Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[C:15]([Br:17])=[CH:16][C:7]=3[CH2:6][CH2:5][C:4]=2[N:3]=1.[CH2:22]([O:24][C:25](=[O:44])[C@H:26]([CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[NH:27][C:28](=[O:36])[C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1)[CH3:23]>C(Cl)Cl>[NH2:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([S:18]([NH:35][C:32]4[CH:31]=[CH:30][C:29]([C:28]([NH:27][C@H:26]([C:25]([O:24][CH2:22][CH3:23])=[O:44])[CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[O:36])=[CH:34][CH:33]=4)(=[O:20])=[O:19])[C:15]([Br:17])=[CH:16][C:7]=3[CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(N)cc1)C(=O)OCC
Reactant: Nc1nc2c(c(=O)[nH]1)-c1cc(S(=O)(=O)Cl)c(Br)cc1CC2
Solvent: ClCCl
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(NS(=O)(=O)c2cc3c(cc2Br)CCc2nc(N)[nH]c(=O)c2-3)cc1)C(=O)OCC
Temperature: 25 °C
Yield: 26.1 %

Procedure:
3-Amino-8-bromo-5,6-dihydrobenzo[f]quinazolin-1(2H)-one-9-sulfonyl chloride (2.00 g, 4.50 mmole) and N-(4-aminobenzoyl)-L-glutamic acid diethyl ester (7.26 g,22.5 mmole) (Aldrich) were placed together in a test tube and melted at 175° C. The mixture was heated for 1 hour, 20 minutes, the cooled residue suspended in methylene chloride and filtered to remove undissolved solid. The filtrate was evaporated to dryness and the residue subjected to chromatography on a Waters Prep 500 instrument (silica column, elution with methanol/methylene chloride(1:24)). The combined fractions containing product were evaporated and the residue dried under high vacuum. The solid was suspended in boiling ethanol (900 ml), the suspension cooled to room temperature and filtered to give diethyl N-(4-(((3-amino-8-bromo-1,2,5,6-tetrahydro-1-oxobenzo[f]quinazolin-9-yl)sulfonyl)amino)benzoyl)-L-glutamate (0.794 g,26%). Mp >250° C. 1H NMR (DMSO-d6, 200 MHz) δ: 1.12 (t, J=7 Hz, 3H, ester-CH3), 1.14 (t, J=7 Hz, 3H, ester-CH3), 1.89-2.09 (m, 2H, glu-CH2), 2.37 (t, J=7 Hz, 2H, glu-CH2), 2.48-2.59 (m, 2H, Ar CH2), 2.77-2.85 (m, 2H, Ar CH2), 3.99 (q, J=7 Hz,2H,ester CH2), 4.05 (q, J=7 Hz, 2H, ester CH2), 4.29-4.40 (m, 1H, glu-CH), 6.84 (br s, 2H, NH2), 7.14 (d, J=9 Hz, 2H, Ar), 7.54 (s, 1H, Ar), 7.69 (d, J=9 Hz, 2H, Ar), 8.48 (d, J=8 Hz, 1H, NH), 9.37 (s, 1H, Ar), 10.87 (br s, 1H, NH), 11.04 (br s, 1H, NH). Anal. Calculated for C28H30BrN5O8S: 1/4 H2O C,49.38; H,4.51; Br,11.73; N,10.20; S,4.71. Found: C,49.33; H,4.40; Br,11.79; N,10.20; S,4.74.
Reaction SMILES: [F:1][CH:2]([F:14])[C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([O:12][CH3:13])[C:5]=2[N:4]=1.Cl[C:16]1[N:21]=[C:20]2[N:22]([CH:25]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]3)[N:23]=[CH:24][C:19]2=[C:18]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)[N:17]=1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl.CCOC(C)=O>CS(C)=O.O>[F:14][CH:2]([F:1])[C:3]1[N:7]([C:16]2[N:21]=[C:20]3[N:22]([CH:25]4[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH2:30]4)[N:23]=[CH:24][C:19]3=[C:18]([N:38]3[CH2:39][CH2:40][O:41][CH2:42][CH2:43]3)[N:17]=2)[C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([O:12][CH3:13])[C:5]=2[N:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(N4CCOCC4)nc(Cl)nc32)CC1
Reactant: COc1cccc2[nH]c(C(F)F)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)c2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2n1
Temperature: 160 °C
Yield: 31.1 %

