Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][C:8]1[C:9]([CH3:35])=[N:10][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[O:25][C:26]4[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:27]=4[C:28]=3[CH3:29])=[O:23])=[CH:17][CH:16]=2)[C:12]=1[CH3:13])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:34][C:33]1[C:26]2[O:25][C:24]([C:22]([NH:21][C:18]3[CH:19]=[CH:20][C:15]([CH2:14][N:11]4[C:12]([CH3:13])=[C:8]([CH2:7][C:6]([OH:36])=[O:5])[C:9]([CH3:35])=[N:10]4)=[CH:16][CH:17]=3)=[O:23])=[C:28]([CH3:29])[C:27]=2[CH:30]=[CH:31][CH:32]=1
Reactant: Cc1nn(Cc2ccc(NC(=O)c3oc4c(Cl)cccc4c3C)cc2)c(C)c1CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nn(Cc2ccc(NC(=O)c3oc4c(Cl)cccc4c3C)cc2)c(C)c1CC(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 45.8 %

Procedure:
To a solution of 7-chloro-3-methylbenzofuran-2-carboxylic acid (185 mg, 0.88 mmol) in 6 mL dichloromethane is added oxalyl chloride (0.123 mL, 1.14 mmol) and a drop of dimethylformamide. After stirring at room temperature for 1 hour the solvent is removed by evaporation in vacuo. The residue is dissolved in dichloromethane (5 mL) and dropped to a solution of [1-(4-aminobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]acetic acid tert-butyl ester (428 mg, 1 mmol) in form of the toluene sulfonate salt and diisopropylethylamine (0.39 mL, 2.27 mmol) in dichloromethane (5 mL). After addition of 4-dimethylaminopyridine (11 mg, 0.09 mmol) the solution is stirred at room temperature for 12 hours. The solution is extracted twice with hydrochloric acid (1 M), twice with water, twice with an aqueous solution of NaOH (1 M) and twice with water. The organic layer is dried over MgSO4, filtered and the solvent is evaporated in vacuo to yield 426 mg of (1-(4-[(7-chloro-3-methyl-benzofuran-2-carbonyl)amino]benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid tert-butyl ester (ESI mass spectrum: [M+H]+=508; Retention time HPLC: 1.60 min (method H)). b) To a solution of (1-(4-[(7-chloro-3-methyl-benzofuran-2-carbonyl)amino]benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid tert-butyl ester (426 mg, 0.84 mmol) in dichloromethane (10 mL) is added trifluoroacetic acid (400 mL, 5.2 mmol) and the mixture is stirred at room temperature for 3 days. The solvent is evaporated in vacuo, and the residue is suspended in water and treated with diethyl ether and the precipitating product is filtered off to yield 174 mg of the title compound (ESI mass spectrum: [M+H]+=452; Retention time HPLC: 1.39 min (method J)).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([CH:25]=[O:26])=[CH:11][C:12]3[N:16]([CH2:17][CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:15]=[N:14][C:13]=3[C:23]=2[F:24])=[C:4]([Cl:27])[CH:3]=1.[S:28]([CH2:38][N+:39]#[C-:40])([C:31]1[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=1)(=[O:30])=[O:29].[C-]#N.[Na+].C1COCC1>CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([CH:25]3[O:26][CH:40]=[N:39][CH:38]3[S:28]([C:31]3[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=3)(=[O:30])=[O:29])=[CH:11][C:12]3[N:16]([CH2:17][CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:15]=[N:14][C:13]=3[C:23]=2[F:24])=[C:4]([Cl:27])[CH:3]=1
Reactant: CS(=O)(=O)CCn1cnc2c(F)c(Nc3ccc(Br)cc3Cl)c(C=O)cc21
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: [C-]#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)C2N=COC2c2cc3c(ncn3CCS(C)(=O)=O)c(F)c2Nc2ccc(Br)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(2-methanesulfonyl-ethyl)-3H-benzoimidazole-5-carbaldehyde 10z (0.050 g, 0.107 mmol) is suspended in EtOH (0.5 mL) under N2 and tosylmethyl isocyanide (0.020 g, 0.105 mmol) is added followed by catalytic NaCN (˜1 mg). After 2 hours, 2 mL THF is added to assist with solubility. After stirring for 16 hours at room temperature, a second equivalent of tosylmethyl isocyanide (0.020 g, 0.105 mmol) is added. After 8 hours, the reaction mixture is concentrated under reduced pressure and used as is in the next reaction: LC/MS ESI (+) m/z 671, 669 (M+ Br pattern) detected.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH:10]2/[CH:22]=[CH:23]/[C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:5][CH:4]=1>CO>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH:10]2/[CH:22]=[CH:23]/[C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(F)cc2)C(/C=C/c2ccc3ccccc3c2)C1
Agent: Cl
Solvent: CO
Product: Fc1ccc(C2CCNCC2/C=C/c2ccc3ccccc3c2)cc1

