Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[CH:18]=[C:17](Br)[CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.CCOC(C)=O.CCCCCCC>C(COC)OC.C(=O)([O-])[O-].[Na+].[Na+].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>[C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[CH:18]=[C:17]([C:29]4[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=4)[CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3ccc(Br)cc3c2CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: COCCOC
Product: COc1ccc(-c2ccc3[nH]c4c(c3c2)CCN(C(=O)c2ccccc2)CC4)cc1
Yield: 36.6 %

Procedure:
A mixture of 3-benzoyl-9-bromo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.738 g, 2.0 mmol) and tetrakis(triphenylphosphine)palladium (0.23 g, 0.20 mmol) in dimethoxyethane (5.0 mL) and a solution of 4-methoxyphenylboronic acid (0.365 g, 2.4 mmol) in dimethoxyethane (5.0 mL) and sodium carbonate solution (2 M, 7.0 mL) were reacted in a manner similar to Preparation 1. Column chromatography (silica gel, 20-60% EtOAc/heptane) afforded 0.29 g (37%) of the title compound as a yellow foam: mp 140-145° C.; 1H NMR (300 MHz, CDCl3) δ 7.92, 7.59-7.49, 7.43, 7.37-7.30, 7.03-6.94, 4.09-3.98, 3.85, 3.75-3.65, 3.25-3.14, 2.95-2.85.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:14][CH3:15])(=[O:13])[CH2:8][C:9]([O:11][CH3:12])=[O:10].F[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25].Cl>CN1CCCC1=O>[F:23][C:20]1[CH:21]=[CH:22][C:17]([CH:8]([C:7]([O:14][CH3:15])=[O:13])[C:9]([O:11][CH3:12])=[O:10])=[C:18]([N+:24]([O-:26])=[O:25])[CH:19]=1
Reactant: COC(=O)CC(=O)OC
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COC(=O)C(C(=O)OC)c1ccc(F)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
185 g of potassium-tert-butoxide are added to a solution of 188 ml of dimethyl malonate in 970 ml of N-methylpyrrolidone, while cooling with ice, and the mixture is stirred for 2 hours. 150 ml of 2,5-difluoronitrobenzene are added dropwise to the resulting suspension over a period of 30 minutes and then stirred for 6 hours at 85° C. The mixture is poured onto 4 litres of ice water and 250 ml of concentrated hydrochloric acid and extracted with 2 litres of ethyl acetate. The organic phase is dried with sodium sulphate and evaporated down. The oily residue is stirred twice with water and then taken up in 600 ml ethyl acetate. The solution is dried with sodium sulphate and evaporated to dryness. The crystallised crude product is recrystallised from 600 ml ethyl acetate/hexane=2:8 and dried.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[C:14]([O:16][CH2:17][CH3:18])[CH:13]=[C:12]([O:19][CH2:20][CH3:21])[N:11]=2)[CH2:6][CH2:5]1)(=O)C.[OH-].[Na+].O>C(O)C>[CH2:17]([O:16][C:14]1[CH:13]=[C:12]([O:19][CH2:20][CH3:21])[N:11]=[C:10]([N:7]2[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]2)[N:15]=1)[CH3:18]
Reactant: CCOc1cc(OCC)nc(N2CCN(C(C)=O)CC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOc1cc(OCC)nc(N2CCNCC2)n1
Yield: 103.7 %

Procedure:
A solution of 1-acetyl-4-(4,6-diethoxypyrimidin-2-yl)piperazine (1.8 g) and sodium hydroxide (1.0 g) in ethanol (10 ml)—water (10 ml) was refluxed under heating for 11 hr. The reaction mixture was poured into water and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated to give the title compound (1.6 g) as a pale-brown oil.