Procedure:
A stirred mixture of 0.44 g (2.2 mmol) of 2-(difluoromethyl)-4-methoxy-1H-benzimidazole, 0.47 g (1.1 mmol) of tert-butyl 4-[6-chloro-4-(4-morpholinyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinecarboxylate (WO 2008/115974), and 0.61 g (4.4 mmol) of powdered K2CO3 in 10 mL of DMSO was heated at 160° C. for 20 hrs. After cooling, the mixture was diluted with water, and the precipitate was collected by filtration, washed with water, and dried. Chromatography on silica eluting with CH2Cl2/EtOAc (17:3) gave 0.20 g (31% yield) of tert-butyl 4-[6-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-4-(4-morpholinyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinecarboxylate: mp (MeOH) 245-247° C.; 1H NMR (CDCl3) δ 7.99 (s, 1H), 7.84 (dd, J=8.4, 0.6 Hz, 1H), 7.47 (t, JHF=53.6 Hz, 1H), 7.37 (t, J=8.2 Hz, 1H), 6.83 (d, J=7.8 Hz, 1H), 4.87 (tt, J=11.4, 4.1 Hz, 1H), 4.32 (m, 2H), 4.07 (s, 3H), 4.06 (m, 4H), 3.91 (m, 4H), 2.99 (m, 2H), 2.23 (dq, J=12.3, 4.5 Hz, 2H), 2.02 (m, 2H), 1.49 (s, 9H); Anal. Calcd. for C28H34F2N8O4: C, 57.5; H, 5.9; N, 19.2. Found: C, 57.2; H, 6.0; N, 19.0%.
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:6]=[C:7]([C:11]([O:13]C)=[O:12])[CH:8]=[N:9][CH:10]=1)([CH3:4])[CH3:3].[OH-].[Na+]>CO>[OH:1][C:2]([C:5]1[CH:6]=[C:7]([C:11]([OH:13])=[O:12])[CH:8]=[N:9][CH:10]=1)([CH3:3])[CH3:4]
Reactant: COC(=O)c1cncc(C(C)(C)O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(O)c1cncc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 5-(2-hydroxypropan-2-yl)pyridine-3-carboxylate (0.179 g, 0.915 mmol) in methanol (4.57 mL) was added 1 N aqueous sodium hydroxide solution (2.74 mL, 2.74 mmol). The reaction was stirred at room temperature for 30 min and then concentrated under reduced pressure. The resulting residue was acidified via the addition of 1 N aqueous hydrogen chloride solution until the pH was 2. Ethyl acetate was then added, and the extracted organics were dried over magnesium sulfate, filtered and concentrated to provide the title compound: LCMS m/z 182.01 [M+H]+; 1H NMR (500 MHz, CD3OD) δ 8.91 (s, 1 H), 8.79 (d, J=1.8 Hz, 1 H), 8.43 (d, J=1.9 Hz, 1 H), 1.51 (s, 6 H).
Reaction SMILES: [CH:1]1([C:4]([NH:12][C:13]([C:15]2[CH:20]=[C:19]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[C:18](Br)=[CH:17][N:16]=2)=[O:14])([C:6]2[N:10]=[C:9]([CH3:11])[O:8][N:7]=2)[CH3:5])[CH2:3][CH2:2]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[F:81][C:82]1([F:86])[CH2:85][NH:84][CH2:83]1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:1]1([C:4]([NH:12][C:13]([C:15]2[CH:20]=[C:19]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[C:18]([N:84]3[CH2:85][C:82]([F:86])([F:81])[CH2:83]3)=[CH:17][N:16]=2)=[O:14])([C:6]2[N:10]=[C:9]([CH3:11])[O:8][N:7]=2)[CH3:5])[CH2:3][CH2:2]1
Reactant: Cc1nc(C(C)(NC(=O)c2cc(OCC(F)(F)F)c(Br)cn2)C2CC2)no1
Reactant: FC1(F)CNC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1nc(C(C)(NC(=O)c2cc(OCC(F)(F)F)c(N3CC(F)(F)C3)cn2)C2CC2)no1
Temperature: 120 °C
Reaction time: 0.75 h
Yield: 27.7 %

