Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Cl:15])[CH:9]=2)[N:5]=[C:4]([N:16]2[CH2:20][CH2:19][CH2:18][CH:17]2[CH3:21])[N:3]=1.[CH3:22][C:23]1[C:24]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[N:25][CH:26]=[C:27]([N+:29]([O-:31])=[O:30])[CH:28]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[Cl:15][C:10]1[CH:9]=[C:8]([C:6]2[CH:7]=[C:2]([N:35]3[CH2:36][CH2:37][N:32]([C:24]4[C:23]([CH3:22])=[CH:28][C:27]([N+:29]([O-:31])=[O:30])=[CH:26][N:25]=4)[CH2:33][CH2:34]3)[N:3]=[C:4]([N:16]3[CH2:20][CH2:19][CH2:18][CH:17]3[CH3:21])[N:5]=2)[CH:13]=[CH:12][C:11]=1[F:14]
Reactant: CC1CCCN1c1nc(Cl)cc(-c2ccc(F)c(Cl)c2)n1
Reactant: Cc1cc([N+](=O)[O-])cnc1N1CCNCC1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc([N+](=O)[O-])cnc1N1CCN(c2cc(-c3ccc(F)c(Cl)c3)nc(N3CCCC3C)n2)CC1

Procedure:
Heat a mixture of 4-chloro-6-(3-chloro-4-fluoro-phenyl)-2-(2-methyl-pyrrolidin-1-yl) -pyrimidine (210 mg), 1-(3-Methyl-5-nitro-pyridin-2-yl)-piperazine, and DIEA (185 mg, 1.44 mmol) in DMA at 120°C. for 16 h. Concentrate under reduced pressure and partition between EtOAc and brine. Dry the organic layer (Na2SO4) and concentrate under reduced pressure. Purify the residue by flash column eluting with EtOAc-Hexanes (1:4) to afford the title compound as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]3[C:12]4[C:17]([C:18]5[C:23]=3[C:22]=2[CH:21]=[CH:20][CH:19]=5)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[B:29](OC(C)C)([O:34]C(C)C)[O:30]C(C)C.Cl>CCCCCC.O1CCCC1>[CH:9]1[C:8]2=[C:22]3[C:21]([C:5]4[C:4]2=[CH:3][CH:2]=[CH:7][CH:6]=4)=[CH:20][CH:19]=[CH:18][C:23]3=[C:11]([C:12]2[CH:13]=[C:14]([B:29]([OH:34])[OH:30])[CH:15]=[CH:16][CH:17]=2)[CH:10]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1cccc(-c2ccc3c4c(cccc24)-c2ccccc2-3)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1cccc(-c2ccc3c4c(cccc24)-c2ccccc2-3)c1
Temperature: -70 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
A flask was charged with 9.2 g of 3-(3-bromophenyl)fluoranthene and 129 mL of tetrahydrofuran. After cooling the reaction solution to −70° C., 17.2 mL of a 1.65 M hexane solution of n-butyllithium was added dropwise to the reaction solution. The mixture was stirred at −70° C. for 2 hours. After the dropwise addition of 17.7 mL of triisopropyl borate to the reaction solution, the reaction solution was stirred at −70° C. for 1 hour. The reaction solution was then stirred for 5 hours while heating the reaction solution to room temperature. After the addition of 2 M hydrochloric acid to the reaction solution so that the reaction solution had a pH in the acidic region, the reaction solution was extracted with ethyl acetate. After removing the aqueous phase, the organic phase was washed with a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After filtering the organic phase, the solvent was evaporated under reduced pressure. The residue was washed with a hexane-ethyl acetate mixture to obtain 7.9 g of the target 3-(fluoranthen-3-yl)phenylboronic acid (yield: 95%).
Reaction SMILES: [CH3:1][Mg]Cl.[CH2:4]([O:9][C:10]1[CH:23]=[CH:22][C:21]2[O:20][C:19]3[C:14](=[CH:15][C:16]([C:24]4[CH:25]=[N:26][CH:27]=[N:28][CH:29]=4)=[CH:17][CH:18]=3)[C:13](=[O:30])[C:12]=2[CH:11]=1)[C:5]([CH3:8])([CH3:7])[CH3:6]>C1COCC1>[CH3:1][C:13]1([OH:30])[C:12]2[CH:11]=[C:10]([O:9][CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])[CH:23]=[CH:22][C:21]=2[O:20][C:19]2[C:14]1=[CH:15][C:16]([C:24]1[CH:25]=[N:26][CH:27]=[N:28][CH:29]=1)=[CH:17][CH:18]=2
Reactant: C[Mg]Cl
Reactant: CC(C)(C)COc1ccc2oc3ccc(-c4cncnc4)cc3c(=O)c2c1
Solvent: C1CCOC1
Product: CC(C)(C)COc1ccc2c(c1)C(C)(O)c1cc(-c3cncnc3)ccc1O2
Reaction time: 2 h

