Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C([Mg]Br)C=C.[F:14][C:15]1[CH:16]=[CH:17][C:18]2[N:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:26][C:25]=3[O:35][CH:36]3[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]3)[O:21][C:20](=[O:43])[C:19]=2[CH:44]=1.[N-]=C=O>C1COCC1.C(OCC)C>[F:14][C:15]1[CH:16]=[CH:17][C:18]([NH:23][C:22](=[O:21])[C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:31][CH2:32][CH2:33][CH2:34]3)=[CH:26][C:25]=2[O:35][CH:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)=[C:19]([CH:44]=1)[C:20]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[F:1])=[O:43]
Reactant: CN1CCC(Oc2cc(N3CCCC3)ccc2-c2nc3ccc(F)cc3c(=O)o2)CC1
Reactant: Nc1ccccc1F
Agent: C=CC[Mg]Br
Agent: [N-]=C=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN1CCC(Oc2cc(N3CCCC3)ccc2C(=O)Nc2ccc(F)cc2C(=O)Nc2ccccc2F)CC1
Reaction time: 0.08 h

Procedure:
A solution of 2-fluoroaniline (22.1 mg, 0.18 mmol) in dry THF (1 mL) was treated with a 1 M diethyl ether solution of allyl magnesium bromide (0.2 mL). The reaction was stirred for 5 minutes before adding 6-fluoro-2-[4-(pyrrolidin-1-yl)-2-(1-methylpiperidin-4-yloxy)phenyl]-4H-3,1-benzoxazin-4-one (25 mg, 0.06 mmol) in THF (1 mL). The reaction was stirred overnight at ambient temperature, concentrated to dryness and mixed with saturated aqueous NaHCO3 (1 mL) and CH2Cl2 (2 mL). The mixture was filtered through a plug of diatomaceous earth and treated with an isocyanate resin (methylisocyanate polystyrene HL, 0.360 mmol) overnight. Purification consisted of applying this mixture directly onto a column of silica and eluting with 1% MeOH in CHCl3.
Reaction SMILES: [C:1](=[O:40])([O:3][CH2:4][CH:5]([NH:16][C:17](=[O:39])[CH2:18][N:19]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[N:21]([CH2:31][CH:32]([OH:37])[C:33]([F:36])([F:35])[F:34])[C:20]1=[O:38])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8](C(F)(F)F)[CH:7]=1)[NH2:2].ClC1C=CC(C2N(CC(O)[C:60]([F:63])([F:62])[F:61])C(=O)N(CC(O)=O)C=2)=CC=1.Cl.C(=O)(OCC(N)C1C=CC=CC=1C(F)(F)F)N>>[C:1](=[O:40])([O:3][CH2:4][CH:5]([NH:16][C:17](=[O:39])[CH2:18][N:19]1[CH:23]=[C:22]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[N:21]([CH2:31][CH:32]([OH:37])[C:33]([F:35])([F:36])[F:34])[C:20]1=[O:38])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=1[C:60]([F:63])([F:62])[F:61])[NH2:2]
Reactant: NC(=O)OCC(NC(=O)Cn1cc(-c2ccc(Cl)cc2)n(CC(O)C(F)(F)F)c1=O)c1cccc(C(F)(F)F)c1
Reactant: O=C(O)Cn1cc(-c2ccc(Cl)cc2)n(CC(O)C(F)(F)F)c1=O
Agent: Cl
Agent: NC(=O)OCC(N)c1ccccc1C(F)(F)F
Product: NC(=O)OCC(NC(=O)Cn1cc(-c2ccc(Cl)cc2)n(CC(O)C(F)(F)F)c1=O)c1ccccc1C(F)(F)F