Procedure:
To a solution of 5-Bromo-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid [1-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide (Example 78g, 0.05 g, 111 μmol) in dry Toluene (1 ml) under argon atmosphere were added palladium(II) acetate (3.75 mg, 16.7 μmol), BINAP (10.4 mg, 16.7 μmol), cesium carbonate (90.7 mg, 278 μmol) and 3,3-difluoroazetidine hydrochloride (CAN 288315-03-7, 15.9 mg, 122 μmol). The reaction mixture was stirred at 120° C. for 45 minutes under microwave radiation. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo. The residue was dissolved in ethylacetate and extracted with an 1.0M aqueous solution of sodium bicarbonate. The organic phase was dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethylacetate gradient to yield the title compound (14.2 mg, 28%) as a white solid. MS (ESI, m/z): 462.4 (M+H+).
Reaction SMILES: [F:1][C:2]1[S:6][C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=2)=[N:4][C:3]=1[C:15]1[CH:16]=[N:17][NH:18][CH:19]=1.[O-:20][C:21]#[N:22].[K+].CC(O)=O>O>[F:1][C:2]1[S:6][C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=2)=[N:4][C:3]=1[C:15]1[CH:16]=[N:17][N:18]([C:21]([NH2:22])=[O:20])[CH:19]=1
Reactant: Cc1cccc(Nc2nc(-c3cn[nH]c3)c(F)s2)n1
Reactant: N#C[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cccc(Nc2nc(-c3cnn(C(N)=O)c3)c(F)s2)n1
Yield: 2.5 %

Procedure:
According to Scheme 19: A solution of N-(5-fluoro-4-(1H-pyrazol-4-yl)thiazol-2-yl)-6-methylpyridin-2-amine (1.22 mmol, 337 mg), potassium cyanate (1.47 mmol, 119 mg), AcOH (5 mL) and water (5 mL) was stirred for 2.5 hours at room temperature. The reaction mixture was quenched with water (100 mL) and the precipitate was filtered. The resulting crude product was purified by flash chromatography over silica gel using DCM/EDA (80:20; EDA: DCM/EtOH/NH3 90:9:1) as eluent to yield 4-(5-fluoro-2-(6-methylpyridin-2-ylamino)thiazol-4-yl)-1H-pyrazole-1-carboxamide (31 μmol, 10 mg, 3%) as a yellow solid.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][B-:9]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([S+:39](C2C=CC(Cl)=CC=2)([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([Br:48])=[CH:44][CH:43]=2)=[O:40])=[CH:35][CH:34]=1.O>C(#N)C>[C:1]1([CH:7]=[CH:8][B-:9]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([SH+:39]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([Br:48])=[CH:44][CH:43]=2)=[O:40])=[CH:37][CH:38]=1
Reactant: O=[S+](Cc1ccc(Br)cc1)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: Fc1ccc([B-](C=Cc2ccccc2)(c2ccc(F)cc2)c2ccc(F)cc2)cc1
Agent: [Li+]
Solvent: O
Solvent: CC#N
Product: O=[SH+](Cc1ccc(Br)cc1)c1ccc(Cl)cc1

Procedure:
A solution of 3.48 g of lithium (2-phenylethenyl)tris(p-fluorophenyl)borate in 50 ml of acetonitrile was added to a solution of 5.00 g of bis(p-chlorophenyl)(p-bromobenzyl)oxosulfonium hexafluorophosphatc in 100 ml of acetonitrile, and the resultant mixture was stirred at room temperature for 30 minutes. Then, 200 ml of water was added. The resultant precipitate of a yellow oily component was recovered, and 100 ml of dichloromethane was added. The dichloromethane layer was washed with water, dried and concentrated to give 1.95 g of (p-chlorophenyl)(p-bromobenzyl)oxosulfonium(2-phenylethenyl)tris(p-fluorophenyl)borate.
Reaction SMILES: CN1CCOCC1.[C:8]([NH:15][C@H:16]([C:24]([OH:26])=O)[C@H:17]([CH3:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].C(OC(Cl)=O)C(C)C.[N+:35](=[CH2:37])=[N-:36].CCOCC>C(Cl)Cl>[C:8]([NH:15][C@H:16]([C:24]([CH:37]=[N+:35]=[N-:36])=[O:26])[C@H:17]([CH3:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9]
Reactant: C[C@H](OC(C)(C)C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C=[N+]=[N-]
Agent: CC(C)COC(=O)Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H](OC(C)(C)C)[C@H](NC(=O)OC(C)(C)C)C(=O)C=[N+]=[N-]
Temperature: -15 °C
Reaction time: 0.33 h

