Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][N:7]1[CH2:11][C@H:10]2[CH:12]([NH2:15])[CH2:13][CH2:14][C@H:9]2[CH2:8]1.C(N(CC)CC)C.[F:28][C:29]([F:41])([F:40])[C:30]1[CH:31]=[C:32]([S:36](Cl)(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=1>ClCCl>[F:41][C:29]([F:28])([F:40])[C:30]1[CH:31]=[C:32]([S:36]([NH:15][C@@H:12]2[C@H:10]3[C@H:9]([CH2:8][N:7]([CH2:6][C:5]4[CH:16]=[CH:17][CH:18]=[C:3]([C:2]([F:19])([F:1])[F:20])[CH:4]=4)[CH2:11]3)[CH2:14][CH2:13]2)(=[O:37])=[O:38])[CH:33]=[CH:34][CH:35]=1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: NC1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@@H]12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (3aS*,6aR*)-2-(3-(trifluoromethyl)benzyl)octahydrocyclopenta[c]pyrrol-4-amine from Example 122 Step E (200 mg, 0.703 mmol) in dichloromethane (2 mL) was added triethylamine (0.147 mL, 1.055 mmol) followed by 3-(trifluoromethyl)benzene-1-sulfonyl chloride (0.124 mL, 0.774 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted with dichloromethane. The organics were reduced in volume and loaded onto a silica gel cartridge (Analogix®, Burlington, Wis., RS-24). The title compounds were eluted with a gradient of 0% to 10% methanol (2 N ammonia)/dichloromethane over 20 minutes.
Reaction SMILES: Cl[Si:2]([CH3:5])([CH3:4])[CH3:3].[CH2:6]([OH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CN1C=CN=C1>>[CH3:3][Si:2]([O:13][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:5])[CH3:4]
Reactant: OCc1ccccc1
Reactant: C[Si](C)(C)Cl
Agent: Cn1ccnc1
Product: C[Si](C)(C)OCc1ccccc1
Temperature: 0 °C
Yield: 88 %

Procedure:
5.50 g (51.0 mmol) of chlorotrimethylsilane were added dropwise to a solution of 5.00 g (46.0 mmol) of benzyl alcohol and 4.20 g (51.0 mmol) of 1-methylimidazole while stirring at 0° C. The reaction mixture was stirred for a further 30 minutes at 0° C. and for 5 minutes at 80° C., resulting in the formation of a liquid two-phase mixture. The upper phase was separated off to give 7.30 g (theory: 8.29 g) of benzyl trimethylsilyl ether as a colorless oil having a purity of 99% (GC).
Reaction SMILES: Cl[C:2]1[C:7]([N:8]2[C:12]([CH2:13]Cl)=[N:11][C:10]([C:15]([OH:17])=[O:16])=[N:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1>>[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:23]([N:24]2[C:2]3[N:3]=[CH:4][CH:5]=[CH:6][C:7]=3[N:8]3[N:9]=[C:10]([C:15]([OH:17])=[O:16])[N:11]=[C:12]3[CH2:13]2)=[CH:22][CH:21]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C(O)c1nc(CCl)n(-c2cccnc2Cl)n1
Product: COc1ccc(N2Cc3nc(C(=O)O)nn3-c3cccnc32)cc1

Procedure:
using 10.00 g (0.037 mol) of 1-(2-chloro-3-pyridyl)-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxylic acid and 15.80 g (0.128 mol) of 4-methoxyaniline there is obtained 5-(4-methoxyphenyl)-4,5-dihydropyrido[2,3-e][1,2,4]triazolo[1,5-a]pyrazine-2-carboxylic acid and the methyl ester thereof which, after recrystallisation from methylene chloride/isopropanol, melts at 190°-196°;
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.CCCCCC.[Li]CCCC.[C:19]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[C:27]1([C:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:2]2[CH:3]=[N:4][CH:5]=[N:6][CH:7]=2)[OH:26])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: Brc1cncnc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC(c1ccccc1)(c1ccccc1)c1cncnc1
Temperature: -100 °C
Reaction time: 0.5 h
Yield: 48.4 %