Reaction SMILES: [OH:1][C:2]([CH2:4][CH2:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)=O.C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>C1C=CC=CC=1.C1COCC1.O.C1COCC1>[OH:1][CH2:2][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]#[N:11])=[CH:12][CH:13]=1
Reactant: N#Cc1ccc(CCC(=O)O)cc1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: N#Cc1ccc(CCCO)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
A 3.27 g (18.7 mmols) quantity of crude 4-(2-hydroxycarbonylethyl)benzonitrile was admixed with 2.86 ml (20.6 mmols) of triethylamine and 40 ml of THF. To the mixture was added 1.96 ml (20.5 mmols) of ethyl chloroformate at 0° C. After stirring the reaction mixture at room temperature for 3 hours, the insolubles were filtered off. The filtrate was concentrated to give a yellow oil, which was then diluted with 100 ml of benzene. The benzene layer was washed with saturated aqueous solution of NaHCO3, dried over Na2SO4 and concentrated to obtain a yelllow oil. This oil was dissolved in 40 ml of THF-water (8:2). To the solution was added 2.13 g (56.1 mmols) of NaBH4 at 0° C. The reaction mixture was stirred at 0° C. for 2 hours and then poured into 100 ml of 3 mol dm-3HCl, followed by extraction with ethyl acetate. The extract was dried over Na2SO4 and concentrated, giving 2.71 g (yield 90%) of 4-(3-hydroxypropyl)benzonitrile in the form of an oil.
Reaction SMILES: OC1C=CC=C2C=1N=CC=C2.C(=O)([O-])[O-].[K+].[K+].Br[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:35][CH2:34][C@@H:33]4[CH2:36][N:37]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:38][C@H:32]34)=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.[N:44]1[NH:45][C:46](=[O:50])[CH:47]=[CH:48][CH:49]=1>CN(C)C=O.[Cu]I>[O:50]=[C:46]1[N:45]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH2:35][CH2:34][C@@H:33]5[CH2:36][N:37]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:38][C@H:32]45)=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[N:44]=[CH:49][CH:48]=[CH:47]1
Reactant: CCOC(=O)N1C[C@H]2CCN(c3ccc(-c4ccc(Br)cc4)cc3)[C@H]2C1
Reactant: O=c1cccn[nH]1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CN(C)C=O
Product: CCOC(=O)N1C[C@H]2CCN(c3ccc(-c4ccc(-n5ncccc5=O)cc4)cc3)[C@H]2C1
Temperature: 140 °C
Yield: 81.9 %

Procedure:
A mixture of 1.98 g of copper (I) iodide (10.4 mmole, 0.10 eq.), 1.66 g of 8-hydroxyquinoline (11.44 mmole, 0.11 eq.), 4.0 g of potassium carbonate (28.94 mmole, 0.29 eq.) in 18.8 g of dimethylformamide (DMF) was mixed at ambient temperature. The mixture was added to another flask containing 41.6 g of the product of Example 41D (100.16 mmole, 1.00 eq.), 23.6 g of potassium carbonate (170.75 mmole, 1.70 eq.), and 14.4 g of pyridazinone (149.86 mmole, 1.50 eq.). Additional DMF (226 g) was used to transfer the catalyst slurry. The resulting mixture was deoxygenated then heated to 140° C. for about 18 hours. After cooling to ambient temperature the mixture was diluted with 567 g of THF and 384 g of 10% sodium chloride solution. The mixture was filtered to remove excess salts and the aqueous phase was separated and back extracted with an additional 177 g of THF. The combined organic phases were then washed with 10% sodium chloride solution (3×384 g). The organic phase was concentrated under reduced pressure and methanol (253 g) was added and the contents were concentrated under reduced pressure. After adding additional methanol (158 g) the contents were cooled to 0° C., filtered, and washed with cold methanol. The resulting solids were transferred to a vacuum oven to yield 35.31 g (81.9% yield). Mass Spectroscopy: 431.5 (m.w. 430.5). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15 (s, 3H), 1.78-1.88 (m, 1H), 2.10 (ddd, J=12.49, 6.17, 6.04 Hz, 1H), 3.03 (s, 1H), 3.24-3.35 (m, 5H), 3.53 (ddd, J=9.23, 6.86, 6.69 Hz, 2H), 3.67 (s, 1H), 4.00 (s, 2H), 4.22 (s, 1H), 6.63 (d, J=8.51 Hz, 2H), 7.07 (dd, J=9.47, 1.51 Hz, 1H), 7.48 (dd, J=9.47, 3.84 Hz, 1H), 7.53-7.60 (m, 4H), 7.68 (d, J=8.64 Hz, 2H), 8.06 (dd, J=3.84, 1.51 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ ppm 14.79 (CH3), 28.89 (CH2), 47.71 (CH2), 60.24 (CH2), 112.34 (CH), 124.87 (CH), 125.27 (CH), 126.02 (C), 126.89 (CH), 130.05 (CH), 131.69 (CH), 136.87 (CH), 138.78 (C), 139.31 (C), 145.61 (C), 153.53 (C), 158.64 (C).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:33][CH3:34])=[C:17]([O:20][C@H:21]4[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[ClH:35]>O1CCOCC1>[ClH:1].[ClH:35].[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:33][CH3:34])=[C:17]([O:20][C@H:21]4[CH2:25][CH2:24][NH:23][CH2:22]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1O[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1O[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 370 mg 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[(S)-1-(tert.-butyloxy-carbonyl)-pyrrolidin-3-yloxy]-7-methoxy-quinazoline in 5 ml dioxane is combined with 0.32 ml concentrated hydrochloric acid and stirred overnight at ambient temperature. The precipitate formed is suction filtered and washed with copious amounts of dioxane. The crude product is dissolved in a little methanol and re-precipitated by the addition of the same amount of ethyl acetate. The white solid thus obtained is suction filtered and dried.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:3].C(N(CC)C(C)C)(C)C.[C:21]1([C:27]2[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[C:27]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:28]=[CH:29][C:30]([CH2:31][NH:32][C:2](=[O:3])[O:4][C:5]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=2)=[CH:33][CH:34]=1
Reactant: O=C(Cl)Oc1ccc(F)cc1
Reactant: NCc1ccc(-c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc(-c2ccccc2)cc1)Oc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.069 ml (0.522 mmol) of 4-fluorophenyl chloroformate and 0.149 ml (0.82 mmol) of N,N-diisopropylethylamine are added, dropwise and at ambient temperature, to a solution of 0.107 g (0.58 mmol) of 4-phenylbenzylamine in 4 ml of methylene chloride. The mixture is stirred at ambient temperature for 1 h. The reaction medium is diluted with a further 2 ml of methylene chloride and washed with a saturated aqueous ammonium chloride solution and with a saturated aqueous sodium chloride solution. The phases are separated and the organic phase is filtered through a hydrophobic sintered glass funnel. The filtrate is concentrated under reduced pressure and the solid residue is washed with 5 ml of diisopropyl ether.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]([CH3:15])[CH3:14])[C:9]2[C:4](=[CH:5][C:6]([O:16][CH3:17])=[CH:7][CH:8]=2)[N:3]=1.Br[CH2:19][C:20](=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[CH3:17][O:16][C:6]1[CH:5]=[C:4]2[C:9]([C:10]([O:12][CH:13]([CH3:14])[CH3:15])=[CH:11][C:2]3[N:3]2[CH:19]=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:1]=3)=[CH:8][CH:7]=1
Reactant: COc1ccc2c(OC(C)C)cc(N)nc2c1
Reactant: CCOC(=O)C(=O)CBr
Product: CCOC(=O)c1cn2c(cc(OC(C)C)c3ccc(OC)cc32)n1

Procedure:
1.5 g of 2-amino-7-methoxy-4-isopropoxy-quinoline and 1.5 g of ethyl bromopyruvate were reacted by the method of Example 11 to obtain ethyl 8-methoxy-5-isopropoxyimidazo-[1,2-a]-quinoline-2-carboxylate melting at 117°-118° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[C:9]1[CH:10]=[N:11][C:12]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[C:30]([CH:31]([F:42])[C:32]4[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=4)=[C:29]([CH:43]4[CH2:48][CH2:47][C:46]([F:50])([F:49])[CH2:45][CH2:44]4)[C:28]4[CH:27]([O:51]CC5C=CC(OC)=CC=5)[CH2:26][C:25]([CH3:62])([CH3:61])[CH2:24][C:23]=4[N:22]=3)[CH2:17][CH2:16]2)=[N:13][CH:14]=1>>[F:50][C:46]1([F:49])[CH2:47][CH2:48][CH:43]([C:29]2[C:28]3[CH:27]([OH:51])[CH2:26][C:25]([CH3:61])([CH3:62])[CH2:24][C:23]=3[N:22]=[C:21]([CH:18]3[CH2:19][CH2:20][N:15]([C:12]4[N:13]=[CH:14][C:9]([N:5]5[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]5)=[CH:10][N:11]=4)[CH2:16][CH2:17]3)[C:30]=2[CH:31]([F:42])[C:32]2[CH:33]=[CH:34][C:35]([C:38]([F:40])([F:41])[F:39])=[CH:36][CH:37]=2)[CH2:44][CH2:45]1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(Br)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Reactant: CN1CCNCC1
Product: CN1CCN(c2cnc(N3CCC(c4nc5c(c(C6CCC(F)(F)CC6)c4C(F)c4ccc(C(F)(F)F)cc4)C(O)CC(C)(C)C5)CC3)nc2)CC1

Procedure:
Reactions similar to those of the first step of Example 5 and Example 7 were performed except for using 1-methyl piperazine instead of morpholine, and from 120 mg (0.144 mmol) of (−)-2-[1-(5-Bromopyrimidin-2-yl)piperidin-4-yl]-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 11, 36 mg of the title compound was obtained as a light yellow solid (yield: 34%).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[N:11]([CH:32]([CH3:34])[CH3:33])[C:12](=[O:31])[CH2:13][C:14]1[NH:19][C:18]2[CH:20]=[CH:21][C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][C:17]=2[S:16](=[O:30])(=[O:29])[N:15]=1)=O)C.[O-]CC.[Na+]>C(O)C>[OH:3][C:4]1[C@H:6]2[C@H:7]([CH2:8][CH2:9][CH2:10]2)[N:11]([CH:32]([CH3:34])[CH3:33])[C:12](=[O:31])[C:13]=1[C:14]1[NH:19][C:18]2[CH:20]=[CH:21][C:22]([NH:24][S:25]([CH3:28])(=[O:26])=[O:27])=[CH:23][C:17]=2[S:16](=[O:29])(=[O:30])[N:15]=1
Reactant: CCOC(=O)C1CCCC1N(C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1)C(C)C
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)N1C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)[C@@H]2CCC[C@@H]21
Temperature: 60 °C
Reaction time: 16 h
Yield: 33.2 %

Procedure:
A solution of the crude 2-{isopropyl-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclopentanecarboxylic acid ethyl ester in ethanol (20 mL) was treated with a 21% w/w solution of sodium ethoxide in ethanol (0.648 g) and stirred for 16 h at 60° C. Upon cooling, the reaction mixture was then quenched with 1.0 M aqueous hydrochloric acid solution (20 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered, and dried in vacuo. The residue was purified by prep-HPLC [Column ODS-A 5μ 100 Å, 150×21.2 mm, 5 micron, 50%-100% in 13.5 min @ 22 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product, cis-N-[3-(4-hydroxy-1-isopropyl-2-oxo-2,4a,5,6,7,7a-hexahydro-1H-[1]pyrindin-3-yl)-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl]-methanesulfonamide (77.6 mg, 0.166 mmol, 33.2% over two steps), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.10-1.32 (6H, m), 1.46-2.13 (7H, m), 2.28 (1H, bs), 3.06 (3H, s), 3.95 (1H, bs), 4.54-5.10 (1H, m), 7.49-7.63 (3H, m), 10.17 (1H, s). LC-MS (ESI) calcd for C19H24N4O6S2 468.11, found 469.3 [M+H+].
