Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[C:3]=1[F:10].CC(C)([O-])C.[K+].[O:17]1[CH2:21][CH2:20][O:19][CH:18]1[C:22]1[CH:23]=[CH:24][C:25]([C:28]2[S:36][C:35]3[C:30](=[N:31][CH:32]=[CH:33][C:34]=3Cl)[CH:29]=2)=[N:26][CH:27]=1.O>CS(C)=O>[O:17]1[CH2:21][CH2:20][O:19][CH:18]1[C:22]1[CH:23]=[CH:24][C:25]([C:28]2[S:36][C:35]3[C:30](=[N:31][CH:32]=[CH:33][C:34]=3[O:8][C:5]3[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([F:10])[C:4]=3[F:9])[CH:29]=2)=[N:26][CH:27]=1
Reactant: Clc1ccnc2cc(-c3ccc(C4OCCO4)cn3)sc12
Reactant: Nc1ccc(O)c(F)c1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1ccc(Oc2ccnc3cc(-c4ccc(C5OCCO5)cn4)sc23)c(F)c1F
Temperature: 100 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
To a solution of 4-amino-2,3-difluorophenol (1.59 g, 7.49 mmol) in DMSO (10 mL) was added potassium tert-butoxide (1.1 g, 8.98 mmol), and the reaction mixture was stirred for 2 hours. Chloride 301 (1.6 g, 4.99 mmol) was added and the reaction mixture was heated at 100° C. for 2 hours. The mixture was cooled down then poured into water (150 mL) at 40-45° C. and stirred for 30 min. The precipitate was collected by filtration, washed with water and dried overnight. The crude product was triturated with EtOAc/Hexane (2/1, 100 mL) for 1 h, to afford title compound 302 (1.7 g, 79% yield) as a pale violet solid. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.70 (d, J=2.1 Hz, 1H), 8.53 (d, J=5.4 Hz, 1H), 8.39 (s, 1H), 8.31 (d, J=8.1 Hz, 1H), 7.98 (dd, J=8.1, 2.1 Hz, 1H), 7.10-7.00 (m, 1H), 6.71 (d, J=5.1 Hz, 1H), 6.72-6.61 (m, 1H), 5.90 (s, 1H), 5.64 (s, 2H), 4.16-3.96 (m, 4H).
Reaction SMILES: [C:1]1([CH:7]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:11][C:10]3[CH:19]=[N:20][CH:21]=[CH:22][C:9]=3[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:23](O)=O.C=O.C(Cl)(Cl)Cl.CCCC(C)C.CCN(CC)CC.CN1CCN(C)C2C=NC=CC1=2.C(N1C2C(CCCC2)N(CC)C2C=NC=CC1=2)C>>[CH3:23][N:11]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:8][C:9]2[CH:22]=[CH:21][N:20]=[CH:19][C:10]1=2
Reactant: O=CO
Reactant: c1ccc(C2Nc3ccncc3NC2c2ccccc2)cc1
Agent: C=O
Agent: CCN1c2ccncc2N(CC)C2CCCCC21
Agent: CN1CCN(C)c2cnccc21
Solvent: CCN(CC)CC
Solvent: CCCC(C)C
Solvent: ClC(Cl)Cl
Product: CN1c2cnccc2NC(c2ccccc2)C1c1ccccc1
Temperature: 120 °C

Procedure:
In a 100 ml round-bottomed flask, 0.600 g (2.08 mmol) of 31 were dissolved in 15.5 ml (417.6 mmol, ρ=1.22 g/ml) of formic acid while cooling in ice and 5.1 ml of formaldehyde solution (183.6 mmol, ρ=1.22 g/ml, <37% in water) were added. The ice bath was subsequently removed and the mixture was heated at an oil bath temperature of 120° C. for 48 hours. After cooling to 0° C., 50% strength NaOH was added while cooling in ice until the