Procedure:
In an analogous manner to that described in Example 22 (l), by cleaving off the BOC group using hydrogen chloride in methanol from tert-butyl (E)-(3RS,4SR)-4-(4-fluoro-phenyl)-3-(2-naphthalen-2-yl-vinyl)-piperidine-1-carboxylate there was obtained (E)-(3RS,4SR)-4-(4-fluoro-phenyl)-3-(2-naphthalen-2-yl-vinyl)-piperidine as a pale yellow oil; MS: 331 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[CH2:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH2:17]([O:19][C:20](=[O:24])[CH2:21][CH2:22][NH2:23])[CH3:18].O>C(N(CC)CC)C>[CH2:17]([O:19][C:20](=[O:24])[CH2:21][CH2:22][NH:23][CH2:15][CH:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:18]
Reactant: CCOC(=O)CCN
Reactant: C=C(C(=O)OCC)c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CCNCC(C(=O)OCC)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 52.4 %

Procedure:
To a solution of the compound (38.1 g) obtained in step 1 in triethylamine (20.4 mL) was added β-alanine ethyl ester monohydrochloride (22.5 g), and the mixture was stirred at room temperature for 14 hr. The reaction mixture was poured into water, and the resultant product was extracted with diethyl ether. The organic layer was washed with brine and dried, and the solvent was evaporated under reduced pressure to give N-[2-(3,4-dichlorophenyl)-3-ethoxy-3-oxopropyl]-β-alanine ethyl ester (27.8 g, 78%) as a colorless oil.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][N:14]1[C:19]2[CH:20]=[C:21]([C:25]([N:27]([CH:41]([CH3:43])[CH3:42])[C@@H:28]3[CH2:33][CH2:32][CH2:31][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:29]3)=[O:26])[C:22]([CH3:24])=[CH:23][C:18]=2[S:17][C:16]([CH3:45])([CH3:44])[C:15]1=[O:46])=O)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[NH2:11][CH2:12][CH2:13][N:14]1[C:19]2[CH:20]=[C:21]([C:25]([N:27]([CH:41]([CH3:42])[CH3:43])[C@@H:28]3[CH2:33][CH2:32][CH2:31][N:30]([C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[CH2:29]3)=[O:26])[C:22]([CH3:24])=[CH:23][C:18]=2[S:17][C:16]([CH3:44])([CH3:45])[C:15]1=[O:46]
Reactant: Cc1cc2c(cc1C(=O)N(C(C)C)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1)N(CCNC(=O)OCc1ccccc1)C(=O)C(C)(C)S2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Cc1cc2c(cc1C(=O)N(C(C)C)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1)N(CCN)C(=O)C(C)(C)S2
Temperature: 25 °C
Reaction time: 3 h
Yield: 116.9 %

Procedure:
tert-Butyl (3R)-3-[{[4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate (1.4 g) was dissolved in methanol (11 ml), and thereto was added a 20% palladium hydroxide/carbon (50% wet.) (0.7 g) under hydrogen atmosphere, and the mixture was vigorously stirred at room temperature for 3 hours. After the reaction was complete, the reaction mixture was filtered on celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (the developing solvent: chloroform/methanol=98/2˜92/8) to give the title compound (1.3 g).
Reaction SMILES: C1(C([NH:20][C@H:21]2[CH2:27][CH2:26][CH2:25][CH2:24][N:23]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:22]2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO.[H][H]>[Pd].CCO>[NH2:20][C@H:21]1[CH2:27][CH2:26][CH2:25][CH2:24][N:23]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:22]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H](NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC[C@H](N)C1
Yield: 100 %