Procedure:
A solution of 5-bromopyrimidine (10 g, 0.063 mol) in a mixture of dry THF (150 mL) and hexane (50 mL) was cooled to −100° C. To this cooled solution was added n-BuLi (4 g, 21 mL, 0.062 mol) over a period of 30 min and stirred for another 30 min. A solution of benzophenone (11.5 g, 0.063 mol) in dry THF (50 mL) was added to this at the same temperature over a period of 30 min. The reaction mixture was warmed slowly to RT and allowed to stir another 1 h at RT. The reaction was quenched with cold water (200 mL), ethyl acetate was added and the organic layer was separated. The organic layer was dried, concentrated and the crude product was purified by column chromatography on silica gel (up-to 25% ethyl acetate in pet ether) to give the product (8 g). TLC: Pet. ether/EtOAc, 1:1, Rf=0.3.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:14][CH2:15][O:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1.[OH-].[Na+]>CO.O1CCCC1.O>[CH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:25]=[CH:26][C:17]=1[O:16][CH2:15][CH2:14][S:11]([C:8]1[CH:9]=[CH:10][C:5]([C:4](=[O:27])[C:3]([OH:28])=[O:2])=[CH:6][CH:7]=1)(=[O:12])=[O:13]
Reactant: COC(=O)C(=O)c1ccc(S(=O)(=O)CCOc2ccc3ccccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(=O)c1ccc(S(=O)(=O)CCOc2ccc3ccccc3c2)cc1
Yield: 53.2 %

Procedure:
A solution of 4-[[2-(2-naphthalenyloxy)ethyl]sulfonyl]-alpha-oxobenzeneacetic acid methyl ester (0.76 g) in warm methanol (5 mL) and tetrahydrofuran (5 mL) was treated with 1N sodium hydroxide (2.1 mL) and after 10 minutes the mixture was diluted with water and concentrated to remove the organic solvents. The residue was acidified with excess hydrochloric acid and extracted with dichloromethane containing a little tetrahydrofuran. The organic layer was washed with water, dried (Na2SO4), filtered and evaporated to give crude product. Crystallization from diethyl ether-hexane provided 0.39 g of purified 4-[[2-(2-naphthalenyloxy)ethyl]sulfonyl]-alpha-oxobenzeneacetic acid as a colorless solid, mp 135°-136° C.
Reaction SMILES: C1COCC1.[CH:6]1([C:9]2[C:18]([CH:19]3[CH2:21][CH2:20]3)=[CH:17][C:12]([C:13](OC)=[O:14])=[C:11]([O:22][CH2:23][CH3:24])[CH:10]=2)[CH2:8][CH2:7]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O>[CH:6]1([C:9]2[C:18]([CH:19]3[CH2:21][CH2:20]3)=[CH:17][C:12]([CH2:13][OH:14])=[C:11]([O:22][CH2:23][CH3:24])[CH:10]=2)[CH2:7][CH2:8]1
Reactant: CCOc1cc(C2CC2)c(C2CC2)cc1C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc(C2CC2)c(C2CC2)cc1CO
Yield: 97.6 %