pH of the mother liquor had risen to 12. The mixture was subsequently extracted three times with 50 ml of DCM and the combined organic phases were dried over Na2SO4. After distilling off the solvent on a rotary evaporator, the crude product was purified by flash chromatography on silica gel (CHCl3/isohexane/NEt3, 10:2:1). This gave 0.564 g (1.87 mmol, 90%) of a yellow solid. Rf=0.40 (CHCl3/isohexane/NEt3, 10:2:1). 1H NMR: (400 MHz, CDCl3): δ=2.85 (s, 3H, CH3), 4.42 (s, 1H, N—H), 4.44 (d, 3J=3.6 Hz, 1H, H-3), 4.95 (d, 3J=3.6 Hz, 1H, H-2), 6.50 (d, 3J=5.2 Hz, 1H, H-8), 6.64 (dd, 4J=2.8 Hz, 3J=9.2 Hz, 2H, 2,6-phenyl-H), 6.90 (m, 2H, 2,6-phenyl-H) 7.05 (m, 2H, phenyl-H), 7.16 (m, 4H, phenyl-H), 7.82 (s, 1H, H-5), 7.84 (d, 3J=5.2 Hz ppm. 13C NMR (75 MHz, CDCl3): δ=37.2 (CH3), 57.8 (C-3), 67.9 (C-2), 107.6 (C-8), 127.4-128.5 (phenyl-C), 131.3 (C-5), 131.6 (Cq, C-4a) 137.4, 138.8 (Cq, phenyl-C), 139.9 (C-7, C-8a) ppm. MS (EI): m/e (%) 302 (22), 301 (M+, 100), 300 (5), 286 (5), 224 (10), 222 (4), 211 (13), 210 (87), 209 (3), 208 (6), 195 (11), 181 (6), 179 (3), 178 (3), 178 (3), 150 (7), 132 (3), 127 (3), 120 (3), 104 (4); 92 (3), 91 (31), 85 (4), 83 (6), 78 (4), 77 (5); IR (neat): ν=3200 (w), 3158 (w), 3029 (w), 2948 (w), 2881 (w), 2824 (w), 1578 (s), 1516 (vs), 1491 (m), 1452 (m), 1421 (m), 1374 (w), 1353 (w), 1326 (w), 1294 (w), 1256 (m), 1235 (m), 1199 (w), 1157 (m), 1131 (m), 1103 (w), 1073 (m), 1054 (m), 1031 (m), 1013 (m), 969 (w), 922 (w), 842 (w), 810 (s), 766 (s), 755 (m), 733 (m), 641 (vs) cm−1. HRMS (EI): calculated for C20H19N3 301.1574 [M+], found: 301.1559.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:14]3[C:15]([CH3:20])=[N:16][O:17][C:18]=3[CH3:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:21]([NH2:23])=[O:22].[CH3:24][C:25]1[O:29][N:28]=[C:27]([CH2:30][NH2:31])[CH:26]=1>C(O)CCC>[CH3:20][C:15]1[C:14]([C:8]2[CH:7]=[C:6]3[C:11]([C:2]([NH:31][CH2:30][C:27]4[CH:26]=[C:25]([CH3:24])[O:29][N:28]=4)=[C:3]([C:21]([NH2:23])=[O:22])[CH:4]=[N:5]3)=[CH:10][C:9]=2[O:12][CH3:13])=[C:18]([CH3:19])[O:17][N:16]=1
Reactant: COc1cc2c(Cl)c(C(N)=O)cnc2cc1-c1c(C)noc1C
Reactant: Cc1cc(CN)no1
Solvent: CCCCO
Product: COc1cc2c(NCc3cc(C)on3)c(C(N)=O)cnc2cc1-c1c(C)noc1C
Temperature: 110 °C

Procedure:
A solution of 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (for a preparation see Intermediate 56, 331 mg) and [(5-methyl-3-isoxazolyl)methyl]amine (2.5 eq) in butanol (20 ml) was heated to 110° C. for 4 h. The reaction mixture was evaporated to dryness and hydrolysed with water. The mixture was extracted with DCM and the organic dried over Na2SO4, filtered and concentrated to dryness (280 mg). Used without purification in the subsequent reaction (Example 52).