Procedure:
Methyl magnesium chloride, 22 wt % in THF (5.0 mL, 14.88 mmol), was added to a solution of 2-(neopentyloxy)-7-(pyrimidin-5-yl)-9H-xanthen-9-one (2.2 g, 6.10 mmol) in THF (61.0 mL) at 0° C. After 2 hours, the reaction mixture was quenched with saturated aqueous ammonium chloride (200 mL) and extracted with EtOAc (3×200 mL). The combined organic extracts were washed with saturated aqueous ammonium chloride, water, saturated aqueous sodium chloride, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to afford 9-methyl-2-(neopentyloxy)-7-(pyrimidin-5-yl)-9H-xanthen-9-ol which used directly for the next reaction without further purification. Pyridinium p-toluene-sulfonate (0.140 g, 0.558 mmol) was added to a solution of 9-methyl-2-(neopentyloxy)-7-(pyrimidin-5-yl)-9H-xanthen-9-ol (0.200 g, 0.531 mmol) in DCE (2 mL) at 65° C. The reaction was monitored by and TLC analysis (1:1 Hex/EtOAc) and after 2 hours the solution was allowed to cool and was poured into saturated aqueous sodium bicarbonate (25 mL) and the layers were separated. The aqueous layer was extracted with CH2Cl2 (3×15 mL). The combined organic extracts were washed with saturated aqueous sodium chloride, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give the crude material which was taken up in toluene and concentrated twice to remove residual pyridine. The product was used without further purification. MS m/z=359.2 [M+H].
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:21])[C:7]([C:16]([O:18]CC)=[O:17])=[CH:8][N:9]2[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:4][C:3]=1[F:22].[CH:23]1([NH:26][CH2:27][C@@H:28]2[C@H:32]([F:33])[CH2:31][NH:30][CH2:29]2)[CH2:25][CH2:24]1.N12CCCN=C1CCCCC2>C(#N)C>[CH:23]1([NH:26][CH2:27][C@@H:28]2[C@H:32]([F:33])[CH2:31][N:30]([C:2]3[N:11]=[C:10]4[C:5]([C:6](=[O:21])[C:7]([C:16]([OH:18])=[O:17])=[CH:8][N:9]4[C:12]([CH3:13])([CH3:14])[CH3:15])=[CH:4][C:3]=3[F:22])[CH2:29]2)[CH2:25][CH2:24]1
Reactant: CCOC(=O)c1cn(C(C)(C)C)c2nc(Cl)c(F)cc2c1=O
Reactant: F[C@@H]1CNC[C@@H]1CNC1CC1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)n1cc(C(=O)O)c(=O)c2cc(F)c(N3C[C@H](CNC4CC4)[C@H](F)C3)nc21
Temperature: 80 °C
Reaction time: 1 h
Yield: 33.5 %