Procedure:
A THF (15 mL) solution of methyl 4,5-dicyclopropyl-2-ethoxybenzoate (3.26 g) was added at 0° C. to a mixture of lithium aluminum hydride (1.09 g) and THF (65 mL), and the resultant mixture was stirred at room temperature for 1 hour in a nitrogen atmosphere. Water (1 mL), a 1 M aqueous sodium hydroxide solution (1 mL), and water (3 mL) were added in this order to the reaction mixture at 0° C., and the mixture was filtered through celite. Then, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to obtain the title compound (2.84 g).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]2[N:12]([CH2:16][CH3:17])[N:13]=[C:14]([CH3:15])[C:3]=12.[CH:18]1([CH2:24][NH2:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.[NH4+].[OH-].Cl>C(Cl)Cl.O.CS(C)=O>[ClH:1].[CH2:16]([N:12]1[C:4]2=[N:5][C:6]3[C:11]([C:2]([NH:25][CH2:24][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:3]2[C:14]([CH3:15])=[N:13]1)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH3:17]
Reactant: CCn1nc(C)c2c(Cl)c3ccccc3nc21
Reactant: NCC1CCCCC1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCn1nc(C)c2c(NCC3CCCCC3)c3ccccc3nc21
Temperature: 80 °C

Procedure:
A mixture of 4-chloro-1-ethyl-3-methyl-1H-pyrazolo[3,4-b]quinoline (1.0 g, 0.0043 mmol), cyclohexanemethylamine (1.2 ml, 0.009 mol) and DMSO (3 ml) was heated at 80° C. overnight. The reaction mixture was pured into water (100 ml)/NH4OH (0.5 ml) and was extracted with CH2Cl2. The solvent was evaporated to about 20 ml and then the mixture was purified by chromatography on silica gel, followed by high pressure liquid chromatography eluting with 20% EtOAc/hexane to 50% EtOAc/hexane to afford the product as the free base. The free base was dissolved in CH2Cl2 (20 ml) and treated with ethereal HCl and the solution was evaporated. The residue was crystallized from ethyl acetate/ether/ethanol to afford 1-ethyl-3-methyl-N-(cyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine hydrochloride, m.p. 215°-217° C.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][CH2:12][C@H:11]([SiH:14]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:25]=[C:24]([F:26])[C:23]([OH:27])=[C:22]([F:28])[CH:21]=3)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:29][C@H:30](O)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[CH2:1]([C@H:8]1[CH2:13][CH2:12][C@H:11]([Si@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]3[CH:25]=[C:24]([F:26])[C:23]([O:27][C@H:30]([CH3:29])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[C:22]([F:28])[CH:21]=3)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCC[C@H]1CC[C@H]([SiH]2CCC(c3cc(F)c(O)c(F)c3)CC2)CC1
Reactant: CCCCCCC[C@H](C)O
Product: CCCCCCC[C@@H](C)Oc1c(F)cc([C@H]2CC[Si@H]([C@H]3CC[C@H](CCCCCCC)CC3)CC2)cc1F

Procedure:
The general procedure of Example 1 was repeated using 4-(4-(trans-4-n-heptylcyclohexyl)-4-silacyclohexyl)-2,6-difluorophenol and (S)-2-nonanol, thereby obtaining the intended compound.
Reaction SMILES: [CH3:1][N-:2][CH3:3].[CH3:4][N-:5][CH3:6].C[N-]C.C[N-]C.[V+4:13].[CH3:14][Si:15]([CH2:18][Li])([CH3:17])[CH3:16]>CCCCC>[CH3:1][N-:2][CH3:3].[CH3:4][N-:5][CH3:6].[CH3:14][Si:15]([CH2:18][V+2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])([CH3:17])[CH3:16]
Reactant: [V+4]
Reactant: [Li]C[Si](C)(C)C
Agent: C[N-]C
Solvent: CCCCC
Product: C[Si](C)(C)C[V+2]C[Si](C)(C)C

