Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=[O:17])[C:5]([N:7]([CH3:16])[CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:6])C.[F:18][C:19]1[CH:32]=[CH:31][C:22]([CH2:23][N:24]2[CH2:29][CH2:28][CH:27]=[CH:26][C:25]2=[O:30])=[CH:21][CH:20]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[C:12]([O:11][C:9]([CH:8]1[N:7]([CH3:16])[C:5](=[O:6])[C:4]([OH:17])=[C:26]2[CH:27]1[CH2:28][CH2:29][N:24]([CH2:23][C:22]1[CH:21]=[CH:20][C:19]([F:18])=[CH:32][CH:31]=1)[C:25]2=[O:30])=[O:10])([CH3:13])([CH3:14])[CH3:15]
Reactant: O=C1C=CCCN1Cc1ccc(F)cc1
Reactant: CCOC(=O)C(=O)N(C)CC(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1C(=O)C(O)=C2C(=O)N(Cc3ccc(F)cc3)CCC2C1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a cooled (−78° C.) solution of tert-butyl N-[ethoxy(oxo)acetyl]-N-methylglycinate (1.43 g, 5.85 mmol) and 1-(4-fluorobenzyl)-5,6-dihydropyridin-2(1H)-one from Step 3 of Example 1 (1 g, 5 mmol) in anhydrous THF (10 mL) was added LiHMDS (1 M in THF) (1.02 g, 6.09 mmol) dropwise. The reaction mixture was stirred for 10 min. at −78° C., warmed to room temperature for 2.5 hours, then heated to 40° C. After heating for 24 hours, the reaction mixture was quenched with cold diluted HCl, then diluted with methanol, and concentrated under vacuum. The residual material was purified using reverse phase HPLC on a C18 stationary phase eluting with 5%-95% acetonitrile (0.1% TFA) in H2O (0.1% TFA) to give the title compound as a mixture of diastereomers. The appropriate fractions were collected for the first-eluting diastereomer, diastereomer 1, and this material was purified further using reverse phase HPLC on a C18 stationary phase eluting with 15%-85% acetonitrile (0.1% TFA) in H2O (0.1% TFA). For the second eluting diastereomer, diastereomer 2, the appropriate fractions were collected and the material was purified further using reverse phase HPLC on a C18 stationary phase eluting with 10%-60% methanol (0.1% TFA) in H2O (0.1% TFA). Diastercomer 1, the hydrogens at positions 4a and 5 have a trans relationship to one another: 1H NMR (400 MHz, CDCl3) δ 6.84 (m, 2H), 6.62 (t, J=8.7 Hz, 2H), 4.31 (d, J=14.7 Hz, 1H), 4.05 (d, J=14.7 Hz, 1H), 3.43 (d, J=6.5 Hz, 1H), 2.91 (m, 2H), 2.69 (m, 1H), 2.57 (s, 3H), 1.42 (m, 1H), 1.21 (m, 1H), 1.15 (s, 9H) ppm. ES MS M+1=405. Diastereomer 2, the hydrogens at positions 4a and 5 have a cis relationship to one another: 1H NMR (400 MHz, CDCl3) δ 13.07 (s, 1H), 7.22 (m, 2H), 7.02 (t, J=8.7 Hz, 2H), 4.67 (d, J=14.7 Hz, 1H), 4.51 (d, J=14.7 Hz, 1H), 3.82 (d, J=6.5 Hz, 1H), 3.33 (m, 1H), 2.99 (s, 3H), 2.02 (m, 3H), 1.68 (m, 1H), 1.44 (s, 9H) ppm. ES MS M+1=405.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:29]([CH2:30][CH3:31])=[CH:28][C:7]2[NH:8][C:9]([C:11]3[C:15]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])=[CH:14][N:13](C4CCCCO4)[N:12]=3)=[N:10][C:6]=2[CH:5]=1)[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C(O)C>[CH2:1]([O:3][C:4]1[C:29]([CH2:30][CH3:31])=[CH:28][C:7]2[NH:8][C:9]([C:11]3[C:15]([NH:16][C:17]([CH:19]4[CH2:20][CH2:21]4)=[O:18])=[CH:14][NH:13][N:12]=3)=[N:10][C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1cc2nc(-c3nn(C4CCCCO4)cc3NC(=O)C3CC3)[nH]c2cc1CC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOc1cc2nc(-c3n[nH]cc3NC(=O)C3CC3)[nH]c2cc1CC