Procedure:
Ethyl 7-chloro-6-fluoro-1,4-dihydro-1-(1,1-dimethylethyl)-4-oxo-1,8-naphthyridine-3-carboxylate (327 mg), (3R,4S)-3-cyclopropylaminomethyl-4-fluoropyrrolidine (174 mg), 1,8-diazabicyclo[5.4.0]undec-7-ene (160 mg) and acetonitrile (5 mL) were mixed together. The reaction mixture was stirred at 80° C. for 1 hour and was concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane (30 mL), washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: dichloromethane: acetone=2:1->1:1->dichloromethane: methanol=10:1). The eluted pale yellow solid was dissolved in ethanol (4 mL), followed by addition of a 10% aqueous solution of sodium hydroxide (4 mL), stirring at 60° C. for 70 min, and concentration under reduced pressure. The resulting residue was diluted with water (10 mL), neutralized with 1 mol/L hydrochloric acid (pH 7.5), and extracted with dichloromethane (2×30 mL). The dichloromethane extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: dichloromethane: methanol=10:1) to give 7-[(3S,4S)-3-cyclopropylaminomethyl-4-fluoro-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-1-(1,1-dimethylethyl)-4-oxo-1,8-naphthyridine-3-carboxylic acid as white crystals (141 mg).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:47]=[CH:46][C:8]([O:9][C:10]2[CH:15]=[C:14]([N:16]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[N:13]3[N:33]=[CH:34][C:35]([C:36]4[CH:37]=[N:38][C:39]5[C:44]([CH:45]=4)=[CH:43][CH:42]=[CH:41][CH:40]=5)=[C:12]3[N:11]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C1C(=O)N([Br:55])C(=O)C1>C(#N)C>[Br:55][C:15]1[C:10]([O:9][C:8]2[CH:46]=[CH:47][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)=[N:11][C:12]2[N:13]([N:33]=[CH:34][C:35]=2[C:36]2[CH:37]=[N:38][C:39]3[C:44]([CH:45]=2)=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:14]=1[N:16]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:22])([CH3:23])[CH3:24]
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Oc2ccc(S(C)(=O)=O)cc2)nc2c(-c3cnc4ccccc4c3)cnn12
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1c(Br)c(Oc2ccc(S(C)(=O)=O)cc2)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound, 5-(4-(methylsulfonyl)phenoxy)-3-(quinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (150 mg, 0.22 mmol) was dissolved in ACN (10 mL). NBS (40 mg, 0.22 mmol) was added and the mixture was stirred at room temperature for 1 h. After concentration, the residue, 6-bromo-5-(4-(methylsulfonyl)phenoxy)-3-(quinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine was used in the next step without further purification. HPLC-MS tR=2.66 min (UV254 nm); mass calculated for formula C34H44BrN5O5SSi2 769.2, observed LCMS m/z 770.0 (M+H).
Reaction SMILES: C([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]([CH3:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[NH:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]([CH3:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1
Reactant: CCOC(=O)CC(C)c1ccc2c(c1)CCN2C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CC(C)c1ccc2c(c1)CCN2

Procedure:
A solution of (R/S) ethyl 3-(1-boc-2,3-dihydro-1H-indol-5-yl)butyrate (3.1 g, Reference Example 6) in dichloromethane (30 ml), cooled in an ice bath, was treated with trifluoroacetic acid (30 ml). After about 30 minutes the reaction mixture was evaporated and traces of trifluoroacetic acid were removed by chasing off with toluene (twice), to give the title compound as a dark viscous gum, which was used immediately without further purification.
Reaction SMILES: [CH3:1][N:2]([C:20]1[CH:25]=[CH:24][C:23]([S:26][CH3:27])=[CH:22][CH:21]=1)[C:3]([C:5]1[C:17](=[O:18])[N:13]2[CH2:14][CH2:15][O:16][C:11]3[C:12]2=[C:7]([CH:8]=[CH:9][CH:10]=3)[C:6]=1[OH:19])=[O:4].ClC1C=CC=C(C(OO)=[O:36])C=1>ClCCl>[CH3:1][N:2]([C:20]1[CH:21]=[CH:22][C:23]([S:26]([CH3:27])=[O:36])=[CH:24][CH:25]=1)[C:3]([C:5]1[C:17](=[O:18])[N:13]2[CH2:14][CH2:15][O:16][C:11]3[C:12]2=[C:7]([CH:8]=[CH:9][CH:10]=3)[C:6]=1[OH:19])=[O:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(N(C)C(=O)c2c(O)c3cccc4c3n(c2=O)CCO4)cc1
Solvent: ClCCl
Product: CN(C(=O)c1c(O)c2cccc3c2n(c1=O)CCO3)c1ccc(S(C)=O)cc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
A mixture of 6-[N-methyl-N-(4-methylthiophenyl)carbamoyl]-2,3-dihydro-7-hydroxy-5-oxo-5H-pyrido[1,2,3-de]-1,4-benzoxazine (1 g) and m-chloroperbenzoic acid (0.5 g) in dichloromethane (50 ml) was stirred at 5° C. for 1 hour. The insoluble material was filtered and the filtrate was concentrated in vacuo. The residue was recrystallized from acetone to give pale brown crystals of 6-[N-methyl-N-(4-methylsulfinylphenyl)carbamoyl]-2,3-dihydro-7-hydroxy-5-oxo-5H-pyrido[1,2,3-de]-1,4-benzoxazine (0.82 g).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]([OH:18])=O)[CH2:12][CH2:11]1)[CH2:6][CH2:7][CH2:8][CH3:9].N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:5]([C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]([Cl:3])=[O:18])[CH2:12][CH2:11]1)[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCC[C@H]1CC[C@H](C(=O)Cl)CC1