Procedure:
To 13.7 g (30 mmol) of 1,1-dimethylethyl (3S)-3-[(triphenylmethyl)amino]azepane-1-carboxylate was carefully added 100 mL MeOH, 75 mL EtOH, and 1.00 g of 10% Palladium on charcoal. The mixture was hydrogenated on a Parr shaker under 30 psi of hydrogen gas for 15 h. The mixture was filtered through a pad of celite, and the filtrate concentrated to afford a quantitative yield (6.43 g) of product. The product was used as such without further purification.
Reaction SMILES: Cl[C:2]1[C:3]2[N:18]=[C:17]([C:19]3[CH:24]=[C:23]([CH3:25])[C:22]([O:26][CH3:27])=[C:21]([CH3:28])[CH:20]=3)[O:16][C:4]=2[N:5]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:7]=1.[CH:29]([Mg]Br)([CH3:31])[CH3:30]>>[Cl:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][C:6]2[N:7]=[C:2]([CH:29]([CH3:31])[CH3:30])[C:3]3[N:18]=[C:17]([C:19]4[CH:24]=[C:23]([CH3:25])[C:22]([O:26][CH3:27])=[C:21]([CH3:28])[CH:20]=4)[O:16][C:4]=3[N:5]=2)=[CH:14][CH:13]=1
Reactant: CC(C)[Mg]Br
Reactant: COc1c(C)cc(-c2nc3c(Cl)nc(Cc4ccc(Cl)cc4)nc3o2)cc1C
Product: COc1c(C)cc(-c2nc3c(C(C)C)nc(Cc4ccc(Cl)cc4)nc3o2)cc1C
Yield: 11 %

Procedure:
Analogously to example 7 (d), the reaction of 1.5 g of 7-chloro-5-(4-chlorobenzyl)-2-(4-methoxy-3,5-dimethylphenyl)oxazolo[5,4-d]pyrimidine with isopropylmagnesium bromide gave 165 mg (11%) of the title compound.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[CH:20]=[C:19]([NH:21][CH:22]3[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]3)[N:18]=[CH:17][N:16]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28](Cl)(=O)[CH:29]=[CH2:30]>CN1C(=O)CCC1>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]2[N:16]=[CH:17][N:18]=[C:19]([NH:21][CH:22]3[CH2:27][CH2:26][CH2:25][N:24]([CH2:30][CH:29]=[CH2:28])[CH2:23]3)[CH:20]=2)=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)Cl
Reactant: c1ccc(Oc2ccc(Nc3cc(NC4CCCNC4)ncn3)cc2)cc1
Solvent: CN1CCCC1=O
Product: C=CCN1CCCC(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)C1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of N4-(4-phenoxyphenyl)-N6-(piperidin-3-yl)pyrimidine-4,6-diamine (0.025 g, 0.069 mmol) in NMP (0.5 mL) at 0° C. was added acryloyl chloride (0.007 g, 0.083 mmol), and the reaction mixture was stirred at 0° C. for 5 min. The reaction mixture was quenched by adding 10% NaHCO3 solution and it was extracted with EtOAc (2×5 mL). The combined EtOAc extract was washed with water (3 mL) and brine (3 mL), was dried over Na2SO4 and was concentrated under reduced pressure. The residue obtained was purified by column chromatography (SiO2, 230-400, chloroform/methanol:98/2) to give 1-(3-(6-(4-phenoxyphenylamino)pyrimidin-4-ylamino)piperidin-1-yl)prop-2-en-lone (I-86) as an off white solid. 1H NMR (MeOD) δ ppm: 1.5-1.75 (m, 2H), 1.80-2.00 (m, 1H), 2.0-2.20 (m, 1H), 2.70-2.90 (m, 1H), 2.90-3.05 (m, 1H), 3.80-4.00 (m, 2H), 4.30-4.45 (m, 1H), 5.65 & 5.75 (d, J=10.8 Hz & d, J=10.8 Hz respectively, together 1H), 5.81 (d, J=10.8 Hz, 1H), 6.14 & 6.18 (d, J=17.2 Hz & d, J=19.2 Hz respectively, together 1H), 6.60-6.70 & 6.70-6.85 (m, together 1H), 6.97-7.00 (m, 4H), 7.04 (t, J=7.6 Hz, 1H), 7.32-7.38 (m, 4H), 8.04 & 8.07 (s, together 1H); LCMS: m/e 416.1 (M+1).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.[CH:7](=O)[C:8]([CH3:11])([CH3:10])[CH3:9]>C1(C)C=CC=CC=1>[CH3:7][C:8]([CH3:11])([CH3:10])[CH:9]=[N:1][CH:2]1[CH2:6][CH2:5][NH:4][CH2:3]1
Reactant: CC(C)(C)C=O
Reactant: NC1CCNC1
Solvent: Cc1ccccc1
Product: CC(C)(C)C=NC1CCNC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
34.5 g (0.4 mol) of 3-aminopyrrolidine are initially introduced into 100 ml of toluene, and 34.5 g (0.3 mol) of 75% strength pivalaldehyde (preparation from Riedel-de-Haen) in 100 ml of toluene are added dropwise at 20° C., while cooling in a water bath. The mixture is subsequently stirred at room temperature for 2 hours, the aqueous phase is then separated off in a separating funnel (4.6 ml) and the toluene solution is dried over sodium sulphate for 1 hour. The toluene is separated off on a rotary evaporator and the residue is distilled using a small Vigreux column. 46.2 g of 3-(2,2-dimethylpropylideneamino)-pyrrolidine of boiling point 61° C./10 mbar are obtained with a purity, determined by gas chromatography, of 98%, corresponding to a yield of 74% and a selectivity of 99% (pivalaldehyde).
Reaction SMILES: CS([O-])(=O)=O.[F:6][C:7]([F:33])([C:18]1N2N=C(C3C=NN(C)C=3)C=CC2=[N:20][N:19]=1)[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2.C(=O)([O-])[O-:35].[Na+].[Na+]>C(OCC)(=O)C.O>[F:6][C:7]([F:33])([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)[C:18]([NH:19][NH2:20])=[O:35]
Reactant: O=C([O-])[O-]
Reactant: Cn1cc(-c2ccc3nnc(C(F)(F)c4ccc5ncccc5c4)n3n2)cn1
Agent: CS(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: NNC(=O)C(F)(F)c1ccc2ncccc2c1