Reaction SMILES: [O:1]=[C:2]1[N:11]([CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([C:19](O)=[O:20])[CH2:15][CH2:14]2)[C:10](=[O:22])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:56]1[CH:61]=[CH:60][CH:59]=[N:58][C:57]=1[N:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1>CN(C=O)C.CO>[N:56]1[CH:61]=[CH:60][CH:59]=[N:58][C:57]=1[N:62]1[CH2:67][CH2:66][N:65]([C:19]([C@H:16]2[CH2:15][CH2:14][C@H:13]([CH2:12][N:11]3[C:10](=[O:22])[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[NH:3][C:2]3=[O:1])[CH2:18][CH2:17]2)=[O:20])[CH2:64][CH2:63]1
Reactant: O=c1[nH]c2ccccc2c(=O)n1C[C@H]1CC[C@H](C(=O)O)CC1
Reactant: c1cnc(N2CCNCC2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=c1[nH]c2ccccc2c(=O)n1C[C@H]1CC[C@H](C(=O)N2CCN(c3ncccn3)CC2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of trans-4-(2,4-Dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl)-cyclohexanecarboxylic acid (100 mg, 0.33 mmol) in DMF(2 mL), diisopropylethylamine (58 μL, 0.33 mmol) and HATU (126 mg, 0.33 mmol) were added. The mixture was left 6 hours stirring at room temperature and then 1-(2-pyrimidyl)piperazine was added. After 16 hours at room temperature the solvent was removed under reduced pressure; the residue was dissolved in 2 mL of DCM and washed with 2 mL of 0.4N Na2CO3 solution. The organic layer was separated, dried over Na2SO4 and the solvent removed under reduced pressure. The titled compound (58 mg, yield 39%) was purified by precipitation from methanol.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)C=O>CCCCCC.O1CCCC1>[Cl:16][C:17]1[CH:24]=[C:23]([CH:8]2[O:7][C:1](=[O:6])[CH:2]=[C:3]([OH:4])[CH2:5]2)[CH:22]=[CH:19][CH:18]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1C=C(O)CC(c2cccc(Cl)c2)O1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The title compound was prepared as described in General Method 1 using 5.0 mL of methyl acetoacetate, 2.0 g of NaH 60% dispersion in oil, 25 mL of 2.0M n-butyl lithium in hexane, 6.5 mL of 3-chlorobenzaldehyde and 150 mL of tetrahydrofuran. After addition of the aldehyde, the reaction was stirred for 15 minutes at 0° C. then allowed to warm to room temperature overnight. The crude product was triturated from diethyl ether to afford a solid (m.p. 122°-124° C.). 'H NMR (CDCl3) δ2.83 (dd, 1H), 2.96 (dd, 1H), 3.60 (dd, 2H), 5.68 (dd, 1H), 7.25-7.42 (m, 4H).
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:17][CH2:16][C:8]2[N:9]=[C:10]([NH:12][CH2:13][CH2:14]C)[S:11][C:7]=2[CH2:6]1)(=[O:3])[CH3:2].C(NC1CCC2N=C(NC(=O)CC)SC=2C1)(=O)C>>[C:1]([NH:4][CH:5]1[CH2:17][CH2:16][C:8]2[N:9]=[C:10]([NH:12][CH2:13][CH3:14])[S:11][C:7]=2[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCCNc1nc2c(s1)CC(NC(C)=O)CC2
Agent: CCC(=O)Nc1nc2c(s1)CC(NC(C)=O)CC2
Product: CCNc1nc2c(s1)CC(NC(C)=O)CC2

Procedure:
6-Acetylamino-2-n-propylamino-4,5,6,7-tetrahydro-benzthiazole prepared from 6-acetylamino-2-propionylamino-4,5,6,7,-tetrahydro-benzthiazole at ambient temperature.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].[CH3:7][O:8][C:9]([C:11]1[S:15][C:14]2[CH:16]=[C:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:18]=[CH:19][C:13]=2[C:12]=1OS(C(F)(F)F)(=O)=O)=[O:10].O>C(Cl)Cl.CCN(CC)CC>[CH3:7][O:8][C:9]([C:11]1[S:15][C:14]2[CH:16]=[C:17]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH:18]=[CH:19][C:13]=2[C:12]=1[S:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])=[O:10]
Reactant: COC(=O)CS
Reactant: COC(=O)c1sc2cc(C(=O)OC(C)(C)C)ccc2c1OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)CSc1c(C(=O)OC)sc2cc(C(=O)OC(C)(C)C)ccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 70 %