Procedure:
20 mL of thionyl chloride was added dropwise to a mixture containing 20.0 g (0.1 mol) of trans-4-pentylcyclohexanecarboxylic acid represented by the following formula (b-i), 0.5 mL of pyridine and 300 mL of toluene in a nitrogen atmosphere, and the mixture was stirred under heating to 80° C. or less for 1 hour. The solvent was distilled off under reduced pressure to provide trans-4-pentylcyclohexanecarboxylic acid chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:9]=2[O:24][CH3:25])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:33][C:34]1[C:35]([OH:45])=[C:36]([S:41](Cl)(=[O:43])=[O:42])[CH:37]=[C:38]([Cl:40])[CH:39]=1>C(Cl)Cl>[Cl:33][C:34]1[C:35]([OH:45])=[C:36]([S:41]([N:15]([CH2:14][C:10]2[C:9]([O:24][CH3:25])=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:13]=[CH:12][CH:11]=2)[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)(=[O:43])=[O:42])[CH:37]=[C:38]([Cl:40])[CH:39]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Reactant: COc1c(CNCc2ccc(F)cc2)cccc1-c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cccc1-c1ccc(Cl)cc1
Reaction time: 0.17 h
Yield: 40.9 %

Procedure:
A solution of 1-(4′-chloro-2-methoxybiphenyl-3-yl)-N-(4-fluorobenzyl)methanamine (590 mg, 1.684 mmol, 1.0 eq) in dry DCM under nitrogen at 0° C. and treated slowly with triethylamine (492 mg, 4.8 mmol, 3 eq). The reaction mixture was stirred for 10 minutes and treated with a solution of 3,5-dichloro-2-hydroxybenzene-1-sulfonyl chloride (527 mg, 2.018 mmol, 1.2 eq) dissolved in DCM. The resulting mixture was stirred for 12 h at ambient temperature and concentrated under reduced pressure. The residue was further diluted with water and extracted with ethyl acetate. The organic layer was dried under anhydrous Na2SO4 and concentrated. The residue was purified by flash column chromatography on silica gel (60-120) eluting with 15-20% ethyl acetate/hexane to afford the title compound (0.400 g, 50%). 1H NMR (400 MHz, DMSO-d6) δ 3.32 (s, 3H), 4.52-4.53 (d, 4H), 7.04-7.08 (m, 3H), 7.17-7.24 (m, 4H), 7.43-7.52 (m, 5H), 7.77 (s, 1H). MS (ESI): 577.8 (M−H)−.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([N+:13]([O-:15])=[O:14])=[C:10]([C:16]([NH2:18])=[O:17])[CH:9]=2)=[CH:4][CH:3]=1.[CH3:19][N:20]1[C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=[N:21]1>O1CCCC1.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>[CH3:19][N:20]1[C:24]([C:2]2[N:7]=[CH:6][C:5]([C:8]3[S:12][C:11]([N+:13]([O-:15])=[O:14])=[C:10]([C:16]([NH2:18])=[O:17])[CH:9]=3)=[CH:4][CH:3]=2)=[CH:23][CH:22]=[N:21]1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: NC(=O)c1cc(-c2ccc(Cl)nc2)sc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1nccc1-c1ccc(-c2cc(C(N)=O)c([N+](=O)[O-])s2)cn1
Temperature: 150 °C