Yield: 49.9 %

Procedure:
A solution of cyclopropanecarboxylic acid [3-(5-ethoxy-6-ethyl-1H-benzoimidazol-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]amide [0.3 g, Reference Example 48(a)] and p-toluenesulfonic acid hydrate (1.2 g) in ethanol (25 mL) was heated in an 80° C. in an oil bath for 1 hour, then cooled, and then poured into aqueous sodium bicarbonate solution. The aqueous mixture was extracted twice with ethyl acetate (75 mL). The combined extracts were evaporated and the residue was redissolved in a mixture of methylene chloride (100 mL) and methanol (10 mL). This solution was washed with aqueous sodium bicarbonate, to remove some residual p-toluenesulfonic acid, then evaporated to give cyclopropanecarboxylic acid[3-(5-ethoxy-6-ethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]amide (120 mg) as a white solid. LC-MS (Method E): RT=2.36 minutes, 340 (M+H)+.
Reaction SMILES: ClC[C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[S:6][CH:7]=1.Cl.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[C:18]=1[N:26]([CH2:31][CH2:32][CH3:33])[CH2:27][CH2:28][NH:29][CH3:30].C(=O)([O-])[O-].[Na+].[Na+].O>CN(C=O)C.C(OCC)(=O)C.CO>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[C:18]=1[N:26]1[CH2:31][CH2:32][CH2:33][N:29]([CH2:30][C:7]2[S:6][C:5]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)=[N:4][CH:3]=2)[CH2:28][CH2:27]1
Reactant: ClCc1csc(-c2ccccc2)n1
Reactant: CCCN(CCNC)c1c(OC)cccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cccc([N+](=O)[O-])c1N1CCCN(Cc2cnc(-c3ccccc3)s2)CC1
Temperature: 45 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
4-(Chloromethyl)-2-phenyl-1,3-thiazole (300 mg, 1.5 mmol, 1 equiv), N-(2-methoxy-6-nitrophenyl)-N′-methyl-N-propylethane-1,2-diamine hydrochloride (all from step 1, 1 equiv), and sodium carbonate (300 mg, 2 equiv) were suspended in 5 mL of anhydrous DMF. The mixture was stirred at 45° C. for 2 hours. After cooling down to room temperature, ethyl acetate (100 mL) and water (50 mL) were added. The organic layer was subjected to flash chromatography (0 to 5% MeOH in ethyl acetate) to give 1-(2-methoxy-6-nitrophenyl)-4-(2-phenylthiazol-5-ylmethyl)-[1,4]diazepane (250 mg, 40%). MS (ES) m/z 425.1 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:26]=[CH:25][C:24]4[CH:27]=[C:28]([C:30]5[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=5)[S:29][C:23]=4[C:22]3=[O:37])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:36][C:33]1[CH:32]=[CH:31][C:30]([C:28]2[S:29][C:23]3[C:22](=[O:37])[N:21]([C:18]4[CH:17]=[N:16][C:15]([O:14][CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)=[CH:20][CH:19]=4)[CH:26]=[CH:25][C:24]=3[CH:27]=2)=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(-n3ccc4cc(-c5ccc(Cl)cc5)sc4c3=O)cn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1c2sc(-c3ccc(Cl)cc3)cc2ccn1-c1ccc(OC2CCNCC2)nc1
Yield: 73.4 %

Procedure:
Combine 4-{5-[2-(4-chloro-phenyl)-7-oxo-7H-thieno[2,3-c]pyridin-6-yl]-pyridin-2-yloxy}-piperidine-1-carboxylic acid tert-butyl ester (1.67g, 3.10 mmol) with trifluoroacetic acid (2.31 mL, 31.04 mmol) in dichloromethane (20 mL) and stir at RT overnight. Load the mixture onto an SCX column and wash with methanol and dichloromethane. Elute the product with 2M NH3 in methanol and concentrate in vacuo. Chromatograph the residue (silica gel, eluting with 0-10% 2M NH3 in MeOH:dichloromethane) to yield 996 mg (73%) of 2-(4-chloro-phenyl)-6-[6-(piperidin-4-yloxy)-pyridin-3-yl]-6H-thieno[2,3-c]pyridin-7-one. Add ammonium chloride (45 mg, 0.85 mmol) to a solution of the free base (350 mg, 0.80 mmol) in 15 mL of methanol/dichloromethane (1:1) and sonicate the solution until complete dissolution of NH4Cl. Concentrate in vacuo to yield 379 mg (100%) of the title compound. MS/ES m/z (35C1) 438.0 [M+H]+.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([OH:21])=O)=[CH:17][C:18]=4[N:9]3[CH:8]=[CH:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C1N=C[N:24](C(N2C=NC=C2)=O)C=1.CNC(N)=O.C(O)(C(F)(F)F)=O>>[CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([NH2:24])=[O:21])=[CH:17][C:18]=4[N:9]3[CH:8]=[CH:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1ccc2cc3n(c2c1)C=CCc1ccccc1-3
Agent: CNC(N)=O
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1ccc2cc3n(c2c1)C=CCc1ccccc1-3

Procedure:
(5H-indolo[2,1-a][2]benzazepine-10-carboxamide, 13-cyclohexyl-N-[(dimethylamino)sulfonyl]-6,7-dihydro-3-methoxy-6-[methyl[(tetrahydro-2H-pyran-4-yl)carbonyl]amino]-) was prepared from (5H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6,7-dihydro-3-methoxy-6-[methyl[(tetrahydro-2H-pyran-4-yl)carbonyl]amino]-) using CDI as a coupling reagent in a similar manner as described before; Analytical HPLC method: Solvent A=10% MeO{tilde over (H)}90% H2Õ0.1% TFA, Solvent B=90% MeO{tilde over (H)}10% H2O0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Flow Rate=5 ml/min, Column: Xterra MS C18 S7 3.0×50 mm; LC/MS: (ES+) m/z (M+H)+=637.27, HPLC Rt=1.958 min.
Reaction SMILES: Br[C:2](Br)=[CH:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.C([Li])CCC.O>O1CCCC1.CCCCCC>[C:3]([C@H:4]1[CH2:5][CH2:6][C@H:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][CH:11]=2)[CH2:8][CH2:9]1)#[CH:2]
Reactant: CCCCCc1ccc([C@H]2CC[C@H](C=C(Br)Br)CC2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: C#C[C@H]1CC[C@H](c2ccc(CCCCC)cc2)CC1
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
A solution of 480 mg of 1-[trans-4-(2,2-dibromovinyl)cyclohexyl]-4-pentylbenzene in 60 ml of absolute tetrahydrofuran was placed at -78° C. in a sulphonation flask under argon gasification and treated within 3 minutes with 3.2 ml of a 0.1N solution of butyl lithium in hexane. After completion of the addition, the mixture was stirred at -78° C. for a further 2.5 hours, then poured into 150 ml of water and extracted three times with 150 ml of petroleum ether each time. The organic phases were washed with 100 ml of water, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.5 bar) of the residue (310 mg) on silica gel with hexane gave 255 mg (83.5%) of 1-(trans-4-ethynylcyclohexyl)-4-pentylbenzene as a colourless oil (purity 95.9%).