Procedure:
A small amount of vanadium tetrakis(dimethylamide) was dissolved in pentane, and an excess of trimethylsilylmethyllithium was added. Lithium dimethylamide precipitated. The mixture was filtered and the esr spectrum was recorded. An eight-line spectrum was observed at g = 1.973 ± 0.001 with a hyperfine coupling constant to vanadium of 60.3 G. This coupling constant is midway between V(NMe2)4 (65.1 G) and (Me3SiCH2)4V (55 G). This spectrum implied the existence of bis(trimethylsilylmethyl)vanadium bis(dimethylamide) in solution.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5](Cl)[C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][N:8]=2)[N:3]=1.[CH3:17][N:18]([CH3:29])[CH2:19][CH2:20][O:21][C:22]1[N:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1>>[Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]2[NH:28][C:25]1[CH:26]=[N:27][C:22]([O:21][CH2:20][CH2:19][N:18]([CH3:29])[CH3:17])=[CH:23][CH:24]=1
Reactant: CN(C)CCOc1ccc(N)cn1
Reactant: CS(=O)(=O)c1cnc2ccc(Cl)nc2c1Cl
Product: CN(C)CCOc1ccc(Nc2c(S(C)(=O)=O)cnc3ccc(Cl)nc23)cn1
Yield: 70.2 %

Procedure:
Following general procedure I, 2,8-dichloro-7-(methylsulfonyl)-1,5-naphthyridine (150 mg, 0.54 mmol) was reacted with 6-[2-(dimethylamino)ethoxy]pyridin-3-amine (120 mg, 0.65 mmol) to afford the desired product (160 mg, 70%) as a light yellow solid; 1H NMR (500 MHz, CDCl3) δ 9.03 (s, 1H), 8.98 (s, 1H), 8.17 (d, J=8.8 Hz, 1H), 7.98 (d, J=2.8 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.42 (dd, J=8.8, 2.8 Hz, 1H), 6.82 (d, J=8.8 Hz, 1H), 4.46 (t, J=5.5 Hz, 2H), 3.20 (s, 3H), 2.76 (t, J=5.6 Hz, 2H), 2.37 (s, 6H); ESI MS m/z 422 [M+H]+
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]2([Cl:16])[Cl:15])(=[O:4])=[O:3].[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>C(Cl)Cl>[CH2:17]([NH:24][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]2([Cl:16])[Cl:15])(=[O:4])=[O:3])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1Nc2ccc(S(=O)(=O)Cl)cc2C1(Cl)Cl
Reactant: NCc1ccccc1
Agent: Cl
Solvent: ClCCl
Product: O=C1Nc2ccc(S(=O)(=O)NCc3ccccc3)cc2C1(Cl)Cl
Reaction time: 4 h

Procedure:
To a solution of 5-chlorosulfonyl-3,3-dichloro-2-oxindole (100 mg, 400 umol) in methylene chloride (3 mL) was added benzylamine (135 uL, 1.2 mmol) dropwise. After stirring for 4 h. 3 N hydrochloric acid was added along with an additional volume of methylene chloride (20 mL). The organic layer was dried over magnesium sulfate, filtered, and silica gel flash chromatography (25 to 35% ethyl acetate/hexanes) yielded the title compound. ES (−) MS m/e=369 (M−H).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH3:4].S(Cl)(Cl)=O.[I:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:22]([CH3:23])=[CH:21][C:20](=[O:24])[C:19]([C:25]([OH:27])=[O:26])=[N:18]2)=[CH:13][CH:12]=1>CCCCCC>[I:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:22]([CH3:23])=[CH:21][C:20](=[O:24])[C:19]([C:25]([O:27][CH2:1][CH2:2][CH2:3][CH3:4])=[O:26])=[N:18]2)=[CH:13][CH:12]=1
Reactant: CCCCO
Reactant: Cc1cc(=O)c(C(=O)O)nn1-c1ccc(I)cc1
Solvent: CCCCCC
Solvent: O=S(Cl)Cl
Product: CCCCOC(=O)c1nn(-c2ccc(I)cc2)c(C)cc1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 52 %

