Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([C:18]1[CH:31]=[CH:30][C:21]2[O:22][C:23]([CH3:29])([CH3:28])[C@@:24]3([CH3:27])[O:26][C@H:25]3[C:20]=2[CH:19]=1)(=[O:17])=[O:16])(C(C)(C)C)(C)C.[CH3:32][N:33]1[C:38](=[O:39])[CH:37]=[CH:36][C:35]([OH:40])=[N:34]1.N1C=CC=CC=1>O1CCOCC1>[CH3:32][N:33]1[C:38](=[O:39])[CH:37]=[CH:36][C:35]([O:40][C@H:25]2[C@@:24]([OH:26])([CH3:27])[C:23]([CH3:29])([CH3:28])[O:22][C:21]3[CH:30]=[CH:31][C:18]([S:15]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[OH:8])(=[O:17])=[O:16])=[CH:19][C:20]2=3)=[N:34]1
Reactant: CC1(C)Oc2ccc(S(=O)(=O)c3ccccc3O[Si](C)(C)C(C)(C)C)cc2[C@@H]2O[C@@]21C
Reactant: Cn1nc(O)ccc1=O
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: Cn1nc(O[C@@H]2c3cc(S(=O)(=O)c4ccccc4O)ccc3OC(C)(C)[C@@]2(C)O)ccc1=O

Procedure:
(3S ,4S)-6-(2-tert-Butyidimethylsilyloxyphenyl)sulphonyl-3,4-dihydro-3,4-epoxy-2,2,3-trimethyl-2H-benzo[b]pyran (0.5 g) (see Preparation 16) and 2,3-dihydro-2-methyl-3-oxo-6-hydroxypyridazine (0.41 g) (see J.Org.Chem., 1971, 36, 3372) were suspended in dry 1,4-dioxane (8 ml), pyridine (0.085 g) was added and the mixture was heated under reflux (a calcium chloride drying tube was attached to the flask) for 20 hours. The solvent was removed under reduced pressure, the residue was stirred with dichloromethane (30 ml) and filtered. The filtrate was evaporated and the residue was chromatographed on silica using 1:1 hexane: ethyl acetate as the eluent to yield a mixture of the required product and the epoxide starting material. This mixture was redissolved in dry 1,4-dioxane (7 ml), 2,3-dihydro-2-methyl-3-oxo-6-hydroxypyridazine (0.2 g) and pyridine (0.08 g) were added and the reaction was heated under reflux for a further 18 hours. The solvent was removed under reduced pressure and the residue was dissolved in 5% methanol/dichloromethane and filtered. The filtrate was evaporated and the residue was chromatographed on silica using 2.5:97.5 methanol: dichioromethane as the eluent to yield (3S,4R)-3,4-dihydro-4-(2,3-dihydro-2-methyl-3-oxopyridazin-6-yl)oxy-3-hydroxy-6-(2-hydroxyphenyl)-sulphonyl-2,2,3-trimethyl-2H-benzo[b]pyran (0.17 g) as a yellow foam. Found: C,54.19; H,4.85; N,5.21. C23H24N2O7S, 0.625 CH2Cl2 requires C,54.06; H,4.73; N,5.34%.