Procedure:
In the same way as for the compound from Example 206, 58 mg (0.11 mmol) of [4-(4-chlorophenyl)-2-oxo-3-(3,3,3-trifluoro-2-hydroxypropyl)-2,3-dihydro-1H-imidazol-1-yl]acetic acid from Example 185A were reacted with 42 mg (0.12 mmol) of the compound from Example 180A. This gave 12 mg (18% of theory) of the target compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[N:7]([CH2:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([NH:18][NH2:19])[N:15]=[C:14]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:13]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[N:27]([O-])=O.[Na+].C(OCC)(=O)C>C(O)(=O)C.O>[C:1]([O:5][C:6](=[O:26])[N:7]([CH2:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([N:18]=[N+:19]=[N-:27])[N:15]=[C:14]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:13]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=N[O-]
Reactant: CN(CCOc1cc(NN)nc(N2CCOCC2)n1)C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CN(CCOc1cc(N=[N+]=[N-])nc(N2CCOCC2)n1)C(=O)OC(C)(C)C

Procedure:
[2-(6-hydrazino-2-morpholin-4-yl-pyrimidin-4-yloxy)-ethyl]-methyl-carbamic acid tert-butyl ester was dissolved in glacial acetic acid (30 mL). To this solution was added a solution of sodium nitrite (1.3 g) in water (4 mL). The reaction was stirred for ten minutes, and poured into ethyl acetate (100 mL). The organic layer was then washed with water (100 mL) and 10% sodium carbonate (2×100 mL). The organic layer was dried over magnesium sulfate and evaporated to give [2-(6-azido-2-morpholin-4-yl-pyrimidin-4-yloxy)-ethyl]-methyl-carbamic acid tert-butyl ester, which was used without purification in the next reaction.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH:12]=[N:11][C:10]([CH2:13][C@H](N)C(O)=O)=[CH:9]2)=[CH:3][CH:2]=1.[CH2:19]=[O:20].S(Cl)(Cl)=O.[OH2:25]>>[CH3:19][O:20][C:9]([CH:10]1[NH:11][CH2:13][C:10]2[N:11]=[CH:12][N:8]([CH2:7][C:4]3[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=3)[C:9]=2[CH2:13]1)=[O:25]
Reactant: C=O
Reactant: N[C@@H](Cc1cn(Cc2ccccc2)cn1)C(=O)O
Reactant: O
Solvent: O=S(Cl)Cl
Product: COC(=O)C1Cc2c(ncn2Cc2ccccc2)CN1
Temperature: 0 °C
Yield: 71 %

Procedure:
A solution of H-His-(Bzl)-OH (2.0 g, 8.16 mmol) and formaldehyde (37% in water, 0.92 ml, 12.24 mmol) in water (16 ml) was heated to reflux for 4 hours and concentrated to dryness. The residue was dissolved in methanol (4.6 ml) cooled to 0° C. and treated with thionyl chloride (0.6 ml, 8.12 mmol). The reaction mixture was reflux for 2.5 hours and concentrated. The solid was dissolved in dichloromethane, washed with a saturated solution of sodium hydrogenocarbonate, brine, dried over sodium sulfate and concentrated to dryness to yield 1-Benzyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid methyl ester (1.58 g, 71%). The ester was dissolved in tetrahydrofuran (26 ml), cooled to 0° C. and treated with 2,3-Dichloro-5,6-dicyanobenzoquinone (2.9 g, 12.81 mmol) in tetrahydrofuran (26 ml) and the reaction mixture was reflux for 4 hours. The solvent was removed and the black residue was dissolved in dichloromethane and treated with a 1M aqueous solution of sodium hydroxide. The aqueous solution was extracted several times with dichloromethane. The combined organic extracts were washed with brine, dried over sodium sulfate, concentrated and purified by flash chromatography over silica gel (gradient ethyl acetate/methanol: 0-10%) to yield 1-Benzyl-1H-imidazo[4,5-c]pyridin-6-carboxylic acid methyl ester (525 mg, 34%) as a beige solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:18][C:19]1[CH:24]=[C:23]([O:25][CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH:22]=[CH:21][C:20]=1[N+:33]([O-:35])=[O:34])[CH2:9][CH2:10][C:11]([O:13]C(C)(C)C)=[O:12].[OH-].[Na+].O.Cl>CO.CCCCC>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:18][C:19]1[CH:24]=[C:23]([O:25][CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH:22]=[CH:21][C:20]=1[N+:33]([O-:35])=[O:34])[CH2:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: Cc1ccccc1[C@@H](CCC(=O)OC(C)(C)C)Oc1cc(OCc2cccnc2)ccc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCC
Solvent: O
Solvent: CO
Product: Cc1ccccc1[C@@H](CCC(=O)O)Oc1cc(OCc2cccnc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 21.2 %