Procedure:
Methanesulphonate (mesylate) salt of the compound of formula (I) (8.7 g) is dissolved in ethyl acetate/water mixture (50/50 vol/vol; 400 mL). Addition of sodium carbonate (2.5 g) liberates the free base form of the compound of formula (I) which crystallises from the solvent mixture. The solids are filtered, washed and dried at 50° C. to provide 6.53 g of Form III.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:34])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:33])[CH2:12][CH2:13][C@@:14]3([C:30](O)=[O:31])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:36])[CH3:35])(=[O:3])[CH3:2].C(Cl)(C(Cl)=O)=O.[NH2:43][C@H:44]1[CH2:47][C@@H:46]([C:48]([N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)=[O:49])[C:45]1([CH3:57])[CH3:56].CCN(CC)CC>C(Cl)Cl>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:34])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:33])[CH2:12][CH2:13][C@@:14]3([C:30](=[O:31])[NH:43][C@H:44]4[CH2:47][C@@H:46]([C:48]([N:50]5[CH2:55][CH2:54][O:53][CH2:52][CH2:51]5)=[O:49])[C:45]4([CH3:57])[CH3:56])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:36])[CH3:35])(=[O:3])[CH3:2]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC1(C)[C@@H](N)C[C@H]1C(=O)N1CCOCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@H]3C[C@@H](C(=O)N4CCOCC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.4 %