Reaction SMILES: Cl.[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[N:8][NH:9]2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[O:38])[CH3:37])=[CH:32][C:31]=1[O:39][CH3:40].CN(C)C=O>O>[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([N:12]3[CH2:13][CH2:14][N:15]([CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]4[CH:35]=[CH:34][C:33]([C:36](=[O:38])[CH3:37])=[CH:32][C:31]=4[O:39][CH3:40])[CH2:16][CH2:17]3)=[N:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1cc(C(C)=O)ccc1OCCCCBr
Reactant: Fc1ccc2c(N3CCNCC3)n[nH]c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(C)=O)ccc1OCCCCN1CCN(c2n[nH]c3cc(F)ccc23)CC1
Temperature: 75 °C
Yield: 35.8 %

Procedure:
A stirred mixture of 6-fluoro-3-(1-piperazinyl)-1H-indazole hydrochloride (5.0 g & 19 mmol), K2CO3 (5.8 g) and 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone (6.3 g, 21 mmol) and dimethylformamide (80 ml) was heated at 75° C. for 6 hours. The reaction was poured into water, and an off-white solid formed from solution. The solid was collected and dried to yield 4.5 g of crude product. The compound was recrystallized from ethanol (3 times) to afford 3.0 g of an off-white solid. The solid was chromatographed on a Waters Prep 500 utilizing silica gel columns and eluting with methylene chloride/methanol (7%). Concentration of the appropriate fractions afford 2.3 g of an off-white solid, which when recrystallized from ethanol yielded 1.9 g (269) of analytically pure 1-[4-[4-[4-(6-fluoro-1H-indazol-3yl)-1-piperazinyl]butoxy]-3-methoxyphenyl]ethanone, m.p.=156-158° C.
Reaction SMILES: [Na].[H-].[Na+].[C:4]1(=[N:16][OH:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[CH2:18]([N:20]([CH2:24][CH3:25])[CH2:21][CH2:22]Cl)[CH3:19].C(O)(=O)/C=C/C([O-])=O>>[CH2:18]([N:20]([CH2:24][CH2:25][O:17][N:16]=[C:4]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[CH2:21][CH3:22])[CH3:19]
Reactant: CCN(CC)CCCl
Reactant: ON=C1CCCCCCCCCCC1
Agent: O=C([O-])/C=C/C(=O)O
Agent: [H-]
Agent: [Na+]
Product: CCN(CC)CCON=C1CCCCCCCCCCC1

Procedure:
The sodium salt is formed in the usual way from 2.4 g. (0.1 moles) of sodium hydride and 19.73 g. (0.1 moles) of cyclododecanone oxime in a toluenic solution and then allowed to react with 14.9 g. (0.11 moles) of 1-diethylamino-2-chloroethane. Otherwise the operations are carried out in accordance with Example 1. Yield: 20 g. (67.56%); b.p. 172°-176° C./0.8 torr. Hydrogen fumarate, m.p.: 112°-114° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[O:18][C@@H:16]([CH3:17])[CH2:15][C@@H:14]2[OH:19])(=O)=O)=CC=1.CN(C)C=O.[N-:25]=[N+:26]=[N-:27].[Na+]>C(OCC)C>[N:25]([CH2:12][C@H:13]1[O:18][C@@H:16]([CH3:17])[CH2:15][C@@H:14]1[OH:19])=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@@H](C)C[C@@H]2O)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C[C@H]1C[C@H](O)[C@@H](CN=[N+]=[N-])O1
Yield: 77.4 %

Procedure:
A mixture, under argon, of 0.560 g of product from Example 337, 2 ml of N,N-dimethylformamide and 0.250 g of sodium azide is stirred at 75° C. for 12 hours. The reaction mixture is diluted with diethyl ether, washed with water and saturated sodium chloride, dried and concentrated in vacuo to give 0.238 g of the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[C:19]([NH2:20])=[N:18][C:12]3[N:13]=[C:14]([NH2:17])[N:15]=[CH:16][C:11]=3[CH:10]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:21]([N:25]=[C:26]=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[NH2:17][C:14]1[N:15]=[CH:16][C:11]2[CH:10]=[C:9]([C:4]3[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=3)[C:19]([NH:20][C:26]([NH:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])=[N:18][C:12]=2[N:13]=1
Reactant: CC(C)(C)N=C=O
Reactant: Cc1cc(C)cc(-c2cc3cnc(N)nc3nc2N)c1
Product: Cc1cc(C)cc(-c2cc3cnc(N)nc3nc2NC(=O)NC(C)(C)C)c1

Procedure:
The title compound was prepared from 0.3 g of 6-(3,5-dimethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,7-diamine from Example 94 and 0.14 mL of tert-butyl isocyanate according to Example 2. The product is purified by MPLC eluting with 1:1 CHCl3 :EtOAc; mp 180°-182° C., CIMS (1% ammonia in methane): m/z (relative intensity) 365 (MH+ +1, 16), 366 (MH+ +2, 3), 84 (100).