Reaction SMILES: Cl.[F:2][C:3]1([F:9])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[OH-].[Na+].[N:12]([O-])=[O:13].[Na+].C(=O)([O-])O.[Na+]>O.C(O)(=O)C>[F:2][C:3]1([F:9])[CH2:8][CH2:7][N:6]([N:12]=[O:13])[CH2:5][CH2:4]1
Reactant: FC1(F)CCNCC1
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=NN1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
To a solution of 4,4-difluoropiperidine hydrochloride (2.0 g) in water (32 mL) was added an aqueous 2N sodium hydroxide solution (7.6 mL) and the mixture was stirred at room temperature for 1 hours. To the reaction mixture was added sodium nitrite (1.75 g) and thereto was added acetic acid (1.27 mL) under ice-cooling. The mixture was stirred at room temperature for 2 hours. To the reaction mixture was added an aqueous sodium hydrogencarbonate solution and the mixture was stirred and extracted with chloroform. The extract was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resultant crude product was purified by column chromatography on silica gel (solvent: hexane/ethyl acetate=4/1) to obtain 4,4-difluoro-1-nitrosopiperidine (1.89 g, yield: 99%) as a pale yellow solid.
Reaction SMILES: CN(C=O)C.Br[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15].[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([O:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:8]([N+:14]([O-:16])=[O:15])[CH:9]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Br
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Cl)ccc1Oc1ccccc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
To a solution of DMF (50 mL) was added 1-bromo-2-nitro-4-chloro-benzene (5.0 g, 21.1 mmol), phenol (1.9 g, 21.1 mmol), and Na2CO3 (2.3 g, 21.1 mmol). The solution was heated to 85° C. and stirred overnight. The reaction was poured into water and extracted with EtOAc. Washed with water and dried over Na2SO4, filtered and concentrated under vacuum giving a yellow oil that was purified by silica gel column chromatography eluting with Hexanes:Ethyl Acetate (90:10) to give the title compound (3.8 g, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].C(=O)([O-])O.[Na+].[CH3:15][O:16][C:17](=[O:21])[CH:18](Br)[CH3:19]>O>[CH3:15][O:16][C:17](=[O:21])[CH:18]([NH:4][C:3]1[C:2]([Cl:1])=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:9])[CH3:19]
Reactant: Nc1c(Cl)cccc1Cl
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COC(=O)C(C)Nc1c(Cl)cccc1Cl

Procedure:
40.5 g of 2,6-dichloroaniline, 21 g of sodium hydrogen carbonate and 84 ml of DL-α-bromopropionic acid methyl ester are stirred in a sulphonating flask for 2 days at 140° bath temperature. After cooling, the reaction mixture is poured into water and extracted with ethyl acetate. The combined ethyl acetate fractions are extracted once with saturated sodium chloride solution, dried over sodium sulphate and concentrated in a rotary evaporator. The excess α-bromopropionic acid methyl ester is recovered in a water-jet vacuum. The darkly coloured residue remaining is fractionally distilled in high vacuum. There is obtained 23.6 g of α-(2,6-dichloroanilino)-propionic acid methyl ester; b.p. 85°-87°/0.001 Torr.
Reaction SMILES: [Cl:1][C:2]([Cl:8])=[CH:3][CH:4]=[C:5]([CH3:7])[CH3:6].Br[CH:10]([C:16]#[N:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[Ca+2].[Ca].[Cl-].[Na+].Cl>[Cu].C(OCCCC)(=O)C.O>[CH2:14]([O:13][C:11]([C:10]1([C:16]#[N:17])[CH:4]([CH:3]=[C:2]([Cl:8])[Cl:1])[C:5]1([CH3:7])[CH3:6])=[O:12])[CH3:15]
Reactant: CC(C)=CC=C(Cl)Cl
Reactant: CCOC(=O)C(Br)C#N
Agent: [Cu]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCCCOC(C)=O
Product: CCOC(=O)C1(C#N)C(C=C(Cl)Cl)C1(C)C