Procedure:
To 50 ml of n-butanol, cooled to -5° C., there is added dropwise 2.62 g (0.022 mol) of thionyl chloride. The solution is stirred at 0° C. for 15 minutes and to it there is added 7.12 g (0.02 mol) of 1-(4-iodophenyl)-1,4-dihydro-4-oxo-6-methylpyridazine-3-carboxylic acid. (See Example 3). The suspension formed is stirred at room temperature for 3 days and to it there is added 150 ml of hexane. The suspension is stirred at room temperature for 2 days and is vacuum filtered. The filter cake (HCl salt of the desired product) is air dried and slurried in 150 ml of water for 3 hrs. The suspension is vacuum filtered to afford 4.25 g (52% yield) of product, mp 134°-137° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH:14]([C:18]1[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=1)[CH:13]([C:27]([O:29][CH3:30])=[O:28])[C:12]2=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[C:14]([C:18]1[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=1)=[C:13]([C:27]([O:29][CH3:30])=[O:28])[C:12]2=[O:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1C(=O)c2cc(OCc3ccccc3)ccc2C1c1ccc2c(c1)OCO2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: c1ccccc1
Product: COC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccc(OCc3ccccc3)cc2C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 60.3 %

Procedure:
To a solution of methyl 5-benzyloxy-1-(3,4-methylenedioxyphenyl)-3-oxoindane-2-carboxylate (27.3 g, 65.6 mmol) in benzene (90 ml), cooled in an ice-H2O bath, was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (15.4 g, 67.8 mmol). The resulting mixture was stirred at 0° C. for 1 h, allowed to warm to room temperature for 1.5 h, and finally warmed to 40° C. for 1 h. The solid which formed was removed by filtration and washed with benzene. The combined filtrate and washings were poured into EtOAc (200 ml) and washed successively with aqueous Na2CO3 (3×), H2O (3×), 3M HCl, H2O (3×) and saturated aqueous NaCl and dried. The solvent was removed in vacuo, and the residue was crystallized from EtOAc/hexanes to afford the title compound (16.4 g, 60%) as a red crystalline solid; m.p. 140°-141° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])=[O:4].[CH3:13][N:14]1[C:22]2[N:21]=[C:20]([Cl:23])[N:19]([CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])[C:18]=2[C:17](=[O:29])[NH:16][C:15]1=[O:30].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:12][O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3](=[O:4])[CH2:2][N:16]1[C:17](=[O:29])[C:18]2[N:19]([CH2:24][CH:25]=[C:26]([CH3:27])[CH3:28])[C:20]([Cl:23])=[N:21][C:22]=2[N:14]([CH3:13])[C:15]1=[O:30]
Reactant: COc1ccccc1C(=O)CBr
Reactant: CC(C)=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccccc1C(=O)Cn1c(=O)c2c(nc(Cl)n2CC=C(C)C)n(C)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.71 g of 2-bromo-1-(2-methoxy-phenyl)-ethanone are added to a mixture of 2.00 g of 3-methyl-7-(3-methyl-2-buten-1-yl)-8-chloro-xanthine and 1.38 mg of potassium carbonate in 15 ml of N,N-dimethylformamide. The reaction mixture is stirred for eight hours at ambient temperature. After aqueous working up the crude product is purified by chromatography through a silica gel column with cyclohexane/ethyl acetate (8:1 to 8:1) as eluant.
Reaction SMILES: [F:1][C:2]1[C:13]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]([CH3:25])[C:15]2=[O:26])=[C:12]([N+:27]([O-])=O)[C:5]2[N:6]([CH3:11])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1>C(O)(=O)C.[Fe]>[NH2:27][C:12]1[C:5]2[N:6]([CH3:11])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=[C:2]([F:1])[C:13]=1[N:14]1[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]([CH3:25])[C:15]1=[O:26]
Reactant: CN1C(=O)COc2cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c([N+](=O)[O-])c21
Agent: [Fe]
Solvent: CC(=O)O
Product: CN1C(=O)COc2cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(N)c21
Reaction time: 72 h
Yield: 81.7 %