Reaction SMILES: [Br-].[CH2:2]([O:4][C:5]([CH2:7][N+:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=O)[CH3:3].Br[CH2:21]CCBr.[OH-].[K+]>C(O)C.O>[O:4]1[C:5]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:9]3[N:8]([C:7]=2[CH2:21][CH2:3][CH2:2]1)[CH:13]=[CH:12][CH:11]=[CH:10]3
Reactant: BrCCCBr
Reactant: CCOC(=O)Cc1cccc[n+]1CC(=O)OCC
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c2c(n3ccccc13)CCCO2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 1,2-di-[(ethoxycarbonyl)methyl]pyridinium bromide (1.5 g, 0.0045 mole) and 1,3-dibromopropane (0.45 ml, 0.0045 mole) in ethanol (10 ml) was added over 5 minutes to a stirred solution of potassium hydroxide (0.75 g, 0.0134 mole) in ethanol (15 ml) at 5° C. The mixture was then allowed to warm upto room temperature and stir for 20 h. The reaction mixture was diluted with water (150 ml) and extracted with ethyl acetate (2×100 ml). The combined extracts were dried (Na2SO4) and concentrated in vacuo to leave a brown oil. This was chromatographed on silica gel eluting with ether to afford the title compound as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.O1CCOCC1.[OH-].[Na+].[F:20][CH:21]([F:23])Cl>O>[F:20][CH:21]([F:23])[O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: FC(F)Cl
Reactant: Cc1cccc(O)c1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc(OC(F)F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 43.0 g of 3-methyl-2-nitrophenol, 250 ml of p-dioxane, 150 ml of water, and 75 ml of 50% sodium hydroxide solution at 70° C. was added gaseous difluorochloromethane at a steady rate. The pH of the reaction was checked periodically. If the pH became acidic, 30 to 40 ml of 50% sodium hydroxide solution was added. After six hours of heating, the flow of the difluorochloromethane was halted and the reaction allowed to cool to room temperature. After standing overnight the reaction solution was poured onto a mixture of 50 g of ice and 250 ml of water and extracted with two 450 ml portions of ethyl acetate. The organic phase was dried with magnesium sulfate, filtered and concentrated. The resulting brown liquid was dried in a vacuum oven at 45° C. overnight to yield 53.3 g of the desired intermediate.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH3:20])[C:7]([NH:9][C:10]1[C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][N:13]=[CH:12][CH:11]=1)=[O:8])(=O)C.C(SCC(C)C(NC1N=CC=CC=1C(OC)=O)=O)(=O)C>>[SH:4][CH2:5][CH:6]([CH3:20])[C:7]([NH:9][C:10]1[C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][N:13]=[CH:12][CH:11]=1)=[O:8]
Reactant: COC(=O)c1cnccc1NC(=O)C(C)CSC(C)=O
Agent: COC(=O)c1cccnc1NC(=O)C(C)CSC(C)=O
Product: COC(=O)c1cnccc1NC(=O)C(C)CS

Procedure:
Following the procedure of Example 2, but substituting an equivalent amount of methyl 4-(2-acetylthiomethyl-propionamido)-nicotinate, obtained as disclosed in Example 4, for methyl 2-(2-acetylthiomethyl-propionamido)-nicotinate, methyl 4-(2-mercaptomethyl-propionamido)-nicotinate is obtained, m.p. 54°-56° C., from petroleum ether.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]2[O:17][CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCOCC1.Cl.Cl.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][C:31]=1[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][N:40]2[CH2:39][CH2:38][N:37]([C:31]3[CH:32]=[C:33]([CH3:36])[CH:34]=[CH:35][C:30]=3[O:29][CH3:28])[CH2:42][CH2:41]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C)cc1N1CCNCC1
Reactant: c1ccc(COc2ccc(OCC3CO3)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1ccc(C)cc1N1CCN(CC(O)COc2ccc(OCc3ccccc3)cc2)CC1
Yield: 89.5 %

Procedure:
Using 1.37 g of 1-(4-benzyloxyphenoxy)-2,3-epoxypropane, 50 ml of dioxane, 1.49 g of 1-(2-methoxy-5-methylphenyl)piperazine dihydrochloride and 1.6 ml of triethylamine, reaction and workup were carried out as in Example 1-A. Purification by column chromatography (silica gel, elution with ethyl acetate:hexane=1:1) gave 2.21 g of pale yellow oil.