Reaction SMILES: [OH:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[I:10][C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[I:10][C:11]1[CH:16]=[CH:15][C:14]([O:1][CH:2]2[CH:7]3[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]3)[CH2:3]2)=[CH:13][CH:12]=1
Reactant: Ic1ccc(I)cc1
Reactant: OC1CN2CCC1CC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: Ic1ccc(OC2CN3CCC2CC3)cc1
Temperature: 110 °C

Procedure:
3-Hydroxy quinuclidine (Aldrich, 2.54 g, 20 mmol) in toluene (anhydrous, Aldrich, 50 mL) was treated with 1,4-diiodobenzene (Aldrich, 7.9 g, 24 mmol), Cul (Strem Chemicals, 0.38 g, 2 mmol), 1,10-phenanthroline (Aldrich, 0.72 g, 4 mmol), and Cs2CO3 (Aldrich, 8.15 g, 25 mmol), heated at 110° C. for 40 hours. The reaction mixture was allowed to cool to room temperature, diluted with chloroform (100 mL), and washed with water (2×10 mL). The organic phase was concentrated and the title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.20) as oil (3.7 g, yield, 56%). 1H NMR (MeOH-d4, 300 MHz) δ 1.40–1.56 (m, 1H), 1.64–1.80 (m, 2H), 1.90–2.08 (m, 1H), 2.10–2.21 (m, 1H), 2.60–3.00 (m, 5H), 3.34–3.40 (m, 1H), 4.46 (m, 1H), 6.73 (d, J=8.8 Hz, 2H), 7.56 (d, J=8.8, Hz, 2H), ppm. MS (DCl/NH3) m/z 330 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][C@@:19]([CH3:25])([CH:22]([CH3:24])[CH3:23])[CH2:20][OH:21]>>[OH:21][CH2:20][C@:19]([NH:18][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([CH3:25])[CH:22]([CH3:24])[CH3:23]
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Reactant: CC(C)[C@](C)(N)CO
Product: CC(C)[C@@](C)(CO)NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 15, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g; 100 mg, 0.42 mmol) and (2S)-2-amino-2,3-dimethyl-1-butanol (CAN 956102-64-0, 107.06 mg, 0.64 mmol) as starting materials, and isolated (25 mg, 16.04%) as off white sticky solid, LC-MS (UV peak area, ESI) 90.02%, 334.4 (M+H).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]2[N:11]=[CH:10][C:9]([C:12]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[O:13])=[C:8]([OH:23])[C:6]=2[N:7]=1.C(N(CC)CC)C.[CH2:31]([OH:34])[C:32]#[CH:33].[NH4+].[Cl-]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][NH:14][C:12]([C:9]2[CH:10]=[N:11][C:5]3[CH:4]=[N:3][C:2]([C:33]#[C:32][CH2:31][OH:34])=[N:7][C:6]=3[C:8]=2[OH:23])=[O:13])=[CH:17][CH:18]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2cnc(Br)nc2c1O
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2cnc(C#CCO)nc2c1O
Temperature: 90 °C

Procedure:
A mixture of 2-bromo-N-(4-chlorobenzyl)-8-hydroxypyrido[3,2-d]pyrimidine-7-carboxamide (Preparation 6, 1.97 g), (Ph3P)2PdCl2 (175 mg), and triethylamine (5.0 mL) in DMF (50 mL) is heated to 90° C. Propargyl alcohol (2.5 mL) is slowly added to the mixture over 20 h. The reaction mixture is allowed to cool to room temperature, poured into saturated aqueous NH4Cl solution (200 mL), and extracted with ethyl acetate (3×100 mL). The combined organic layers are dried (MgSO4) and concentrated. The crude product is purified by column chromatography.