Procedure:
N-methylmorpholine (1.7 mL, 2.2 equiv) was added to a solution of (2S, 3S)-N-Boc-O-t-butylthreonine (2.0 g, 7.0 mmol, 1.0 equiv) in anhydrous CH2Cl2 (40 mL). The resulting solution was cooled to −15° C. under an argon atmosphere. Iso-butylchloroformate (0.94 mL, 1.03 equiv) was added and the mixture was stirred for 20 min. A solution of diazomethane in Et2O (75 mL, about 67 mmol) was added over 5 min, the cold bath was removed and the reaction was allowed to warm over a 1 h period. Acetic acid was added dropwise until the bubbling stopped. The reaction solution was diluted with CH2Cl2 (150 mL) and washed sequentially with saturated sodium bicarbonate (2×100 mL), water (1×100 mL) and saturated brine (1×100 mL). The organic layer was dried over Na2SO4, decanted and concentrated in vacuo to yield (2S, 3S)-N-Boc-O-t-butyl-threonyldiazomethane as a yellow oil that was used without further purification.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C@@H:7]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[O:12])[C:8](=O)[CH2:9][C@H:5]12)[CH3:3].[N+:26]([C:29]1[CH:63]=[CH:62][C:32]([CH2:33][O:34][C:35]([NH:37][CH2:38][CH2:39][S:40][C:41]2[N:42]=[CH:43][N:44]3[CH:48]=[C:47]([Sn](CCCC)(CCCC)CCCC)[S:46][C:45]=23)=[O:36])=[CH:31][CH:30]=1)([O-:28])=[O:27]>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[O:12])=[C:8]([C:47]3[S:46][C:45]4=[C:41]([S:40][CH2:39][CH2:38][NH:37][C:35]([O:34][CH2:33][C:32]5[CH:62]=[CH:63][C:29]([N+:26]([O-:28])=[O:27])=[CH:30][CH:31]=5)=[O:36])[N:42]=[CH:43][N:44]4[CH:48]=3)[CH2:9][C@H:5]12)[CH3:3]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(SCCNC(=O)OCc3ccc([N+](=O)[O-])cc3)c2s1
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(SCCNC(=O)OCc5ccc([N+](=O)[O-])cc5)c4s3)C[C@H]12
Yield: 48.9 %

Procedure:
The procedure of Example 1a) was repeated, except that 201 mg of 4-nitrobenzyl (3R,5R,6S)-6-((1R)-1-hydroxyethyl)-2-oxo-1-carbapenam-3-carboxylate and 424 mg of 7-[2-(4-nitrobenzyloxycarbonyl)aminoethyl]thio-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds. Thus, 200 mg of 4-nitrobenzyl (5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-[2-(4-nitrobenzyloxycarbonyl)aminoethyl]thioimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate was prepared.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1C=CC(N2C3C=CN=CC=3N=C2C)=NC=1)=[O:5])[CH3:2].N1C=CC=C(C(O)=O)C=1.[CH3:31][C:32]1[N:33]([C:41]2[N:46]=[CH:45][C:44]([C:47]([OH:49])=O)=[CH:43][CH:42]=2)[C:34]2[CH:39]=[CH:38][N:37]=[CH:36][C:35]=2[N:40]=1.CC1N(C2C=CC(C(O)=O)=CC=2)C2C=CN=CC=2N=1>>[CH3:31][C:32]1[N:33]([C:41]2[CH:42]=[CH:43][C:44]([C:47]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:49])=[CH:45][N:46]=2)[C:34]2[CH:39]=[CH:38][N:37]=[CH:36][C:35]=2[N:40]=1
Reactant: Cc1nc2cnccc2n1-c1ccc(C(=O)O)cn1
Reactant: CCOC(=O)c1ccc(-n2c(C)nc3cnccc32)nc1
Agent: Cc1nc2cnccc2n1-c1ccc(C(=O)O)cc1
Agent: O=C(O)c1cccnc1
Product: CCOC(=O)CC(=O)c1ccc(-n2c(C)nc3cnccc32)nc1