Reaction SMILES: FC1(F)CCN(C(C2NC3C(C=2)=CC(OC2CCN(C(C)C)CC2)=CC=3)=O)CC1.Cl.[Cl:31][C:32]1[CH:40]=[C:39]2[C:35]([CH:36]=[C:37]([C:41](O)=[O:42])[NH:38]2)=[CH:34][C:33]=1[O:44][CH:45]1[CH2:50][CH2:49][N:48]([CH:51]([CH3:53])[CH3:52])[CH2:47][CH2:46]1.ClC1C=C2C(C=C(C(N3CCC(F)(F)CC3)=O)N2C2C=NC=NC=2)=CC=1OC1CCN(C(C)C)CC1.[CH3:90][C:91]1([OH:97])[CH2:96][CH2:95][NH:94][CH2:93][CH2:92]1>>[Cl:31][C:32]1[CH:40]=[C:39]2[C:35]([CH:36]=[C:37]([C:41]([N:94]3[CH2:95][CH2:96][C:91]([OH:97])([CH3:90])[CH2:92][CH2:93]3)=[O:42])[NH:38]2)=[CH:34][C:33]=1[O:44][CH:45]1[CH2:46][CH2:47][N:48]([CH:51]([CH3:52])[CH3:53])[CH2:49][CH2:50]1
Reactant: CC(C)N1CCC(Oc2cc3cc(C(=O)O)[nH]c3cc2Cl)CC1
Reactant: CC1(O)CCNCC1
Agent: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCC(F)(F)CC4)n(-c4cncnc4)c3cc2Cl)CC1
Agent: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Agent: Cl
Product: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCC(C)(O)CC4)[nH]c3cc2Cl)CC1

Procedure:
In analogy to the procedure described for the synthesis of intermediate 1, step 4, the title compound was synthesized from 6-chloro-5-(1-isopropyl-piperidin-4-yloxy)-1H-indole-2-carboxylic acid hydrochloride salt with 1 eq. lithium chloride (example 39, step 4) and 4-methyl-piperidin-4-ol (CAS Nr. 3970-68-1). The title compound was obtained in 72% yield as yellow foam. MS (m/e): 434.3 (MH+, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:32]([OH:35])[C:33]#[CH:34].C(N(C(C)C)CC)(C)C>[Cl-].[Na+].O.[Cu]I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([C:34]#[C:33][CH2:32][OH:35])[CH:5]=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10]
Reactant: C#CCO
Reactant: Fc1cc(I)ccc1C(F)(F)F
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: OCC#Cc1ccc(C(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 11 h

Procedure:
A mixture of 2-fluoro-4-iodobenzotrifluoride (5.00 g), copper(I) iodide (65.5 mg), triphenylphosphine (226 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (356 mg), propargyl alcohol (1.12 ml), diisopropylethylamine (12.0 ml) and tetrahydrofuran (80 ml) was stirred at room temperature for 11 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-80:20) to give the object product (3.08 g) as a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:34])[N:7]3[CH2:15][CH:14]([CH3:16])[N:13](C(OCC4C5C=CC=CC=5C5C4=CC=CC=5)=O)[CH2:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1.N1CCCCC1>C(Cl)Cl.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:34])[N:7]3[CH2:15][CH:14]([CH3:16])[NH:13][CH2:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC1Cn2c(nc3cc(Br)ccc3c2=O)CN1C(=O)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: C1CCNCC1
Solvent: O
Product: CC1Cn2c(nc3cc(Br)ccc3c2=O)CN1

Procedure:
A solution of (9H-fluoren-9-yl)methyl 9-bromo-3-methyl-6-oxo-3,4-dihydro-1H-pyrazino[2,1-b]quinazoline-2(6H)-carboxylate (2 g, 3.9 mmol, 1 equiv) and piperidine (4 mL) in DCM (50 mL) was stirred at room temperature overnight. The reaction mixture was then diluted with water and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel chromatography to give the desired product.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([F:16])[CH:10]=2)[N:5]=[C:4]([C:17]([O:19][CH3:20])=[O:18])[C:3]=1I.[CH3:22][Si:23]([CH3:40])([CH3:39])/[CH:24]=[CH:25]/[Sn](CCCC)(CCCC)CCCC>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([F:16])[CH:10]=2)[N:5]=[C:4]([C:17]([O:19][CH3:20])=[O:18])[C:3]=1/[CH:25]=[CH:24]/[Si:23]([CH3:40])([CH3:39])[CH3:22]
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(F)c2)c(F)c(N)c1I
Reactant: CCCC[Sn](/C=C/[Si](C)(C)C)(CCCC)CCCC
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(-c2ccc(Cl)c(F)c2)c(F)c(N)c1/C=C/[Si](C)(C)C
Temperature: 120 °C
Yield: 79.5 %

Procedure:
Methyl 4-amino-6-(4-chloro-3-fluorophenyl)-5-fluoro-3-iodopicolinate (350 mg, 0.824 mmol), and tetrakis triphenylphosphine palladium(0) (95 mg, 0.082 mmol) were combined in a Biotage microwave reaction vessel that was then sealed and purged with nitrogen. (E)-trimethyl(2-(tributylstannyl)vinyl)silane (417 mg, 1.072 mmol) in dioxane (4122 μl) was added and the reaction mixture was heated in a microwave reactor at 120° C. for 30 min The cooled reaction mixture was diluted with ethyl acetate and washed with saturated sodium chloride. The organic phase was dried over magnesium sulfate, filtered and concentrated on to silica. The product was purified by flash chromatography. (SiO2, 0-20% EtOAc:Hex gradient) to provide the title compound as a tan solid (260 mg, 0.655 mmol, 79% yield); 1H NMR (400 MHz, DMSO-d6) d 0.17 (s, 9H), 3.76 (s, 3H), 6.09 (d, J=19.2 Hz, 1H), 6.60 (s, 2H), 6.91 (d, J=19.2 Hz, 1H), 7.75 (dd, J=3.8, 1.9 Hz, 2H), 7.83 (dd, J=10.8, 1.3 Hz, 1H); 19F NMR (376 MHz, DMSO-d6) d −145.16 , −115.98; ESIMS m/z 398 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[N:12]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([F:20])=[CH:15][CH:14]=3)=[O:10])[CH:5]=[CH:4][N:3]=1.Cl[CH2:30][C:31](=O)[CH3:32]>C(#N)C>[CH3:32][C:31]1[N:1]=[C:2]2[CH:7]=[C:6]([NH:8][C:9]([C:11]3[N:12]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=4)[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([F:20])=[CH:15][CH:14]=4)=[O:10])[CH:5]=[CH:4][N:3]2[CH:30]=1
Reactant: CC(=O)CCl
Reactant: Nc1cc(NC(=O)c2cc3cc(F)ccc3n2Cc2cccc(F)c2)ccn1
Solvent: CC#N
Product: Cc1cn2ccc(NC(=O)c3cc4cc(F)ccc4n3Cc3cccc(F)c3)cc2n1
Yield: 37.5 %

Procedure:
Compound 19 was prepared according to a process similar to that described in step 10.2, by reacting 0.12 g (0.32 mmol) of N-[2-aminopyrid-4-yl]-5-fluoro-1-[(3-fluoro-phenyl)methyl]-1H-indole-2-carboxamide, prepared according to the protocol described in step 10.1, with 0.059 g (0.63 mmol) of 1-chloropropan-2-one in 4 mL of acetonitrile. 50 mg of the expected product are thus obtained.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1B1OC(C)(C)C(C)(C)O1)(=[O:3])[CH3:2].Br[C:37]1[CH:38]=[C:39]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([CH:52]3[CH2:55][N:54]([CH3:56])[CH2:53]3)=[CH:48][N:47]=2)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1>>[C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:37]1[CH:38]=[C:39]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([CH:52]3[CH2:53][N:54]([CH3:56])[CH2:55]3)=[CH:48][N:47]=2)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1)(=[O:3])[CH3:2]