Procedure:
5-(6-Chloropyridin-3-yl)-2-nitrothiophene-3-carboxamide (300 mg, 1.06 mmol), 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (352 mg, 1.69 mmol), and tetrakis(triphenylphosphine)palladium(0) (61.1 mg, 0.05 mmol) were dissolved in tetrahydrofuran (8.5 ml) and 2 M sodium carbonate (2.1 ml) and the mixture was bubbled with nitrogen for 5 min. The reaction was then heated in the microwave to 150° C. for 15 min. The mixture was poured into ethyl acetate and water and extracted with ethyl acetate (3×100 mL). The combined organic fractions were washed with brine, dried over magnesium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate/hexane to yield the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].Br[CH2:11][CH:12]1[O:17][CH2:16][CH2:15][CH2:14][O:13]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH:6][CH2:11][CH:12]1[O:17][CH2:16][CH2:15][CH2:14][O:13]1)[CH3:2]
Reactant: CCOC(CN)OCC
Reactant: BrCC1OCCCO1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(CNCC1OCCCO1)OCC

Procedure:
2,2-Diethoxyethylamine (23.3 grams), 2-bromomethyl-1,3-dioxane (29.2 grams), triethylamine (25 ml) and toluene (150 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux overnight. After this time the mixture is cooled and filtered. The filtrate is then distilled under reduced pressure to yield the desired product N-(2,2-diethoxyethyl)-N-(1,3-dioxan-2-ylmethyl)amine.
Reaction SMILES: [OH:1]/[N:2]=[C:3](\Cl)/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[F:10].[C:12]([CH2:15][C:16](=O)[CH3:17])(=[O:14])[CH3:13].[O-]CC.[Na+].Cl>C(O)C>[F:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]1[C:15]([C:12](=[O:14])[CH3:13])=[C:16]([CH3:17])[O:1][N:2]=1
Reactant: CC(=O)CC(C)=O
Reactant: O/N=C(\Cl)c1ccccc1F
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(=O)c1c(-c2ccccc2F)noc1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86.3 %

Procedure:
A solution of (E)- and/or (Z)-N-hydroxy-2-fluoro-benzenecarboximidoyl chloride (6.5 g, 37 mmol) in ethanol (29 mL) was added dropwise to a solution of acetylacetone (4.6 g, 46 mmol) containing sodium ethoxide (14.8 g, 46 mmol) in ethanol (83 mL) at ice-bath cooling temperature. After complete addition, the resulting mixture was allowed to warm up to room temperature and stirred for 1.5 h. The mixture was then acidified with HCl (6 N) and concentrated and the mixture extracted with ethyl acetate and then washed with water and brine and dried over sodium sulphate. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 75:25) afforded the title compound (7.0 g, 85%) which was obtained as a light yellow liquid. MS: m/e=220.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:12][CH2:11][N:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[C:9]2[CH:23]=[CH:24][CH:25]=[CH:26][C:8]=2[C:7]1=[O:27])=[O:5])[CH3:2].Br[CH2:29][CH2:30][N:31]1[C:35](=[O:36])[C:34]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:33]2[C:32]1=[O:41]>>[CH2:1]([O:3][C:4]([C:6]1([CH2:29][CH2:30][N:31]2[C:32](=[O:41])[C:33]3[C:34](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:35]2=[O:36])[CH2:12][CH2:11][N:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:14])=[O:15])[C:9]2[CH:23]=[CH:24][CH:25]=[CH:26][C:8]=2[C:7]1=[O:27])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCN(S(=O)(=O)c2ccc(C)cc2)c2ccccc2C1=O
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Product: CCOC(=O)C1(CCN2C(=O)c3ccccc3C2=O)CCN(S(=O)(=O)c2ccc(C)cc2)c2ccccc2C1=O