Procedure:
Methyl thioglycolate (1.1 ml, 12 mmol) was added to a solution of 3-trifluoromethanesulfonyloxy-benzo[b]thiophene-2,6-dicarboxylic acid 6-tert-butyl ester 2-methy ester in DCM (30 ml) and Et3N (15 ml) and stirred for 24 hr at RT then 24 hr at 40° C. When the starting material was absent in LC trace, water was added. Extraction with EtOAc and evaporation left an orange liquid. Purification by column chromatography yielded 2.7 g (70%) of 3-methoxycarbonylmethylsulfanyl-benzo[b]thiophene-2,6-dicarboxylic acid 6-tert-butyl ester 2-methyl ester.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([NH:11][C:12]2[CH:17]=[C:16](Cl)[N:15]=[N:14][C:13]=2[C:19]([NH2:21])=[O:20])[CH:8]=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:22][C@@H:23]1[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]1[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33]>CN1C(=O)CCC1>[C:1]([C:5]1[N:10]=[C:9]([NH:11][C:12]2[CH:17]=[C:16]([NH:22][C@@H:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[N:15]=[N:14][C:13]=2[C:19](=[O:20])[NH2:21])[CH:8]=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cccc(Nc2cc(Cl)nnc2C(N)=O)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1N
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1cc(Nc2cccc(C(C)(C)C)n2)c(C(N)=O)nn1
Temperature: 130 °C
Reaction time: 24 h
Yield: 46 %

Procedure:
A resealable pressure tube was charged with 4-(6-tert-butylpyridin-2-ylamino)-6-chloropyridazine-3-carboxamide (100 mg, 327 μmol) dissolved in NMP (2.00 mL) To this solution was added tert-butyl (3R,4R)-4-aminotetrahydro-2H-pyran-3-ylcarbamate (70.7 mg, 327 μmol) and the reaction mixture was heated in an oil bath with stirring at 130° C. for 24 h. Added additional tert-butyl (3R,4R)-4-aminotetrahydro-2H-pyran-3-ylcarbamate (70.7 mg, 327 μmol) and reaction continued for 24 h. Added more tert-butyl (3R,4R)-4-aminotetrahydro-2H-pyran-3-ylcarbamate (70.7 mg, 327 μmol) and reaction continued for 72 h. The NMP was evaporated under high vacuum. The residue was purified by flash chromatography (silica gel 50 μm, 40 g, Analogix) eluting with 0 to 5% over 20 min (MeOH containing 10% NH4OH)/CH2Cl2 to yield tert-butyl (3R,4R)-4-(5-(6-tert-butylpyridin-2-ylamino)-6-carbamoylpyridazin-3-ylamino)tetrahydro-2H-pyran-3-ylcarbamate (73 mg, 46.0% yield) as a yellow foam. 1H NMR (CHLOROFORM-d) δ: 11.45 (br. s., 1H), 8.33 (s, 1H), 8.14 (s, 1H), 8.06 (d, J=3.4 Hz, 1H), 7.52 (t, J=7.9 Hz, 1H), 6.91 (d, J=7.9 Hz, 1H), 6.66 (d, J=7.9 Hz, 1H), 5.65 (br. s., 1H), 5.37 (d, J=8.3 Hz, 1H), 3.38-4.31 (m, 6H), 1.63-2.23 (m, 2H), 1.46 (s, 9H), 1.39 (s, 9H); LC-MS 486.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:52]([CH3:54])[CH3:53])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:18][C:17]2[C:19]3[C:24]([CH:25]=[CH:26][C:16]=2[N:15]=1)=[CH:23][C:22]([C:27]1[CH:32]=[CH:31][C:30]([C:33]2[NH:37][C:36]([C@@H:38]4[C@@H:43]5[CH2:44][C@@H:40]([CH2:41][CH2:42]5)[N:39]4C(OC(C)(C)C)=O)=[N:35][CH:34]=2)=[CH:29][CH:28]=1)=[CH:21][CH:20]=3)=[O:8])=[O:4].Cl.[CH3:56][O:57][C@H:58]([CH3:68])[C@H:59]([NH:63][C:64]([O:66][CH3:67])=[O:65])[C:60]([OH:62])=O.CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH3:67][O:66][C:64]([NH:63][C@@H:59]([C@H:58]([O:57][CH3:56])[CH3:68])[C:60]([N:39]1[C@H:38]([C:36]2[NH:37][C:33]([C:30]3[CH:31]=[CH:32][C:27]([C:22]4[CH:23]=[C:24]5[C:19](=[CH:20][CH:21]=4)[C:17]4[NH:18][C:14]([C@@H:10]6[CH2:11][CH2:12][CH2:13][N:9]6[C:7](=[O:8])[C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[CH:52]([CH3:53])[CH3:54])=[N:15][C:16]=4[CH:26]=[CH:25]5)=[CH:28][CH:29]=3)=[CH:34][N:35]=2)[C@@H:43]2[CH2:44][C@H:40]1[CH2:41][CH2:42]2)=[O:62])=[O:65]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4ccc(-c5cnc([C@@H]6[C@H]7CC[C@H](C7)N6C(=O)OC(C)(C)C)[nH]5)cc4)ccc3c2[nH]1)C(C)C