Procedure:
A solution of tert-butyl (R)-4-(2-methylphenyl)-4-(2-nitro-5-(3-pyridylmethoxy)phenoxy)butanoate (800 mg) in methanol (20 mL) containing 5 N sodium hydroxide (10 mL) is stirred at ambient temperature for 48 hours. The reaction mixture is poured into water (50 mL), acidified to pH 5 with 1 N HCl and extracted three times with ethyl acetate (50 mL). The combined organic phases are washed with brine (50 mL), dried over magnesium sulphate, filtered and concentrated under reduced pressure The residual brown gum is purified by flash chromatography on silica eluting with ethyl acetate. Fractions homogeneous in the required product are combined and evaporated to give a yellow oil. Trituration with pentane afforded (R)-4-(2-methylphenyl)-4-(2-nitro-5-(3-pyridylmethoxy)phenoxy)butanoic acid as a white solid (150 mg), m.p. 117-119° C. [Elemental analysis:- C,65.4, H, 5.21, N, 6.64%. Calculated:- C,65.3, H, 5.17, N, 6.59%]
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20].O>C1C=CC=CC=1>[CH3:18][S:19]([O:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: O
Product: CS(=O)(=O)On1nnc2ccccc21
Temperature: 10 °C
Reaction time: 2.2 h
Yield: 84.6 %

Procedure:
1-Hydroxy-1,2,3-benzotriazole (648 g) and triethylamine (675 ml) are dissolved in benzene (2,800 ml). To the solution is added dropwise a solution of methanesulfonyl chloride (535 g) in benzene (675 ml) with stirring at a temperature of lower than 10° C. over a period of 2.2 hours. The mixture is stirred at the same temperature for 2.3 hours and allowed to stand overnight. To the reaction mixture is added water (1,000 ml). The benzene layer is separated out. The aqueous layer is extracted twice with ethyl acetate (3,000 ml and 2,000 ml), and the extracts are combined and washed with a saturated aqueous sodium hydrogen carbonate (200 ml×2) and water and dried over anhydrous magnesium sulfate. After drying, the solvent is distilled off under a reduced pressure. The resulting crystals are washed with petroleum ether (500 ml) and dried to give faint yellow crystals of 1-methane-sulfonyloxy-1,2,3-benzotriazole (842 g), melting point: 88°-90° C.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:21])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=2[O:19][CH3:20])=[N:7][CH:8]=1.Cl[C:24]1[C:33]2[C:28](=[CH:29][C:30]([O:36][CH3:37])=[C:31]([O:34][CH3:35])[CH:32]=2)[N:27]=[CH:26][N:25]=1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[CH3:22][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:21])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:24]3[C:33]4[C:28](=[CH:29][C:30]([O:36][CH3:37])=[C:31]([O:34][CH3:35])[CH:32]=4)[N:27]=[CH:26][N:25]=3)=[CH:14][C:13]=2[O:19][CH3:20])=[N:7][CH:8]=1
Reactant: COc1cc(O)ccc1CC(=O)Nc1ccc(N(C)C)cn1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc(Oc2ncnc3cc(OC)c(OC)cc23)ccc1CC(=O)Nc1ccc(N(C)C)cn1
Temperature: 140 °C
Yield: 83.8 %