Procedure:
The title compound was prepared from 5-oxo-1-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid ethyl ester and N-(2-bromoethyl)phthalimide as described in Example 1. 1H NMR (CDCl3) δ 7.85(m, 4H), 7.75(m, 4H), 7.55-7.45(m, 2H), 7.4-7.35(m, 1H), 7.25-7.2(m, 1H), 4.2-4.0(m, 6H), 3.9-3.85(m, 1H), 3.65-3.55(m, 3H), 3.4(br s, 1H), 2.4(s, 3H), 2.4-2.35(m, 1H), 1.35-1.15(m, 3H). MS (ES) m/z 583(MNa)+
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]=[C:5]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)[N:6]([C@@H:8]([C:12]2[O:13][C:14]3[C:19]([C:20](=[O:29])[C:21]=2[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:18][CH:17]=[C:16]([Cl:30])[CH:15]=3)[CH:9]([CH3:11])[CH3:10])[CH:7]=1.N1C=CC=CC=1.[CH3:44][C:45](OC(C)=O)=[O:46]>C(Cl)Cl>[CH2:22]([CH:21]1[C:20](=[O:29])[C:19]2[C:14](=[CH:15][C:16]([Cl:30])=[CH:17][CH:18]=2)[O:13][CH:12]1[C@H:8]([N:6]1[CH:7]=[C:3]([CH2:2][NH:1][C:45](=[O:46])[CH3:44])[N:4]=[C:5]1[C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1)[CH:9]([CH3:11])[CH3:10])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(-c2nc(CN)cn2[C@@H](c2oc3cc(Cl)ccc3c(=O)c2Cc2ccccc2)C(C)C)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NCc1cn([C@H](C(C)C)C2Oc3cc(Cl)ccc3C(=O)C2Cc2ccccc2)c(-c2ccc(C)cc2)n1
Yield: 88.8 %

Procedure:
To 2-[(R)-1-(4-aminomethyl-2-p-tolyl-imidazol-1-yl)-2-methyl-propyl]-3-benzyl-7-chloro-chromen-4-one (0.17 g, 0.33 mMol) in CH2Cl2 (5 mL) was added with stirring, pyridine (27 uL, 0.33 mMol) and Ac2O (63 uL, 0.67 mMol). After stirring at RT for 4 h the reaction was concentrated under vacuum. The remaining residue was triturated with (1:1) Et2O/pet. ether, filtered and dried under vacuum to give the title compound (163 mg, 89%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J=8.6 Hz, 1H), 7.59 (d, J=1.8 Hz, 1H), 7.43 (m, 6H), 7.17 (m, 3H), 6.84 (br s, 1H), 6.71 (d, J=2.2 Hz, 1H), 6.69 (s, 1H), 5.07 (d, J=10.9 Hz, 1H), 4.50 (2d, 1H), 4.43 (2d, 1H), 4.07 (d, J=15.5 Hz, 1H), 2.66 (m, 1H), 2.51 (s, 3H), 2.48 (d, J=15.5 Hz, 1H), 2.00 (s, 3H), 0.95 (d, J=6.6 Hz, 3 H), 0.34 (d, J=6.7 Hz, 3H); MS (ES) m/e 554.4 (M+H)+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([Cl:13])=[C:11]([CH:14]2[CH2:16][CH2:15]2)[N:10]=[C:9]([C:17]2[S:18][C:19]([S:22](=[O:29])(=[O:28])[NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:21]=2)[N:8]=1)(=O)=O.[NH2:32][C:33]1[N:37](C(OC(C)(C)C)=O)[N:36]=[C:35]([CH:45]2[CH2:47][CH2:46]2)[CH:34]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[C:24]([NH:23][S:22]([C:19]1[S:18][C:17]([C:9]2[N:10]=[C:11]([CH:14]3[CH2:16][CH2:15]3)[C:12]([Cl:13])=[C:7]([NH:32][C:33]3[NH:37][N:36]=[C:35]([CH:45]4[CH2:47][CH2:46]4)[CH:34]=3)[N:8]=2)=[CH:21][CH:20]=1)(=[O:28])=[O:29])([CH3:26])([CH3:25])[CH3:27]
Reactant: CC(C)(C)OC(=O)n1nc(C2CC2)cc1N
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2nc(OS(=O)(=O)C(F)(F)F)c(Cl)c(C3CC3)n2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2nc(Nc3cc(C4CC4)n[nH]3)c(Cl)c(C3CC3)n2)s1
Temperature: 100 °C
Reaction time: 3 h
Yield: 32 %