Procedure:
To a (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-acetoxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (0.4 g, 0.803 mmol) in DCM (1 ml) 2M solution of (COCl)2 in DCM (4 ml, 8.03 mmol) was added at about 0° C. and the reaction mixture was stirred at room temperature for about 3 hours. After completion of the reaction (monitored by TLC) the solvent was evaporated under nitrogen atmosphere and dissolved in DCM (4 ml), which was added to a solution of ((1R,3S)-3-amino-2,2-dimethylcyclobutyl)(morpholino)methanone (Intermediate 11, 0.306 g, 1.45 mmol) in DCM (5 ml) and Et3N (0.22 ml, 1.61 mmol) at about 0° C. and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC) the reaction mixture was diluted with DCM and washed with water, 1N HCl, water brine and dried with Na2SO4, the solvent was evaporated and purified by silica gel column (100-200 mesh, elution 10% EtOAc in hexane) to afford the title compound as an off white solid. Wt: 0.380 g: Yield: 68.4%; 1H NMR (300 MHz, CDCl3): δ 5.88 (d, 1H), 4.73 (s, 1H), 4.58 (s, 1H), 4.51-4.42 (m, 1H), 4.17-4.06 (m, 1H), 3.80-3.41 (m, 7H), 3.17-3.08 (m, 1H), 2.93-2.84 (m, 1H), 2.50-2.29 (m, 2H), 2.05 (s, 3H), 1.99-1.86 (m, 3H), 1.80-1.02 (m, 22H), 0.95, 0.92 (s, 9H), 0.83 (s, 15H); Mass: [M+Na]+ 693 (100%); M.R: 144.8° C.-156.2° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([CH3:12])[N:3]=1.[OH-].[K+].Cl>CC(O)(C)C.CO>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:12])[N:3]=1
Reactant: COC(=O)c1ccc(Cl)nc1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: CO
Product: Cc1nc(Cl)ccc1C(=O)O
Temperature: 60 °C

Procedure:
Methyl 6-chloro-2-methylnicotinate (Example 423, Step 2) (900 mg, 4.85 mmol) was taken up in 2-methylpropan-2-ol (48.5 ml) and methanol (48.5 ml) and aqueous 1 molar potassium hydroxide (24.2 ml, 24.2 mmol) was added. The resulting slurry was heated at 60° C. for 4 hours, cooled to room temperature, and hydrochloric acid (1 M in water, 24.2 mL, 24.2 mmol) was added dropwise. The solution was then concentrated under reduced pressure until to afford a white solid, which was taken up in methanol and concentrated under reduced pressure. Water and ethyl acetate were added and the layers were separated. The aqueous layer was extracted with ethyl acetate three times. The combined organic layers were concentrated under reduced pressure to afford the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3=[N:12][O:13][C:14]([C:15]4[C:19]([C:20]([F:23])([F:22])[F:21])=[C:18]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[O:17][N:16]=4)=[C:10]3[CH2:9][O:8][C:6]=2[CH:7]=1.[CH2:30]([Sn](CCCC)(CCCC)C=C)[CH2:31]CC.[Cl-].[Li+]>O1CCOCC1.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:24]1([C:18]2[O:17][N:16]=[C:15]([C:14]3[O:13][N:12]=[C:11]4[C:5]5[CH:4]=[CH:3][C:2]([CH:30]=[CH2:31])=[CH:7][C:6]=5[O:8][CH2:9][C:10]=34)[C:19]=2[C:20]([F:22])([F:21])[F:23])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: FC(F)(F)c1c(-c2onc3c2COc2cc(Br)ccc2-3)noc1-c1ccccc1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: C=Cc1ccc2c(c1)OCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Reaction time: 0.08 h
Yield: 66.5 %