Procedure:
A mixture of N-(5-dimethylaminopyridin-2-yl)-2-(4-hydroxy-2-methoxyphenyl) acetamide (0.111 g), 4-chloro-6,7-dimethoxyquinazoline (0.075 g), potassium carbonate (0.2 g) and DMA (2 ml) was stirred and heated to 140° C. in a microwave oven for 20 minutes. The reaction mixture was purified by preparative HPLC using a Waters ‘β Basic Hypersil’ reversed-phase column (5 microns silica, 30 mm diameter, 250 mm length) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. There was thus obtained the title compound (0.137 g); 1H NMR: (CDCl3) 2.92 (s, 6H), 3.75 (s, 2H), 3.91 (s, 3H), 4.07 (s, 3H), 4.08 (s, 3H), 6.86 (s, 1H), 6.88 (m, 1H), 7.10 (m, 1H), 7.33 (s, 1H), 7.41 (d, 1H), 7.55 (s, 1H), 7.73 (d, 1H), 8.09 (d, 1H), 8.16 (br s, 1H), 8.64 (s, 1H); Mass Spectrum: M+H+ 490.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]([C:14]3[S:15][C:16]([C:19]4[CH:20]=[N:21][N:22]([CH2:24][C:25]5([CH3:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]5)[CH:23]=4)=[CH:17][CH:18]=3)=[O:13])=[CH:6][C:5]=12.CN1CC[O:36][CH2:35][CH2:34]1.BrCC(ON1C(=O)CCC1=O)=O.[NH2:51][C@@H:52]([CH2:56][SH:57])[C:53]([OH:55])=[O:54]>C(N(CC)C(C)C)(C)C.O.C(O)(C(F)(F)F)=O>[N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]([C:14]3[S:15][C:16]([C:19]4[CH:20]=[N:21][N:22]([CH2:24][C:25]5([CH3:31])[CH2:30][CH2:29][N:28]([C:35](=[O:36])[CH2:34][S:57][CH2:56][C@@H:52]([C:53]([OH:55])=[O:54])[NH2:51])[CH2:27][CH2:26]5)[CH:23]=4)=[CH:17][CH:18]=3)=[O:13])=[CH:6][C:5]=12
Reactant: CN1CCOCC1
Reactant: CC1(Cn2cc(-c3ccc(C(=O)NCc4ccn5ccnc5c4)s3)cn2)CCNCC1
Reactant: N[C@@H](CS)C(=O)O
Agent: O=C(CBr)ON1C(=O)CCC1=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC1(Cn2cc(-c3ccc(C(=O)NCc4ccn5ccnc5c4)s3)cn2)CCN(C(=O)CSC[C@H](N)C(=O)O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of N-(imidazo[1,2-a]pyridin-7-ylmethyl)-5-{1-[(4-methylpiperidin-4-yl)methyl]-1H-pyrazol-4-yl}thiophene-2-carboxamide (0.100 g, 0.197 mmol) and 4-methylmorpholine (0.108 ml, 0.985 mmol) in N,N-diisopropylethylamine (0.5 ml) was added to 2,5-dioxopyrrolidin-1-yl 2-bromoacetate (0.056 g, 0.236 mmol) in N,N-diisopropylethylamine (0.5 ml) and stirred at room temperature. After 1 hour, (R)-2-amino-3-mercaptopropanoic acid (0.119 g, 0.985 mmol) as a solution in water (1 ml) was added. After stirring an additional 1 hour, a few drops of TFA were added to form a homogeneous solution which was purified by revere phase chromatography. The product containing peaks were lyophilized to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 9.30 (t, J=6.0 Hz, 1H), 8.86 (d, J=7.0 Hz, 1H), 8.44 (bs, 2H), 8.32 (d, J=2.0 Hz, 1H), 8.18-8.11 (m, 2H), 7.86-7.77 (m, 3H), 7.46 (dd, J=7.0, 1.5 Hz, 1H), 7.27 (dd, J=3.7, 1.8 Hz, 1H), 4.65 (d, J=5.8 Hz, 2H), 4.21-4.13 (m, 1H), 4.13-4.02 (m, 2H), 4.02-3.92 (m, 1H), 3.87-3.57 (m, 3H), 3.42-3.29 (m, 1H), 3.29-3.18 (m, 1H), 3.10 (dd, J=14.6, 4.7 Hz, 1H), 2.98 (dd, J=14.6, 7.6 Hz, 1H), 1.60-1.18 (m, 4H), 0.96 (s, 3H); MS (ESI(+)) m/e 596 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[CH2:8](OC(OCC)CBr)[CH3:9].Br.[OH-].[Na+]>C(O)C.CC(O)C.C(Cl)Cl>[N:1]1[CH:8]=[CH:9][N:3]2[CH:4]=[CH:5][N:6]=[CH:7][C:2]=12
Reactant: CCOC(CBr)OCC
Reactant: Nc1cnccn1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Solvent: CC(C)O
Product: c1cn2ccnc2cn1
Temperature: 25 °C
Yield: 94 %