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A mixture of 1,1-dichloro-4-methylpenta-1,3-diene (30.2 parts), ethyl bromocyanoacetate (38.4 parts), calcium carbonate (20 parts), copper catalyst, phase transfer catalyst and calcium or sodium chloride (each as indicated in the table below) and water (100 parts) is heated at 80° C. and held at 80° C. for 6 hours. The reaction mixture is cooled and stirred with water (100 parts), butyl acetate (100 parts by volume) and concentrated hydrochloric acid (100 parts by volume). The mixture is filtered and the residue is washed with butyl acetate (2×20 parts by volume). The filtrate and washes are combined and the butyl acetate layer is separated and washed with water (4×50 parts). The crude ethyl-1-cyano-3-(2',2'-dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylate is isolated by removal of the butyl acetate under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)=[C:6]([NH:27][C@H:28]([C:30]2[N:35]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:34](=[O:42])[C:33]3=[C:43]([CH3:46])[CH:44]=[CH:45][N:32]3[N:31]=2)[CH3:29])[N:5]=[CH:4][N:3]=1.Cl>O1CCOCC1>[NH2:1][C:2]1[N:3]=[CH:4][N:5]=[C:6]([NH:27][C@H:28]([C:30]2[N:35]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:34](=[O:42])[C:33]3=[C:43]([CH3:46])[CH:44]=[CH:45][N:32]3[N:31]=2)[CH3:29])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]2)=[CH:10][CH:9]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)n(-c3ccccc3)c(=O)c12
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3ccc(N4CCNCC4)cc3)n(-c3ccccc3)c(=O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.2 %

Procedure:
(S)-tert-Butyl 4-(4-(4-amino-6-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidin-5-yl)phenyl)piperazine-1-carboxylate (75 mg, 0.12 mmol) was dissolved in 2 ml dioxane. A solution of hydrochloric acid (4M in dioxane, 30 μL, 0.12 mol) was added and the reaction was stirred at room temperature for 2 h. The solvent was removed and the residue was purified by preparative HPLC-MS to give 12 mg (19% yield) of the title compound as a solid. Purity 100%.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[C:5]([F:12])[C:4]=1[F:13])#[N:2].C(Cl)(=O)C(Cl)=O.[CH3:20][C:21]1[CH:27]=[C:26]([C:28]([F:37])([C:33]([F:36])([F:35])[F:34])[C:29]([F:32])([F:31])[F:30])[CH:25]=[C:24]([CH3:38])[C:22]=1[NH2:23].N1C=CC=CC=1.C(=O)([O-])O.[Na+]>CN(C)C=O.ClCCl.O1CCCC1>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:23][C:22]2[C:24]([CH3:38])=[CH:25][C:26]([C:28]([F:37])([C:29]([F:30])([F:31])[F:32])[C:33]([F:34])([F:35])[F:36])=[CH:27][C:21]=2[CH3:20])=[O:9])=[C:5]([F:12])[C:4]=1[F:13])#[N:2]
Reactant: N#Cc1ccc(C(=O)O)c(F)c1F
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1N
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(C#N)c(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.6 %

Procedure:
To a solution of 4-cyano-2,3-difluoro-benzoic acid (623 mg, 3.4 mmol) (Example I10) and N,N-dimethylformamide (2 drops) in dichloromethane (17 ml) under a nitrogen atmosphere was added oxalyl chloride (0.3455 ml, 4.08 mmol). The reaction mixture was stirred for one hour at ambient temperature and then at 60° C. for 1.5 hours. The reaction mixture was concentrated and the residue dissolved in tetrahydrofuran (5 ml). The solution was added drop-wise to a solution of 2,6-dimethyl-4-(heptafluoroprop-2-yl)aniline (prepared according to EP 1,006,102) (787 mg, 2.72 mmol) and pyridine (547 μl, 6.8 mmol) in tetrahydrofuran (12 ml). The reaction mixture was stirred at ambient temperature for 16 hours. Then the reaction mixture was poured into aqueous sodium hydrogen carbonate (1M) and the mixture extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated. The residue was purified by reverse-phase chromatography (eluent: trifluoroacetic acid/water/acetonitrile 1:4:5 to 1:1:8) to give 4-cyano-2,3-difluoro-N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-benzamide (0.675 g, 44% yield). 1H-NMR (400 MHz, CDCl3): 2.35 (6H, s), 7.38 (2H, s), 7.57 (1H, m), 7.79 (1H, d), 8.03 (1H, m) ppm.