Reactant: COC(=O)N[C@H](C(=O)O)[C@@H](C)OC
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4ccc(-c5cnc([C@@H]6[C@H]7CC[C@H](C7)N6C(=O)[C@@H](NC(=O)OC)[C@@H](C)OC)[nH]5)cc4)ccc3c2[nH]1)C(C)C
Reaction time: 3 h
Yield: 27.4 %

Procedure:
(1R,3S,4S)-tert-butyl 3-(5-(4-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-naphtho[1,2-d]imidazol-7-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (73 mg, 0.0997 mmol) was dissolved in DCM (5 mL) and treated with HCl (4M in dioxane, 1 mL). After 3 h, the reaction mixture was concentrated. The residue was treated with (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (23 mg, 0.120 mmol), COMU (51 mg, 0.120 mmol) and DMF (2 mL). DIPEA (0.090 mL, 0.499 mmol) was added and the reaction mixture was stirred for 25 min before being quenched with H2O and purified by HPLC to afford the title compound (22 mg, 28%). (ESI) m/z 805 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[N:10]=2)[CH:5]=[C:4]([C:16](O)=[O:17])[C:3]1=[O:19].C(Cl)(=O)C([Cl:23])=O.CN(C)C=O>ClCCl>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[N:10]=2)[CH:5]=[C:4]([C:16]([Cl:23])=[O:17])[C:3]1=[O:19]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1c(=O)c(C(=O)O)cc2ccc(C(F)(F)F)nc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1c(=O)c(C(=O)Cl)cc2ccc(C(F)(F)F)nc21
Temperature: 40 °C
Reaction time: 2 h

Procedure:
0.83 g (3.0 mmol) of 1-methyl-2-oxo-7-(trifluoromethyl)-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid was dissolved in dichloromethane (50 mL), and 1.0 mL (12 mmol) of oxalyl chloride was added thereto. Two droplets of N,N-dimethylformamide were added to the above mixture, and the resulting mixture was stirred for 2 hours at 40° C. The reaction solution was concentrated under reduced pressure, and thus 1-methyl-2-oxo-7-(trifluoromethyl)-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid chloride was obtained. The acid chloride thus obtained was dissolved in acetonitrile (30 mL), and this solution was added to an acetonitrile (50 mL) solution of 0.38 g (3.4 mmol) of 1,3-cyclohexanedione and 0.51 mL (3.7 mmol) of triethylamine under ice cooling. The resulting mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic phase was washed with water, an aqueous solution of sodium hydrogen carbonate, and water in this order, and was dried and concentrated. The residue was washed with diisopropyl ether, and thus 0.51 g (yield: 46%) of the title compound was obtained as brown crystals.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]2[C@H:10]([C:13]([OH:15])=[O:14])[CH2:11][CH2:12][N:6]2[C:5](=[O:16])[CH2:4][CH2:3]1.O=[C:18]([CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:19]([OH:21])=[O:20]>>[C:19]([CH:18]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]2[C@H:10]([C:13]([OH:15])=[O:14])[CH2:11][CH2:12][N:6]2[C:5](=[O:16])[CH2:4][CH2:3]1)[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([OH:21])=[O:20]
Reactant: N[C@H]1CCC(=O)N2CC[C@@H](C(=O)O)N2C1=O
Reactant: O=C(O)C(=O)CCc1ccccc1
Product: O=C(O)C(CCc1ccccc1)N[C@H]1CCC(=O)N2CC[C@@H](C(=O)O)N2C1=O
Yield: 18.1 %

Procedure:
In a manner analogous to that described in the first paragraph of Example 1, from 1.13 g of 8(S)-amino-2,3,6,7,8,9-hexahydro-5,9-dioxo-1H,5H-pyrazolo[1,2-a][1,2]diazepine-1(S)-carboxylic acid and 2.7 g of 2-oxo-4-phenylbutyric acid there were obtained 350 mg of 8(S)-(1-carboxy-3-phenylpropylamino)-2,3,6,7,8,9-hexahydro-5,9-dioxo-1H,5H-pyrazolo[1,2-a][1,2]diazepine-1(S)-carboxylic acid in the form of a lyophilized mixture.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[CH:8][C:7]=1[N:21]1[N:30]=[CH:29][C:28]2[C:23](=[C:24]([F:35])[CH:25]=[C:26]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:27]=2)[C:22]1=[O:36])(=[O:3])[CH3:2].Cl[C:38]1[CH:39]=[C:40]([NH:46][C:47]2[CH:52]=[CH:51][C:50]([O:53][C:54]([CH3:60])([CH3:59])[CH2:55][N:56]([CH3:58])[CH3:57])=[CH:49][N:48]=2)[C:41](=[O:45])[N:42]([CH3:44])[N:43]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(O)CCC.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]>[C:31]([C:26]1[CH:27]=[C:28]2[C:23](=[C:24]([F:35])[CH:25]=1)[C:22](=[O:36])[N:21]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:38]3[CH:39]=[C:40]([NH:46][C:47]4[CH:52]=[CH:51][C:50]([O:53][C:54]([CH3:59])([CH3:60])[CH2:55][N:56]([CH3:57])[CH3:58])=[CH:49][N:48]=4)[C:41](=[O:45])[N:42]([CH3:44])[N:43]=3)[C:6]=1[CH2:5][O:4][C:1](=[O:3])[CH3:2])[N:30]=[CH:29]2)([CH3:33])([CH3:34])[CH3:32]
Reactant: CN(C)CC(C)(C)Oc1ccc(Nc2cc(Cl)nn(C)c2=O)nc1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCCCO
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(OC(C)(C)CN(C)C)cn3)c(=O)n(C)n2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Temperature: 110 °C
Reaction time: 2.5 h

Procedure:
A flask was charged with 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (391 mg, 0.55 mmol), 6-chloro-4-(5-(1-(dimethylamino)-2-methylpropan-2-yloxy)pyridin-2-ylamino)-2-methylpyridazin-3(2H)-one (150 mg, 0.43 mmol), X-phos (31 mg, 0.06 mmol) and potassium phosphate tribasic (199 mg, 0.94 mmol). The mixture was taken up in n-butanol (2.8 ml) and water (0.67 ml) and vacuum de-gassed and placed under argon atmosphere. To this mixture was added bis(dibenzylideneacetone)palladium (17 mg, 0.03 mmol) and the vacuum de-gas cycle was repeated. The material was heated at 110° C. (oil bath) with vigorous stirring under argon atmosphere for 2.5 hours. The flask was cooled to ambient and the contents were taken up in water (35 ml) and ethyl acetate (35 ml). The contents were transferred to a separatory funnel and shaken. The organic phase was collected and washed with water (35 ml). The aqueous phases were back extracted with ethyl acetate (2×30 ml) and the organic phases combined, dried (magnesium sulfate), filtered and stripped. The remainder was purified by preparative thin layer chromatography (3 plates), eluting with 8% methanol/dichloromethane to provide desired product (together with some des-acetyl product) as a golden brown oil (312 mg). (M+H)+=684 (642) m/e.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[NH:23]1[CH2:26][CH2:25][CH2:24]1>CO>[N:23]1([C:4]2[C:5]3[CH2:10][CH2:9][CH:8]([C:11]4[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=4)[C:6]=3[N:7]=[C:2]([Cl:1])[N:3]=2)[CH2:26][CH2:25][CH2:24]1
Reactant: FC(F)(F)Oc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Reactant: C1CNC1
Solvent: CO
Product: FC(F)(F)Oc1ccc(C2CCc3c2nc(Cl)nc3N2CCC2)cc1
Yield: 89.9 %

Procedure:
A solution of 2,4-dichloro-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (250 mg, 0.716 mmol) and azetidine (82 mg, 1.432 mmol) in MeOH (3 mL) was stirred at rt for 1 h. The solvent was removed in vacuum and the crude product was purified by column chromatography on silica gel to afford 4-(azetidin-1-yl)-2-chloro-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (238 mg, 0.644 mmol, 90% yield). LC-MS (M+H)+=371.2.