Procedure:
To a solution of aminopyrazine (5 g, 53 mol, 1 eq.) in ethanol (212 ml) was added bromoacetaldehyde diethylacetal (12 ml, 80 mol, 1.5 eq.) and HBr (48%, 26.5 ml). The mixture was heated at 70–80° C. for 17 hours. The mixture was then cooled to rt (room temperature), then a mixture of 1N NaOH (200 ml) and 20% IPA/DCM (isopropyl alcohol/Dichloromethane) was added to the reaction mixture. The combined organic layer was dried over sodium sulfate and concentrated to afford 5.9 g of brown solid of imidazo[1,2-a]pyrazine (yield 94%).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[O:10][N:9]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=1)CCC.[C:24]([O:32][CH2:33][C@:34]12[CH2:67][CH2:66][C@@H:65]([C:68]([CH3:70])=[CH2:69])[C@@H:35]1[C@@H:36]1[C@@:49]([CH3:52])([CH2:50][CH2:51]2)[C@@:48]2([CH3:53])[C@@H:39]([C@:40]3([CH3:64])[C@@H:45]([CH2:46][CH2:47]2)[C:44]([CH3:55])([CH3:54])[C:43](OS(C(F)(F)F)(=O)=O)=[CH:42][CH2:41]3)[CH2:38][CH2:37]1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[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]([O:32][CH2:33][C@:34]12[CH2:67][CH2:66][C@@H:65]([C:68]([CH3:70])=[CH2:69])[C@@H:35]1[C@@H:36]1[C@@:49]([CH3:52])([CH2:50][CH2:51]2)[C@@:48]2([CH3:53])[C@@H:39]([C@:40]3([CH3:64])[C@@H:45]([CH2:46][CH2:47]2)[C:44]([CH3:54])([CH3:55])[C:43]([C:6]2[O:10][N:9]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=2)=[CH:42][CH2:41]3)[CH2:38][CH2:37]1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C=C(C)[C@@H]1CC[C@]2(COC(=O)c3ccccc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C(=O)OCC)no1
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=C(C)[C@@H]1CC[C@]2(COC(=O)c3ccccc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6cc(C(=O)OCC)no6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 85 °C
Yield: 20.3 %

Procedure:
To a sealable vial containing ethyl 5-(tributylstannyl)isoxazole-3-carboxylate (0.052 g, 0.122 mmol) was added ((1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-9-(trifluoromethylsulfonyloxy)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-3a-yl)methyl benzoate (0.075 g, 0.111 mmol), lithium chloride (0.014 g, 0.332 mmol), and tetrakis(triphenylphosphine)palladium(0) (6.40 mg, 5.54 μmol). The mixture was diluted with 1,4-Dioxane (2 mL) and was flushed with N2. The vial was sealed and heated to 85° C. After 15.5 h of heating, the mixture was cooled to rt, was diluted with water (4 mL), and was extracted with dichloromethane (3×4 mL). The combined organic layers were dried over Na2SO4. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by Biotage flash chromatography using a 0-10% EtOAc in hexanes gradient. The fractions containing the expected product were combined and concentrated under reduced pressure. Ethyl 5-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(benzoyloxymethyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)isoxazole-3-carboxylate was isolated as an off-white foam (0.015 g total mass, 0.022 mmol, 20.3% yield). LCMS: m/e 668.53 (M+H)+, 3.11 min (method 1).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[C:6](#[N:9])[CH:7]=[CH2:8]>>[N:1]1([CH2:8][CH2:7][CH2:6][NH2:9])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: C=CC#N
Reactant: c1nc[nH]n1
Product: NCCCn1cncn1
Reaction time: 8 h