Reactant: CN1CC(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)C1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C4CN(C)C4)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Yield: 51.9 %

Procedure:
Following Example 148b, 482 mg of 4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 210d and 350 mg 5-bromo-1-methyl-3-(5-(1-methylazetidin-3-yl)pyridin-2-ylamino)pyridin-2(1H)-one 172a, were reacted to give 213a as a yellow solid (324 mg, 52%). MS: [M+H]+ 625
Reaction SMILES: [Mg:1].CO.[CH3:4][O:5][C:6]1[CH:27]=[CH:26][C:9]2[NH:10][C:11]([S:13]([CH2:15][C:16]3[C:21]([CH3:22])=[C:20]([O:23][CH3:24])[C:19]([CH3:25])=[CH:18][N:17]=3)=[O:14])=[N:12][C:8]=2[CH:7]=1.C[O-].[Mg+2].C[O-]>O.C(Cl)Cl>[CH3:25][C:19]1[C:20]([O:23][CH3:24])=[C:21]([CH3:22])[C:16]([CH2:15][S@@:13]([C:11]2[N-:10][C:9]3[CH:26]=[CH:27][C:6]([O:5][CH3:4])=[CH:7][C:8]=3[N:12]=2)=[O:14])=[N:17][CH:18]=1.[CH3:25][C:19]1[C:20]([O:23][CH3:24])=[C:21]([CH3:22])[C:16]([CH2:15][S@@:13]([C:11]2[N-:10][C:9]3[CH:26]=[CH:27][C:6]([O:5][CH3:4])=[CH:7][C:8]=3[N:12]=2)=[O:14])=[N:17][CH:18]=1.[Mg+2:1]
Reactant: COc1ccc2[nH]c(S(=O)Cc3ncc(C)c(OC)c3C)nc2c1
Reactant: [Mg]
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COc1ccc2[n-]c([S@@](=O)Cc3ncc(C)c(OC)c3C)nc2c1
Reaction time: 5 h
Yield: 44.5 %

Procedure:
Magnesium (0.11 g, 4.5 mmol) was dissolved and reacted with methanol (50 ml) at 40° C. with a catalytic amount of methylene chloride. The reaction was run under nitrogen and was finished after five hours. At room temperature a mixture of the two enantiomers [90%(-)-isomer and 10%(+)-isomer] of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole (2.84 g, 8.2 mmol) was added to the magnesium methoxide solution. The mixture was stirred for 12 hours whereupon a small amount of water (0.1 ml) was added in order to precipitate inorganic magnesium salts. After 30 minutes stirring, these inorganic salts were filtered off and the solution was concentrated on a rotavapor. The residue was now a concentrated methanolic solution of the enantiomeric mixture (i.e. the title compound contaminated with the (+)-isomer), with an optical purity (enantiomeric excess, e.e.) of 80%. This mixture was diluted with acetone (100 ml) and after stirring at room temperature for 15 minutes, a white precipitate was obtained. Additional stirring for 15 minutes and thereafter filtration afforded 1.3 g (50%) of the title compound as white crystals. Chiral analyses of the crystals and mother liquor were performed by chromatography on an analytical chiral column. The optical purity of the crystals and mother liquor was found to be 98.4 e.e. and 64.4% e.e., respectively. Thus, the optical purity (e.e.) has been enhanced from 80% to 98.4% simply by crystallising the Mg-salt from a mixture of acetone and methanol. The product was crystalline as shown by powder X-ray diffraction and the magnesium content was 3.44% as shown by atomic absorption spectroscopy. [α]D20 =-131.5°(c=0.5%, methanol).