Procedure:
A mixture of 2-(5-(N-tert-butylsulfamoyl)thiophen-2-yl)-5-chloro-6-cyclopropylpyrimidin-4-yl trifluoromethane sulfonate (200 mg, 0.38 mmol, 1.0 eq), tert-butyl 5-amino-3-cyclopropyl-1H-pyrazole-1-carboxylate (129 mg, 0.58 mmol, 1.2 eq), Ph3P (30 mg, 0.11 mmol, 0.3 eq), Ph(Ph3P)4 (44 mg, 0.038 mmol, 0.1 eq) and K2CO3 (158 mg, 1.14 mmol, 3 eq) in dioxane (5 mL) was stirred at 100° C. for 3 h. The mixture was extracted with EtOAc. The combined organic phases were washed (brine), dried (Na2SO4), filtered and concentrated to give a residue, which was purified by silica gel column chromatography (PE/EtOAc/MeOH=1:1:0.1) to provide N-tert-butyl-5-(5-chloro-4-cyclopropyl-6-(3-cyclopropyl-1H-pyrazol-5-ylamino)pyrimidin-2-yl)thiophene-2-sulfonamide (60 mg, 32%) as a white solid. LC-MS (m/z)=493.9 [M+H]+
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5]2.[CH3:21][N:22](C)C=O>[C-]#N.[Zn+2].[C-]#N.C(OCC)(=O)C>[C:21]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5]2)#[N:22]
Reactant: CN(C)C=O
Reactant: CCOC(=O)C1=Cc2cc(I)ccc2NC1C(F)(F)F
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=Cc2cc(C#N)ccc2NC1C(F)(F)F
Temperature: 80 °C
Yield: 48 %

Procedure:
N,N-Dimethylformamide (5 mL) was degassed with nitrogen for thirty minutes in a three neck round bottom flask equipped with a condenser, temperature monitoring, nitrogen purge and heating mantle. Ethyl 6-iodo-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate (Example 158) (0.522 g, 1.32 mmol) and zinc cyanide (0.102 g, 0.792 mmol) were added to the N,N-dimethylformamide and stirred vigorously for ten minutes. Tetrakis(triphenyl-phosphine)palladium(0) (0.068 g, 0.53 mmol) was added and the contents gently warmed to 80° C. for 2 hours under a nitrogen atmosphere. Ethyl acetate (20 mL) was added, followed by extraction with aqueous 2 N ammonium hydroxide (2×10 mL), water (2×10 mL), saturated ammonium chloride (2×mL), dried over sodium sulfate and solvent removed in vacuo to yield a yellow solid. The product was purified by flash chromatography (silica gel, ethyl acetate-hexanes, 3:1) to yield, upon concentration of the appropriate fractions, ethyl 6-cyano-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate as a yellow solid (188 mg, 48%): mp 211-212° C. 1H NMR (CDCl3 /300 MHz) 7.68 (s, 1H), 7.43 (m, 2H), 6.69 (d, 1H, J=8.3 Hz), 5.22 (m, 1H), 4.98 (br s, 1H), 1.30 (m, 2H), 1.36 (t, 3H, J=7.1 Hz). EIHRMS m/z 314.1147 (M+NH4+, Calc'd 314.1116). Anal. Calc'd for C14H11F3N2O2 : C, 56.76; H, 3.74; N, 9.46. Found: C, 56.44; H, 4.03; N, 9.29.