Procedure:
A mixture of 20.7 g of 1H-1,2,4-triazole and 37.5 ml of acrylonitrile was heated on a steam bath for 3 hours and then concentrated to an oil. This oil was added to 200 ml of methanol and 100 ml of concentrated ammonium hydroxide containing Raney nickel catalyst in a Parr apparatus and hydrogenated for 8 hours with an uptake of about 46 psi of hydrogen. The catalyst was removed by filtration and ethanol was added to the filtrate. The mixture was filtered, the filtrate was concentrated, then reconcentrated from toluene, giving 36.6 g of the desired intermediate as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14](Cl)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[O:29][CH3:30])[N:25]=[CH:24][CH:23]=[C:22]2[O:31][C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+].O>C1COCC1>[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[O:29][CH3:30])[N:25]=[CH:24][CH:23]=[C:22]2[O:31][C:32]1[CH:33]=[CH:34][C:35]([NH:38][C:14]([C:11]2([C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[O:10])[CH2:13][CH2:12]2)=[O:15])=[CH:36][CH:37]=1
Reactant: O=C(Cl)C1(C(=O)Nc2ccc(F)cc2)CC1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2nccc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3)c2cc1OC
Temperature: 22.5 °C
Reaction time: 10 h

Procedure:
The solution from the previous step containing 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride was added to a mixture of 4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (3.0 kg) and potassium carbonate (4.0 kg) in THF (27.0 kg) and water (13.0 kg) at a rate such that the batch temperature did not exceed 30° C. When the reaction was complete (in typically 10 minutes), water (74.0 kg) was added. The mixture was stirred at 15-30° C. for approximately 10 hours, which resulted in the precipitation of the product. The product was recovered by filtration, washed with a premade solution of THF (11.0 kg) and water (24.0 kg), and dried at approximately 65° C. under vacuum for approximately 12 hours to afford the title compound (free base, 5.0 kg). 1H NMR (400 MHz, d6-DMSO): δ 10.2 (s, 1H), 10.05 (s, 1H), 8.4 (s, 1H), 7.8 (m, 2H), 7.65 (m, 2H), 7.5 (s, 1H), 7.35 (s, 1H), 7.25 (m, 2H), 7.15 (m, 2H), 6.4 (s, 1H), 4.0 (d, 6H), 1.5 (s, 4H). LC/MS: M+H=502.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Si:9]([O:16][CH2:17][CH:18]1[CH2:22][N:21]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=2[O:32][CH3:33])[C:20](=[O:34])[CH2:19]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].CN(C)P(N(C)C)(N(C)C)=O.I[CH2:47][C:48]#[C:49][CH2:50][CH2:51][CH2:52][C:53]([O:55][CH3:56])=[O:54]>C1COCC1>[CH3:56][O:55][C:53](=[O:54])[CH2:52][CH2:51][CH2:50][C:49]#[C:48][CH2:47][C@@H:19]1[C@@H:18]([CH2:17][O:16][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH2:22][N:21]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=2[O:32][CH3:33])[C:20]1=[O:34]
Reactant: COC(=O)CCCC#CCI
Reactant: COc1ccc(CN2CC(CO[Si](C)(C)C(C)(C)C)CC2=O)c(OC)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)CCCC#CC[C@H]1C(=O)N(Cc2ccc(OC)cc2OC)C[C@@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.1 %