Procedure:
To a heterogeneous solution of 7-bromo-3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4H-chromeno[4,3-c]isoxazole (Preparation 62F, 0.105 g, 0.227 mmol) in dioxane (2.0 mL) in a sealed tube was added sequentially tributyl(vinyl)stannane (0.073 mL, 0.249 mmol) and lithium chloride (0.029 g, 0.680 mmol). The mixture was degassed under reduced pressure and charged with nitrogen (3×). To the mixture was added tetrakis(triphenylphosphine)palladium(0) (0.026 g, 0.023 mmol), and the mixture was stirred under a strong stream of nitrogen for 5 min. The reaction mixture was sealed, immersed in an oil bath at 100° C., and stirred overnight. As it reached 100° C., the solution became near homogeneous. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with dichloromethane (10 mL), filtered through a pad of Celite, and rinsed with dichloromethane (10 mL). The filtrate was concentrated, and the residue was purified by flash silica gel chromatography using a 5% mixture of ethyl acetate in hexane to give 3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-7-vinyl-4H-chromeno[4,3-c]isoxazole (0.062 g, 0.151 mmol, 67% yield) as a white solid. The product had an HPLC ret. time=3.84 min.−Column: Chromolith SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=411.0.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:32][CH2:31][NH:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.C([O:36][CH2:37][C:38](Cl)=[O:39])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:32][CH2:31][N:30]([C:37](=[O:36])[CH2:38][OH:39])[CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1ccc(-c2ncnc3c(C(=O)N[C@@H]4CCNC4)c(C)[nH]c23)c(OCC2CC2)c1
Agent: Cl
Product: COc1ccc(-c2ncnc3c(C(=O)N[C@@H]4CCN(C(=O)CO)C4)c(C)[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-6-methyl-N-[(3R)-pyrrolidin-3-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f21) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: C([Li])CCC.[F:6][C:7]([F:22])([F:21])[C:8]([C:17]([F:20])([F:19])[F:18])([OH:16])[CH2:9][CH2:10][CH2:11][C:12]([CH3:15])([OH:14])[CH3:13].[C:23](Cl)(=[O:27])[C:24]([CH3:26])=[CH2:25]>O1CCCC1>[C:23]([O:14][C:12]([CH3:13])([CH3:15])[CH2:11][CH2:10][CH2:9][C:8]([C:17]([F:18])([F:19])[F:20])([OH:16])[C:7]([F:21])([F:22])[F:6])(=[O:27])[C:24]([CH3:26])=[CH2:25]
Reactant: C=C(C)C(=O)Cl
Reactant: CC(C)(O)CCCC(O)(C(F)(F)F)C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=C(C)C(=O)OC(C)(C)CCCC(O)(C(F)(F)F)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 35 %

Procedure:
To a flame-dried, nitrogen-purged 500 mL 3-neck roundbottom flask with 250 mL pressure-equalizing addition funnel and magnetic stirbar was charged 156 mL n-butyl lithium (250 mmol, 2 equiv., 1.6 M in hexanes). A degassed solution of 1,1,1-trifluoro-6-methyl-2-(trifluoromethyl)heptane-2,6-diol (III) (˜125 mmol, 1 eq.) in 100 mL anhydrous tetrahydrofuran was charged to the addition funnel and added to the reaction mixture dropwise at 0° C. over 30 minutes. The reaction mixture was warmed for 15 minutes on a hot water bath to ensure the reaction was complete. The reaction vessel was cooled to 0° C. and 14.4 g methacryloyl chloride (138 mmol, 1.1 eq.) was added dropwise and allowed to stir for 15 minutes. The addition funnel was replaced with a reflux condenser and the reaction heated to reflux for 20 hours. After the reaction was complete, it was cooled to 0° C. and quenched with dilute HCl solution until the pH was less than 5.0. The reaction solution was neutralized with saturated aqueous sodium bicarbonate until the pH was greater than 8. The product was extracted into ethyl ether and the organic phase washed sequentially with aqueous sodium bicarbonate, water, and brine and then dried over magnesium sulfate, filtered, concentrated in vacuo, and stored over a small amount of sodium bicarbonate. The crude product mixture was purified via silica gel column chromatography (20:1 hexane:ethyl acetate eluent) to afford 14.7 g (35%) of 1,1,1-trifluoro-2-trifluoromethyl-2-hydroxy-6-methyl-hept-6-yl methacrylate (IV) as a colorless liquid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2(O)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.CS(Cl)(=O)=O.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:14][CH2:13][O:12][CH2:11][CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: OC1(c2cc(F)cc(F)c2)CCOCC1
Agent: CS(=O)(=O)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: Fc1cc(F)cc(C2=CCOCC2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
4-(3,5-difluorophenyl)tetrahydro-2H-pyran-4-ol (1.0 equiv.) was dissolved in DCM (0.2 M) and cooled to 0° C. TEA (2.8 equiv.) was added to the solution, followed by MsCl (1.3 equiv.). The reaction was stirred at rt for 2 hrs. The solution was cooled to 0° C. and DBU (3.0 equiv.) was added. The reaction was stirred at rt for 18 hrs. The solution was concentrated and the residue was purified by SiO2 chromatography (0-100% EtOAc in Heptanes) to afford 4-(3,5-difluorophenyl)-3,6-dihydro-2H-pyran in 38% yield.