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[CH2:4]1)#[CH:2].I[C:18]1[CH:19]=[N:20][N:21]2[CH:26]=[C:25]([C:27]3[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=3)[CH:24]=[C:23]([O:33][CH3:34])[C:22]=12.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.C(NC(C)C)(C)C>[CH2-]C=C.[CH2-]C=C.Cl[Pd+].Cl[Pd+].[Cu]I.C(#N)C>[CH3:34][O:33][C:23]1[C:22]2[N:21]([N:20]=[CH:19][C:18]=2[C:2]#[C:1][CH:3]2[CH2:4][N:5]([C:7]([O:9][CH2:10][C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[O:8])[CH2:6]2)[CH:26]=[C:25]([C:27]2[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=2)[CH:24]=1
Reactant: COc1cc(-c2cnn(C)c2)cn2ncc(I)c12
Reactant: C#CC1CN(C(=O)OCc2cccnc2)C1
Agent: Cl[Pd+]
Agent: [Cu]I
Agent: C=C[CH2-]
Solvent: CC(C)NC(C)C
Solvent: CC#N
Product: COc1cc(-c2cnn(C)c2)cn2ncc(C#CC3CN(C(=O)OCc4cccnc4)C3)c12
Temperature: 45 °C

Procedure:
Pyridin-3-ylmethyl 3-ethynylazetidine-1-carboxylate (50 mg, 0.23 mmol), 3-iodo-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine (40 mg, 0.11 mmol), allylpalladium chloride dimer (12 mg, 0.03 mmol), tri(2-furyl)phosphine (16 mg, 0.07 mmol) and copper (I) iodide (2.1 mg, 0.011 mmol) were combined into one vial fitted with a Teflon septum. The vial was flushed with nitrogen and acetonitrile (1.6 ml) and diisopropylamine (0.048 mL, 0.34 mmol) were added. After sparging with nitrogen for 5 minutes, the reaction was heated to 45° C. for two hours. The mixture was cooled to ambient temperature, diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was separated and the aqueous layer was back extracted with ethyl acetate two times. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC reverse phase (C-18), eluting with acetonitrile/water+0.05% TFA. The fractions containing product were combined and diluted in ethyl acetate, then washed with aqueous sodium bicarbonate and dried over sodium sulfate. The solution was filtered and concentrated under reduced pressure to give pyridin-3-ylmethyl 3-{[4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl]ethynyl}azetidine-1-carboxylate. 1H NMR (500 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.58 (s, 1H), 8.50-8.54 (m, 1H), 8.29 (s, 1H), 8.02 (s, 2H), 7.74-7.82 (m, 1H), 7.35-7.43 (m, 1H), 6.94 (s, 1H), 5.09 (s, 2H), 4.12-4.38 (br, 2H), 3.80-3.98 (m, 8H), 3.67-3.76 (m, 1H). LRMS (ESI) calculated for C24H23N6O3 [M+H]+, 443.2; found 443.2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=2[CH2:24][CH2:25][CH3:26])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH:31]1C1C=CC(B2OC(C)(C)C(C)(C)O2)=CN=1>>[CH3:12][CH:11]([N:8]1[C:9]2[CH:10]=[C:2]([C:18]3[CH:19]=[N:20][C:21]([N:33]4[CH2:32][CH2:31][N:30]([CH3:29])[CH2:35][CH2:34]4)=[CH:22][CH:23]=3)[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=3[CH2:24][CH2:25][CH3:26])=[O:15])[C:5]=2[CH:6]=[N:7]1)[CH3:13]
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1cnn2C(C)C
Reactant: CN1CCNCC1c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(N3CCN(C)CC3)nc2)cc2c1cnn2C(C)C

Procedure:
The title compound was prepared in a similar manner as described for example 8 from 6-bromo-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (90 mg, 0.202 mmol) and 1-methyl [5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperazine (92 mg, 0.303 mmol). The final product was collected as a light brown solid (54 mg, 49%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (br. s., 1H) 8.65 (d, J=2.27 Hz, 1H) 8.61 (t, J=4.80 Hz, 1H) 8.36 (s, 1H) 8.04-8.08 (m, 2H) 7.83 (s, 1H) 6.96 (d, J=9.09 Hz, 1H) 5.92 (s, 1H) 5.14 (quin, J=6.57 Hz, 1H) 4.42 (d, J=4.80 Hz, 2H) 3.53-3.59 (m, 4H) 2.53-2.61 (m, 2H) 2.40-2.45 (m, 4H) 2.23 (s, 3H) 2.14 (s, 3H) 1.51-1.58 (m, 2H) 1.50 (s, 3H) 1.49 (s, 3H) 0.88 (t, J=7.33 Hz, 3H). LC-MS (ES) m/z=542.2 [M+H]+
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:10]1[S:14][N:13]=[C:12]([CH3:15])[C:11]=1[N+:16]([O-:18])=[O:17])#[N:9].[CH2:19]([S:31]([C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1)(=[O:33])=[O:32])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].[OH-].[Na+]>O1CCCC1>[C:8]([C:10]1[S:14][N:13]=[C:12]([CH2:15][C:38](=[O:39])[C:37]2[CH:36]=[CH:35][C:34]([S:31]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])(=[O:33])=[O:32])=[CH:42][CH:41]=2)[C:11]=1[N+:16]([O-:18])=[O:17])#[N:9]
Reactant: CCCCCCCCCCCCS(=O)(=O)c1ccc(C(=O)Cl)cc1
Reactant: Cc1nsc(C#N)c1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCS(=O)(=O)c1ccc(C(=O)Cc2nsc(C#N)c2[N+](=O)[O-])cc1
Temperature: 0 °C
Yield: 23.5 %

Procedure:
Triethylamine (20.2 grams, 0.200 mol) was added to 200 ml of a tetrahydrofuran (THF) solution of 16.9 grams (0.100 mol) of 5-cyano-3-methyl-4-nitroisothiazole, and 74.6 grams (0.200 mol) of 4-dodecylsulfonylbenzoyl chloride was added dropwise. After heating under reflux for 8 hours, 200 ml of 1N aqueous sodium hydroxide solution was added dropwise. After heating under reflux for 3 hours, the reaction mixture was left to cool, poured into ice water and extracted with ethyl acetate. 5-Cyano-3-(4-dodecylsulfonylbenzoylmethyl)-4-nitroisothiazole (11.9 grams, 23.5 mmol) was obtained on refinement using silica gel column chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].C(N(CC)CC)C.[NH2:19][C:20]1[CH:42]=[CH:41][C:23]([C:24]([N:26]2[CH2:32][C:31]3[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=3[CH2:29][C:28]3[CH:37]=[CH:38][CH:39]=[CH:40][C:27]2=3)=[O:25])=[CH:22][CH:21]=1>C(Cl)Cl>[CH:37]1[C:28]2[CH2:29][C:30]3[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=3[CH2:32][N:26]([C:24]([C:23]3[CH:22]=[CH:21][C:20]([NH:19][C:5](=[O:6])[C:4]4[CH:8]=[CH:9][C:10]([Cl:11])=[C:2]([Cl:1])[CH:3]=4)=[CH:42][CH:41]=3)=[O:25])[C:27]=2[CH:40]=[CH:39][CH:38]=1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1)c1ccc(Cl)c(Cl)c1
Reaction time: 2 h
Yield: 71.9 %

Procedure:
A mixture of 314 mg of 3,4-dichlorobenzoyl chloride and 151 mg of triethylamine in 2 ml of methylene chloride is stirred while 314 mg of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine in 5 ml of methylene chloride is added. Stirring is continued for 2 hours. The reaction mixture is partitioned with water and the organic layer is washed 1N HCl, water, 0.5N NaOH and brine. The organic layer is dried with Na2SO4 and passed through a short pad of hydrous magnesium silicate. Hexane is added to the filtrate at the boil to give 0.35 g of off-white crystalline solid, m.p. 238°-241° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[CH:9][S:8][C:6]=2[N:7]=1.C(N(CC)C(C)C)(C)C.[Cl:33][C:34]1[CH:44]=[CH:43][C:37]([O:38][CH2:39][C:40](Cl)=[O:41])=[CH:36][CH:35]=1>O1CCOCC1.ClCCl>[NH2:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][N:21]([C:40](=[O:41])[CH2:39][O:38][C:37]3[CH:43]=[CH:44][C:34]([Cl:33])=[CH:35][CH:36]=3)[CH2:20][CH2:19]2)[C:5]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: O=C(Cl)COc1ccc(Cl)cc1
Reactant: Nc1nc(N2CCNCC2)c2c(-c3ccc(F)cc3)csc2n1
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(N2CCN(C(=O)COc3ccc(Cl)cc3)CC2)c2c(-c3ccc(F)cc3)csc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 1 (135 mg, 0.41 mmol) in 1,4-dioxane (15 mL) were added N,N-diisopropylethylamine (169 μL, 1.02 mmol) and 4-chlorophenoxyacetyl chloride (0.45 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and the organic layer was extracted several times with water. The combined organic layers were evaporated in vacuo and the crude residue was purified by silica gel flash chromatography, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 0.5% to 1% methanol in dichloromethane), yielding the title compound as a white powder. MS (m/z) 498 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([N:10]2[CH2:21][C:20]3[N:19]4[C:14]([CH2:15][CH2:16][CH2:17][CH2:18]4)=[CH:13][C:12]=3[C:11]2=[O:22])[N:5]=[CH:4][CH:3]=1.[CH3:23][N:24]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[C:26]([NH:39][C:40]2[CH:45]=[CH:44][C:43]([N:46]3[CH2:51][CH2:50][N:49]([CH:52]4[CH2:55][O:54][CH2:53]4)[CH2:48][C@@H:47]3[CH3:56])=[CH:42][N:41]=2)[C:25]1=[O:57].C([O-])(=O)C.[Na+].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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].O.C(#N)C>[CH3:23][N:24]1[C:25](=[O:57])[C:26]([NH:39][C:40]2[CH:45]=[CH:44][C:43]([N:46]3[CH2:51][CH2:50][N:49]([CH:52]4[CH2:53][O:54][CH2:55]4)[CH2:48][CH:47]3[CH3:56])=[CH:42][N:41]=2)=[CH:27][C:28]([C:2]2[C:7]([CH:8]=[O:9])=[C:6]([N:10]3[CH2:21][C:20]4[N:19]5[C:14]([CH2:15][CH2:16][CH2:17][CH2:18]5)=[CH:13][C:12]=4[C:11]3=[O:22])[N:5]=[CH:4][CH:3]=2)=[CH:29]1
Reactant: O=Cc1c(Cl)ccnc1N1Cc2c(cc3n2CCCC3)C1=O
Reactant: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(N4Cc5c(cc6n5CCCC6)C4=O)c3C=O)cn(C)c2=O)nc1
Temperature: 85 °C
Yield: 29.5 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 238e (150 mg, 0.48 mmol, 1.0 eq.), (S)-1-methyl-3-(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 191j (459 mg, 0.95 mmol, 2.0 eq.), Pd(dppf)Cl2 (39 mg, 0.048 mmol, 0.1 eq.), sodium acetate (78 mg, 0.95 mmol, 2.0 eq.), K3PO4 (202 mg, 0.95 mmol, 2.0 eq.), acetonitrile (10 mL), and water (1 mL). After three cycles of vacuum/argon flush, the mixture was heated at 85° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 40:1 dichloromethane/ethanol to afford 238f (90 mg, 30%) as a yellow solid. MS-ESI: [M+H]+ 635.3.