Reaction SMILES: C([Mg]Br)C.I[C:6]1[N:7]=[C:8]([CH3:30])[N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1.CON(C)[C:34]([C:36]1([C:39]([F:42])([F:41])[F:40])[CH2:38][CH2:37]1)=[O:35].[Cl-].[NH4+]>C(Cl)Cl>[CH3:30][C:8]1[N:9]([C:11]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=[C:6]([C:34]([C:36]2([C:39]([F:42])([F:41])[F:40])[CH2:38][CH2:37]2)=[O:35])[N:7]=1
Reactant: Cc1nc(I)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CON(C)C(=O)C1(C(F)(F)F)CC1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: Cc1nc(C(=O)C2(C(F)(F)F)CC2)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
Ethylmagnesium bromide (3 M solution in diethyl ether) (633 mL, 1.9 mol) was added over 1 h to a 5° C. solution of 4-iodo-2-methyl-1-trityl-1H-imidazole (855 g, 1.9 mol) in methylene chloride (8 L). After stirring at 5° C. for 30 min, the reaction mixture was allowed to warm to ca. 12° C. and a solution of N-methoxy-N-methyl-1-(trifluoromethyl)cyclopropanecarboxamide (355 g, 1.8 mol) in methylene chloride (2 L) was added over 1 h. After stirring at ambient temperature overnight, the reaction mixture was poured into saturated aqueous ammonium chloride. The organic phase was washed with saturated aqueous sodium bicarbonate, dried (magnesium sulfate) and concentrated in vacuo. The residue was dissolved in a minimal volume of ether and crashed out with heptane. After stirring in heptane (ca. 3 L) for 1 h, solid was collected by filtration, washing with heptane to afford (2-methyl-1-trityl-1H-imidazol-4-yl)[1-(trifluoromethyl)cyclopropyl]methanone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10](O)[CH3:11])=[CH:7][C:6]=2[CH:13]=1.CS(Cl)(=O)=O.C(N(CC)CC)C.[N-:26]=[N+:27]=[N-:28].[Na+]>CN(C=O)C>[N:26]([CH:10]([C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:13][C:6]=2[CH:7]=1)[CH3:11])=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(O)c1cc2cc(Br)ccc2o1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(N=[N+]=[N-])c1cc2cc(Br)ccc2o1
Yield: 77.2 %

Procedure:
Using 1-(5-bromo-1-benzofuran-2-yl)ethanol (6.11 g, 25.4 mmol), DMF (50 mL), methanesulfonyl chloride (2.9 mL, 38.0 mmol), triethylamine (7.5 mL, 50.8 mmol) and sodium azide (8.64 g, 127 mmol), an operation in the same manner as in Reference Example 22 was performed to give the title compound 5.22 g as an oil. This was used for the next step without purification.
Reaction SMILES: O[CH:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]#[N:12])[C:5]=2[CH2:4][CH2:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCCl>[CH2:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][C:6]=2[C:11]#[N:12])[CH2:2][CH2:3]1
Reactant: N#Cc1cccc2c1CCC2O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCCl
Product: N#Cc1cccc2c1CCC2
Temperature: 25 °C
Yield: 46.4 %

Procedure:
5.9 g of 1-hydroxy-4-indanecarbonitrile in 60 ml of 1,2,-dichloroethane and 210 mg of paratoluene sulphonic acid (APTS, 1H2O) are taken to reflux for 2 hours. After cooling to ambient temperature and concentrating to dryness at 40° C. under reduced pressure, the residue is chromatographed on silica in a hexane-isopropyl ether mixture (9-1), and 2.46 g of expected product is isolated.