Procedure:
3-[7-Fluoro-4-methyl-5-nitro-2H-1,4-benzoxazine-3(4H)-on-6-yl]-1-methyl-6-trifluoromethyl-2,4-(1H, 3H)-pyrimidinedione (1.45 g) was dissolved in acetic acid (80 ml) containing iron powder (1.16 g). The mixture was stirred for 3 days under nitrogen atmosphere. After filtration, water (100 ml) and ethyl acetate (150 ml) were added to the filtrate, the organic phase was washed with water (30 ml×3) and brine (30 ml), dried over sodium sulfate. After filtration and evaporation, the residue was purified by silica gel column (hexane to 40% ethyl acetate) to afford the title compound (1.1 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[H-].[Na+].I[CH2:14][CH:15]([CH3:17])[CH3:16].O>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH:6]=[CH:5]2
Reactant: CC(C)CI
Reactant: Brc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)Cn1ccc2cc(Br)ccc21
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 5-bromo-1H-indole (1 g) in DMF (dry) (10 mL) was added NaH (60%, 0.612 g) at room temperature. The mixture was stirred at 80° C. for 10 min. 1-Iodo-2-methylpropane (0.587 mL) was added at room temperature and the mixture was stirred at 80° C. for 1 hr. Another 1-iodo-2-methylpropane (0.587 mL) was added and the mixture was stirred at 80° C. for 1 hr. Water and EtOAc were added and the extracted organic layer was washed with brine. Silica-gel was added to the organic layer and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (554 mg) as colorless oil.
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH3:4][C:5]1[O:9][C:8]2[CH:10]=[CH:11][C:12]([C:14](=[O:18])[C:15]([OH:17])=[O:16])=[CH:13][C:7]=2[CH:6]=1>C(OCC)C.C(O)(=O)C>[CH3:4][C:5]1[O:9][C:8]2[CH:10]=[CH:11][C:12]([C:14](=[O:18])[C:15]([O:17][CH3:3])=[O:16])=[CH:13][C:7]=2[CH:6]=1
Reactant: C=[N+]=[N-]
Reactant: Cc1cc2cc(C(=O)C(=O)O)ccc2o1
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC(=O)C(=O)c1ccc2oc(C)cc2c1
Reaction time: 0.08 h

Procedure:
An ethereal solution of diazomethane is added in portions to a solution of 2-methyl-5-benzo(b)furanylglyoxylic acid in dry ethyl ether until the yellow color of diazomethane persists. The resulting mixture is stirred five minutes and a few drops of ethereal acetic acid added to consume the excess reagent. The ether solution is washed with water, dilute sodium bicarbonate solution, water again and dried over anhydrous magnesium sulfate. The ether is evaporated to obtain methyl 2-methyl-5-benzo(b)furanylglyoxylate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[N:14]([CH3:17])[C:13](SC)=[N:12]3)[CH2:10][CH:9]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[O:8][C:5]2=[CH:6][CH:7]=1.[NH4+:27].[I-]>N.CCO>[NH2:27][C:13]1[N:14]([CH3:17])[C:15](=[O:16])[C:11]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[O:8][CH:9]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[CH2:10]2)[N:12]=1
Reactant: [NH4+]
Reactant: CSC1=NC2(CC(c3ccc(Cl)cc3)Oc3ccc(Br)cc32)C(=O)N1C
Agent: N
Agent: [I-]
Solvent: CCO
Product: CN1C(=O)C2(CC(c3ccc(Cl)cc3)Oc3ccc(Br)cc32)N=C1N
Yield: 12.4 %