Procedure:
The method of Preparation 1, Method C, (b) was followed substituting the pyridine-3-carboxylic acid from (c) above for 4-(2-methylimidazo[4,5-c]pyrid-1-yl)benzoic acid. The title compound was an orange gum.
Reaction SMILES: [N:1]1[CH:2]=[C:3]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[S:6][C:5]([C:13]([OH:15])=O)=[CH:4]2.ON1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.Cl.Cl.[NH2:38][CH2:39][C:40]1[CH:58]=[CH:57][C:43]([CH2:44][N:45]2[CH2:50][CH2:49][CH:48]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[CH2:47][CH2:46]2)=[CH:42][CH:41]=1.C1CCN2C(=NCCC2)CC1>C(#N)C.C(N(CC)CC)C>[C:51]1([CH:48]2[CH2:47][CH2:46][N:45]([CH2:44][C:43]3[CH:57]=[CH:58][C:40]([CH2:39][NH:38][C:13]([C:5]4[S:6][C:7]5[N:12]6[C:3](=[CH:2][N:1]=[C:11]6[CH:10]=[CH:9][CH:8]=5)[CH:4]=4)=[O:15])=[CH:41][CH:42]=3)[CH2:50][CH2:49]2)[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: NCc1ccc(CN2CCC(c3ccccc3)CC2)cc1
Reactant: O=C(O)C1=Cc2cnc3cccc(n23)S1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(NCc1ccc(CN2CCC(c3ccccc3)CC2)cc1)C1=Cc2cnc3cccc(n23)S1
Reaction time: 1 h

Procedure:
To a suspension of 1.0 g (4.58 mM) of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid and 0.90 g (7.82 mM) of N-hydroxysuccinimide in acetonitrile (10 ml) was added 1.51 g (7.88 mM) of N-ethyl-N′-3-(N,N-dimethylamino)propylcarbodiimide hydrochloride at room temperature, and the mixture was stirred for 1 hour. To this reaction mixture was added a solution of 1.67 g (4.73 mM) of 1-[4-(aminomethyl)benzyl]-4-phenylpiperidine dihydrochloride, 1.44 g (9.46 mM) of DBU, and 0.55 ml (3.95 mM) of triethylamine in acetonitrile (20 ml), and the mixture was further stirred for 4 hours. The solvent was then distilled off under reduced pressure and the residue was diluted with water and extracted with ethyl acetate (a small amount of ethanol was additionally used). The organic layer was washed with saturated aqueous solution of sodium chloride and dried over MgSO4. This crude product was purified by column chromatography (methanol/ethyl acetate 20-30%) to provide the title compound as red amorphous substance.
Reaction SMILES: Cl[C:2]1[N:13]=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH2:7][C:8]#[CH:9])=[O:5].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)CO>[C:15]1([NH:14][C:2]2[N:13]=[CH:12][CH:11]=[CH:10][C:3]=2[C:4]([NH:6][CH2:7][C:8]#[CH:9])=[O:5])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C#CCNC(=O)c1cccnc1Cl
Reactant: Nc1ccccc1
Solvent: OCCO
Product: C#CCNC(=O)c1cccnc1Nc1ccccc1
Temperature: 140 °C

Procedure:
Compound 8 (194 mg, 1 mmol) and aniline (9a, 93 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(phenylamino)-N-(prop-2-ynyl)nicotinamide 10a as pure product. To a solution of 2-(phenylamino)-N-(prop-2-ynyl)nicotinamide (10a, 150 mg, 0.59 mmol) and 1-(azidomethyl)-3-phenoxybenzene (12a, 147 mg, 0.65 mmol) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.005 mmol) were added sequentially. The reaction was stirred at room temperature for 10 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product as solid (210 mg, 74%); mp: 124-126° C.; 1H NMR (300 MHz, CDCl3) δ 10.51 (s, 1H), 8.25 (dd, J=2.2, 1.5 Hz, 1H), 7.84 (dd, J=2.2, 1.5 Hz, 1H), 7.80 (brs, 1H), 7.66-7.60 (m, 3H), 7.33-7.25 (m, 4H), 7.08 (t, J=7.5 Hz, 1H), 7.00-6.90 (m, 7H), 6.61-6.59 (m, 1H), 5.45 (s, 2H), 4.62 ppm (d, J=5.2 Hz, 2H); MS (ESI m/z): 477 [M+H]+. Yield: 74%
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.FC(F)(F)C(O)=O.[NH:19]1[CH2:24][CH2:23][CH:22]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[NH:32][S:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)(=[O:35])=[O:34])[CH2:21][CH2:20]1.C(=O)(O)[O-].[Na+]>CCO>[CH3:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([N:19]3[CH2:24][CH2:23][CH:22]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[NH:32][S:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=4)(=[O:35])=[O:34])[CH2:21][CH2:20]3)[O:3][C:4]=2[CH:10]=1
Reactant: O=S(=O)(Nc1ccccc1OC1CCNCC1)c1ccccn1
Reactant: Cc1ccc2nc(Cl)oc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: Cc1ccc2nc(N3CCC(Oc4ccccc4NS(=O)(=O)c4ccccn4)CC3)oc2c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
Compound 21 is prepared using synthesis method 3: intermediate 2e (0.21 g, 1.25 mmol) and intermediate 6a are placed in 5 mL of EtOH in the presence of 0.3 g (3.58 mmol) of sodium bicarbonate, and the mixture is then stirred for 2 h at 80° C. After evaporation under reduced pressure the residue is taken up by water and extracted using AcOEt. After drying of the organic phases and reduction to dryness the residue obtained is triturated in a mixture of EtOH/Et2O and 0.32 g of solid is isolated by filtration (yield: 77%).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[C:9](Br)[C:10]([O:13][CH:14](F)F)=[N:11][CH:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1.CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.[Cl:52][C:53]1[CH:54]=[N:55][NH:56][CH:57]=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]>[N:1]1([CH2:6][C:7]2[CH:8]=[C:9]([N:55]3[CH:54]=[C:53]([Cl:52])[CH:57]=[N:56]3)[C:10]([O:13][CH3:14])=[N:11][CH:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: FC(F)Oc1ncc(Cn2cncn2)cc1Br
Reactant: Clc1cn[nH]c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: COc1ncc(Cn2cncn2)cc1-n1cc(Cl)cn1
Temperature: 100 °C
Yield: 46.5 %