Procedure:
Lithium diisopropylamide (1.5 M in cyclohexane, 9.22 mL, 13.83 mmol) was added to a solution of 4-(tert-butyldimethylsilanyloxymethyl)-1-(2,4-dimethoxybenzyl)-pyrrolidin-2-one (2.63 g, 6.93 mmol) in THF (41 mL) at −78° C. under nitrogen. After 30 min at −78° C., hexamethylphosphoramide (3.61 mL, 20.7 mmol) was added dropwise. After 30 min at −78° C., methyl 7-iodohept-5-ynoate (5.52 g, 20.7 mmol) in THF (20 mL+3 mL) was added. The reaction mixture was allowed to warm to room temperature. After 18 h at room temperature, the reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc (3×50 mL). Combined extracts were dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography on silica gel (40% EtOAc/hexane) to afford 579 mg (16%) of 7-[(3R*,4R*)-4-(tert-butyldimethylsilanyloxymethyl)-1-(2,4-dimethoxybenzyl)-2-oxo-pyrrolidin-3-yl]-hept-5-ynoic acid methyl ester.
Reaction SMILES: Br[C:2]([F:10])([F:9])[C:3]([F:8])([F:7])[CH2:4][CH2:5][OH:6].C(#N)C.C(=O)([O-])O.[Na+:18].[S:19](S([O-])=O)([O-:21])=[O:20].[Na+].[Na+]>O>[F:9][C:2]([F:10])([S:19]([O-:21])=[O:20])[C:3]([F:8])([F:7])[CH2:4][CH2:5][OH:6].[Na+:18]
Reactant: O=S([O-])S(=O)[O-]
Reactant: OCCC(F)(F)C(F)(F)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=S([O-])C(F)(F)C(F)(F)CCO
Temperature: 25 °C
Reaction time: 12 h
Yield: 77 %

Procedure:
A 2 litter reactor was charged with 151 g (0.67 mol) of 4-bromo-3,3,4,4-tetrafluorobutan-1-ol, 600 ml of acetonitrile, 600 ml of water, 112 g (1.33 mol/2.0 equivalent)) of sodium hydrogencarbonate, and 235 g (1.35 mol/2.0 equivalent) of sodium dithionite in a nitrogen stream. The mixture was stirred at room temperature for 12 hours. The reaction solution was extracted four times with 500 ml of acetonitrile. The solvent was evaporated from the resulting organic layer to obtain 120 g of the target sodium 1,1,2,2-tetrafluoro-4-hydroxybutane-1-sulfinate. The purity of the product was 80% and the yield was 77%.
Reaction SMILES: [CH2:1]([C:5]1[C:6](Cl)=[N:7][C:8]([Cl:12])=[N:9][C:10]=1[CH3:11])[CH2:2][CH2:3][CH3:4].[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.[H][H].O.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>[CH2:1]([C:5]1[C:10]([CH3:11])=[N:9][C:8]([Cl:12])=[N:7][C:6]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(C)nc(Cl)nc1Cl
Reactant: OB(O)c1ccccc1
Reactant: [H][H]
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: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCc1c(C)nc(Cl)nc1-c1ccccc1

Procedure:
A mixture of 5-butyl-2,4-dichloro-6-methyl-pyrimidine (711 mg, 3.24 mmol), phenylboronic acid (475 mg, 3.89 mmol), Na2CO3 (1.03 g, 9.73 mmol), and Pd(PPh3)4 (187 ma, 0.162 mmol) in toluene-EtOH—H2 (4 ml-0.5 ml-2 mL) is stirred at reflux for 6 hours. After cooling, the reaction mixture is diluted with H2O and extracted with EtOAc. The extract is then washed with brine, dried over Na2SO4, and concentrated. The residue is purified by flash chromatography on silica gel. Elution with 8:1 hexanes-EtOAc followed by 7:1 hexanes-EtOAc affords 5-butyl-2-chloro-4-methyl-6-phenyl-pyrimidine as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ 7.45 (m, 5H), 2.65-2.62 (m, 2H), 2.60 (s, 3H), 1.46-1.36 (m, 2H), 1.25 (sext, J=7.2 Hz, 2H), 0.81 (t, J=7.2 Hz, 3H) ppm.