and dimethylformamide (2 mL) was added copper(I) iodide (15 mg, 0.08 mmol), bis(triphenylphosphine)palladium(II)chloride (105 mg, 0.15 mmol) and (trimethylsilyl)acetylene (221 mg, 2.25 mmol) at room temperature. The mixture was stirred for 4 hours at room temperature and concentrated. The concentrate was diluted with water (30 mL) and extracted with ethyl acetate (20 mL×3), dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:4) to give title compound (353 mg, 52%).