Reaction SMILES: C(OC(=O)C)(=O)C.[N+:8]([O-:11])(O)=[O:9].[CH3:12][S:13]([NH:16][C:17]1[N:21]([C:22]2[C:27]([F:28])=[C:26]([F:29])[C:25]([C:30]([F:33])([F:32])[F:31])=[C:24]([F:34])[C:23]=2[F:35])[N:20]=[CH:19][CH:18]=1)(=[O:15])=[O:14].O>C(O)(=O)C>[CH3:12][S:13]([NH:16][C:17]1[N:21]([C:22]2[C:23]([F:35])=[C:24]([F:34])[C:25]([C:30]([F:33])([F:32])[F:31])=[C:26]([F:29])[C:27]=2[F:28])[N:20]=[CH:19][C:18]=1[N+:8]([O-:11])=[O:9])(=[O:14])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: CS(=O)(=O)Nc1ccnn1-c1c(F)c(F)c(C(F)(F)F)c(F)c1F
Solvent: O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CS(=O)(=O)Nc1c([N+](=O)[O-])cnn1-c1c(F)c(F)c(C(F)(F)F)c(F)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
1.07 ml (0.011 mol) of acetic anhydride and 0.45 ml (0.0106 mol) of 98 percent strength nitric acid are added in succession to a solution of 3.8 g (0.01 mol) of 5-methanesulphonamido-1-(2,3,5,6-tetrafluoro-4-trifluoromethyl-phenyl)-pyrazole in 20 ml of glacial acetic acid at about 15° C. The mixture is stirred at room temperature for 16 hours and the reaction solution is poured onto 100 ml of water. The precipitate is filtered off with suction, washed neutral and dried in vacuo. 3.4 g (80% of theory) of 5-methanesulphonamido-4-nitro-1-(2,3,5,6-tetrafluoro-4-trifluoromethyl-phenyl)-pyrazole of melting point 163° C.-168° C. are obtained.
Reaction SMILES: ClC(Cl)(Cl)C(=N)O[CH:5]([C:7]1[C:15]2[C:11](=[C:12]([Br:24])[N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:14]=2)[CH:10]=[C:9]([C:25]([F:28])([F:27])[F:26])[CH:8]=1)[CH3:6].[OH:32][CH2:33][C:34]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]1>ClCCl.C1CCCCC1>[Br:24][C:12]1[N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:22])([CH3:21])[CH3:23])[N:14]=[C:15]2[C:11]=1[CH:10]=[C:9]([C:25]([F:28])([F:27])[F:26])[CH:8]=[C:7]2[CH:5]([O:32][CH2:33][C:34]1([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:45])([CH3:46])[CH3:44])=[O:41])[CH2:36][CH2:35]1)[CH3:6]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Reactant: CC(OC(=N)C(Cl)(Cl)Cl)c1cc(C(F)(F)F)cc2c(Br)n(COCC[Si](C)(C)C)nc12
Solvent: C1CCCCC1
Solvent: ClCCl
Product: CC(OCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(C(F)(F)F)cc2c(Br)n(COCC[Si](C)(C)C)nc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(±)-1-(3-Bromo-5-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethyl 2,2,2-trichloroacetimidate (1.29 g, 2.21 mmol) and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (0.71 g, 2.43 mmol) were combined in a dichloromethane/cyclohexane mixture (1:1, 8 mL) and cooled to 0° C. The reaction was treated with tetrafluoroboric acid-diethyl ether complex (60 μL, 0.44 mmol), stirred at 0° C. for 1 h, quenched by addition of saturated sodium bicarbonate and diluted with diethyl ether and the layers separated. The ethereal was washed with water (2×), 1 M potassium bisulfate (2×), brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (10% ethyl acetate/hexanes) gave 840 mg (53%) as a yellow film. 1H-NMR (CDCl3, 500 MHz) δ 7.82 (s, 1H), 7.54 (s, 1H), 7.24-7.27 (m, 2H), 7.18-7.22 (m, 3H), 5.51 (s, 2H), 5.07 (q, J=6.4 Hz, 1H), 3.74 (m, 2H), 3.44-3.51 (m, 2H), 3.27 (d, J=9.2 Hz, 1H), 3.24 (d, J=9.2 Hz, 1H), 2.99-3.03 (m, 2H), 2.11-2.16 (m, 2H), 1.82-1.88 (m, 2H), 1.50 (d, J=6.4 Hz, 3H), 1.43 (s, 9H), 0.70-0.83 (m, 2H), 0.08 (s, 9H). Mass spec.: 736.03 (MNa)+.