Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([Br:15])[CH:9]=[C:10]([CH2:11][CH2:12][CH2:13]O)[N:6]2[N:5]=[CH:4][N:3]=1.C(Br)(Br)(Br)[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:15][C:8]1[CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][Br:17])[N:6]2[C:7]=1[C:2]([NH2:1])=[N:3][CH:4]=[N:5]2
Reactant: BrC(Br)(Br)Br
Reactant: Nc1ncnn2c(CCCO)cc(Br)c12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1ncnn2c(CCCBr)cc(Br)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.2 %

Procedure:
To a solution of 3-(4-Amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)-propan-1-ol (1.20 g, 4.43 mmol) in anhydrous THF (22 mL) at 0° C. was added carbon tetrabromide (1.62 g, 4.87 mmol, 1.1 eq) and triphenylphosphine (1.16 g, 4.43 mmol, 1.0 eq). After 5 minutes the ice bath was removed and the reaction mixture was stirred at RT for 1 hour. Then another 0.1 equivalents of both carbon tetrabromide (0.15 g, 0.44 mmol) and triphenylphosphine (0.12 g, 0.44 mmol) were added. The reaction was stirred another hour at ambient temperature before it was filtered to remove some solid which was rinsed with some THF. The combined filtrate and rinse were concentrated at reduced pressure to give a crude product which was purified by MPLC on 120 g of silica gel eluted with a gradient from 0-100% EtOAc in hexane to give 950 mg (64.2%) of desired product as a white solid after evaporation of best fractions which eluted from 55-65% EtOAc. 1H-NMR (DMSO-d6) 7.84 (s, 1H), 6.65 (s, 1H), 3.54 (t, 2H, J=6.4), 2.94 (t, 2H, J=6.4), and 2.16 (q, 2H, J=6.4); MS LC-MS [M+H]+=333.3/335.1/337.1, RT=2.77 min. Evidence showed in the NMR and the LC-MS for about 16% contamination with 5,6-dibromo-7-(3-bromopropyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine which came from an analogous contaminant (3-(4-Amino-5,6-dibromopyrrolo[2,1-f][1,2,4]triazin-7-yl)-propan-1-ol) in the starting material. Products that came from this contaminant were removed by chromatography of the product of step 5 below.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH:34]1[CH2:38][CH2:37][O:36][CH2:35]1>CN(C=O)C>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH2:33][CH:34]2[CH2:38][CH2:37][O:36][CH2:35]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: BrCCC1CCOC1
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCC3CCOC3)c2n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 138.8 %