Procedure:
To a solution of 5-((1H-1,2,4-triazol-1-yl)methyl)-3-Bromo-2-methoxypyridine (Intermediate 13), (100 mg, 0.37 mmol), in toluene (5 mL) was added tris(dibenzylideneacetone)dipalladium(0) (34.1 mg, 0.04 mmol), sodium tert-butoxide (71.6 mg, 0.74 mmol), (2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (29.3 mgs, 0.07 mmol) and 4-chloro-1H-pyrazole (37.3 mg, 0.37 mmol). The mixture was heated at 100° C. for 30 min. The mixture was quenched with water (0.5 mL), diluted with ethyl acetate (10 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. Purification (FCC, SiO2, 20-100% EtOAc/hexanes) afforded the title compound (50 mg, 46%). 1H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.07 (s, 2H), 8.01 (q, J=2.3 Hz, 2H), 7.99 (s, 1H), 5.37 (s, 2H), 3.94 (s, 3H), 2.52 (s, 1H). [M+H]=292.12.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][N:7]=[C:6](OC)[CH:5]=1)[CH3:2].O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:6]1[CH:5]=[C:4]([NH:3][CH2:1][CH3:2])[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCNc1cc(OC)ncc1[N+](=O)[O-]
Product: CCNc1cc(Cl)ncc1[N+](=O)[O-]

Procedure:
A solution of 4-(ethylamino)-2-methoxy-5-nitropyridine (5.0 g, 25.3 mmol) in POCl3 (25 mL) was heated to 100° C. in a sealed tube for 1 week. The reaction mixture was cooled and concentrated and the residue was taken up in EtOAc/H2O and carefully quenched with sat. K2CO3. The aqueous layer was extracted with EtOAc, washed with H2O, dried (MgSO4) and concentrated to give an orange oil which solidified on standing which was used without further purification. MS (ES+) m/e 202 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH:12]([CH3:14])[CH3:13])[CH:8]=[C:7]([O:15][CH:16]([CH3:18])[CH3:17])[C:3]=1[C:4](O)=[O:5].CC[N:21]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.N>C1COCC1.O>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH:12]([CH3:14])[CH3:13])[CH:8]=[C:7]([O:15][CH:16]([CH3:18])[CH3:17])[C:3]=1[C:4]([NH2:21])=[O:5]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)Oc1cc(OC(C)C)c(C(=O)O)c(N)n1
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)Oc1cc(OC(C)C)c(C(N)=O)c(N)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-amino-4,6-diisopropoxy-nicotinic acid (1.48 g, 5.83 mmol) in THF (30 mL) were added EDCl (1.34 g, 6.99 mmol), HOBt (0.94 g, 6.99 mmol), NMM (0.70 g, 6.99 mmol) and liquid NH3 (10 mL). Then, the reaction mixture was stirred at room temperature for 24 hours. Then, water (100 mL) was added and the products were extracted with ethyl acetate (2×200 mL). The combined organic phase was washed with water, then brine, and dried over anhydrous Na2SO4. Removal of solvent gave crude 2-amino-4,6-diisopropoxy-nicotinamide as a yellow oil. Yield: 450 mg (26%, crude).