Procedure:
A solution of 6-bromo-2-(4-chlorophenyl)-1′-methyl-2′-(methylthio)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (300 mg, 0.67 mmol) and NH4I (194 mg, 1.33 mmol) in NH3/EtOH (5 mL, 1.5 N) was heated at 110° C. in a tube in a microwave reactor for 2-2.5 h. After cooling, the mixture was concentrated in vacuo to give a residue, which was purified by preparative TLC to afford 2′-amino-6-bromo-2-(4-chlorophenyl)-1′-methylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (35 mg, 12%). 1H-NMR (MeOD): 2.19 (m, 1H), 2.41 (m, 1H), 3.11 (m, 3H), 5.15 (m, 0.5H), 5.38 (m, 0.5H), 6.78 (m, 1H), 6.82 (m, 0.5H), 7.02 (m, 0.5H), 7.23 (m, 1H), 7.31 (m, 3H), 7.44 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:14]=[CH:13][C:12]([O:15][C@H:16]2[C:24]3[C:19](=[C:20]([OH:26])[CH:21]=[CH:22][C:23]=3[F:25])[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)=[O:5])[CH3:2].F[C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:10]=[CH:11][C:12]([O:15][C@H:16]2[C:24]3[C:19](=[C:20]([O:26][C:28]4[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=4)[CH:21]=[CH:22][C:23]=3[F:25])[CH2:18][CH2:17]2)=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: N#Cc1ccc(F)cc1
Reactant: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O[C@@H]2CCc3c(O)ccc(F)c32)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O[C@@H]2CCc3c(Oc4ccc(C#N)cc4)ccc(F)c32)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 33.1 %

Procedure:
(1S,2S)-2-[4-((R)-7-Fluoro-4-hydroxy-indan-1-yloxy)-phenyl]-cyclopropanecarboxylic acid ethyl ester (Intermediate 5, 146 mg, 0.41 mmol), 4-fluorobenzonitrile (55 mg, 0.45 mmol), and cesium carbonate (145 mg, 0.45 mmol) are suspended in dry dimethylformamide (10 mL) and stirred for 3 hours at 100° C. followed by room temperature overnight. The mixture is diluted with water and extracted with ethyl acetate. The organic extract is dried over sodium sulfate, filtered and the solvent removed. The residue is purified by flash chromatography (10% ethyl acetate in cyclohexane) to give the title compound (Yield 62 mg). LC (METHOD 5): tR=1.54 min; Mass spectrum (ES+): m/z=458 [M+H]+.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:8][C:9]1[C:18]([F:19])=[C:17]2[C:12]([C:13]([C:24]3[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=3)=[CH:14][C:15]([C:20]([O:22][CH3:23])=[O:21])=[N:16]2)=[CH:11][CH:10]=1.FC(F)(F)C1OCCNC1>CN(C=O)C.CCOC(C)=O>[F:19][C:18]1[C:9]([CH3:8])=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[C:15]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=[C:13]2[C:24]1[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=1
Reactant: COC(=O)c1cc(-c2cnn(C)c2)c2ccc(CBr)c(F)c2n1
Agent: FC(F)(F)C1CNCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(-c2cnn(C)c2)c2ccc(C)c(F)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Cs2CO3 (345 mg, 1.06 mmol) was added to a mixture of methyl 7-(bromomethyl)-8-fluoro-4-(1-methyl-1H-pyrazol-4-yl)quinoline-2-carboxylate (7-18, 160 mg, 0.42 mmol) and 2-(trifluoromethyl)morpholine (79 mg, 0.51 mmol) in DMF (4.2 mL). After stirring at room temperature for 2 h, the mixture was diluted with EtOAc, washed with H2O, then brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc/Hexane (0-100%) to afford methyl 8-fluoro-7-methyl-4-(1-methyl-1H-pyrazol-4-yl)quinoline-2-carboxylate as racemic mixture (31.4 mg, 16%). LRMS m/z (M+H)+ 453.3 found, 453.1 required. Chiral separation using SFC chromatography provided (R)-methyl 8-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-7-((2-(trifluoromethyl)morpholino)methyl)quinoline-2-carboxylate (7-19a, 15 mg) and (S)-methyl 8-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-7-((2-(trifluoromethyl)morpholino)methyl)quinoline-2-carboxylate (7-19b, 14.3 mg).