Procedure:
A mixture of 2-butoxy-8-methoxy-9H-purin-6-amine trifluoroacetate salt (200 mg) and potassium carbonate (236 mg) in dry DMF (2 mL) was heated at 60° C. with stirring for 1 h. 3-(2-Bromoethyl)tetrahydrofuran (123 mg) was added and the reaction was continued for 2 h. The mixture was quenched with water and extracted with EtOAc (×3). The combined organics were washed with water and brine, dried using a hydrophobic frit and evaporated to give an oil (265 mg). The crude material was purified by normal phase chromatography (ISCO) using 0-15% MeOH/EtOAc as eluent to give the title compound (102 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:12])[CH:5]=[C:6]2[C:10]=1[CH2:9][C:8]([CH3:11])=[CH:7]2.[Li]CCCC.[CH:18]1[C:30]2[CH:29]([Si:31](Cl)([CH3:33])[CH3:32])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]=2[CH:21]=[CH:20][CH:19]=1.O>CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([F:12])[CH:5]=[C:6]2[C:10]=1[CH:9]=[C:8]([CH3:11])[CH:7]2[Si:31]([CH:29]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:22]2[C:30]1=[CH:18][CH:19]=[CH:20][CH:21]=2)([CH3:32])[CH3:33]
Reactant: C[Si](C)(Cl)C1c2ccccc2-c2ccccc21
Reactant: CC1=Cc2cc(F)cc(Br)c2C1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CC1=Cc2c(Br)cc(F)cc2C1[Si](C)(C)C1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 3.41 g (15.0 mmol) of 7-bromo-5-fluoro-2-methyl-1H-indene in 80 ml of ether, 6.00 ml (15.0 mmol) of 2.5 M nBuLi in hexanes was added. The reaction mixture was stirred for 12 h at room temperature; then, this solution was added dropwise to a solution of 3.88 g (15.0 mmol) of (9H-fluoren-9-yl)chlorodimethylsilane in 80 ml of ether over 1 h at room temperature. The resulting mixture was stirred for 12 h, and then 100 ml of water was added. The organic layer was separated, dried over Na2SO4, and evaporated to dryness. The product was isolated by flash chromatography on Silica Gel 60 (40-63 um, d 30 mm, l 400 mm, eluent: hexanes). Yield 3.71 g (55%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([OH:14])[C:6](=[CH:12][CH:13]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[N-:15]=[N+]=[N-].[Na+]>CN(C)C=O.ClCCl>[NH2:15][CH2:2][C:3]1[CH:4]=[C:5]([OH:14])[C:6](=[CH:12][CH:13]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1ccc(CBr)cc1O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(CN)cc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl 4-bromomethylsalicylate (4.8 g, 18.6 mmoles) was dissolved in dry N,N-dimethylformamide (50 mL) and sodium azide (1.2 g, 18.9 mmoles) was added. The suspension was stirred at room temperature for 2 hours. The reaction mixture was then diluted with dichloromethane (150 mL) and extracted with 1N aqueous hydrochloric acid (100 mL), water (100 mL), and saturated aqueous sodium chloride(50 mL). Finally, the solution was then dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness to give ethyl 4-aminomethylsalicylate as an oil.
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([C:5]([CH2:12][O:13][CH2:14][C:15]3([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)=[CH:6][C:7]([CH3:11])=[CH:8]2)=[N:3]1>FC(F)(F)C(O)=O>[CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([C:5]([CH2:12][O:13][CH2:14][C:15]3([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]3)=[CH:6][C:7]([CH3:11])=[CH:8]2)=[N:3]1
Reactant: Cc1cc(COCC2(c3ccccc3)CCN(C(=O)OC(C)(C)C)CC2)c2nn(C)cc2c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(COCC2(c3ccccc3)CCNCC2)c2nn(C)cc2c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
tert-Butyl 4-(((2,5-dimethyl-2H-indazol-7-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (8 mg, 0.018 mmol) was dissolved in trifluoroacetic acid (25% in dichloromethane, 1.5 mL) and stirred at room temperature for 45 min. The reaction was concentrated, and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol to give 6.8 mg (quant.) as a colorless film. 1H-NMR (CDCl3, 500 MHz) δ 7.73 (s, 1H), 7.41 (m, 2H), 7.35 (m, 2H), 7.22 (m, 2H), 6.84 (s, 1H), 4.82 (s, 2H), 4.15 (s, 3H), 3.54 (s, 2H), 2.91 (m, 2H), 2.75 (m, 2H), 2.33 (s, 3H), 2.18 (m, 2H), 1.98 (m, 2H), 1.50-2.30 (bs, 1H); 13C-NMR (CDCl3, 126 MHz) δ 146.3, 144.6, 131.1, 128.3, 127.4, 127.3, 126.0, 125.7, 122.8, 122.5, 116.9, 79.8, 69.1, 42.8, 42.0, 40.3, 33.5, 21.9. Mass spec.: 350.04 (MH)+. Accurate mass spec.: m/z 350.2230 [MH]+, Δ=0.7 ppm.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[F:21][C:22]([F:41])([F:40])[C:23]1[CH:24]=[C:25]([C:33]2[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=2)[CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1.[OH-].[Na+]>>[F:21][C:22]([F:40])([F:41])[C:23]1[CH:24]=[C:25]([C:33]2[CH:34]=[CH:35][C:36]([O:39][CH2:16][CH2:15][CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=3)=[CH:37][CH:38]=2)[CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1
Reactant: Oc1ccc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cc2)cc1)C(=O)O

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 173, Step A was treated with 3′,5′-Bis-trifluoromethyl-biphenyl-4-ol from Step A under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C (NaOH) to give the title compound. MS(ES) for C27H24F6O5 [M+Na]+: 565, [M+H]+: 543.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]([CH3:10])[C:7](O)=[O:8])=[CH:2]1.S(Cl)([Cl:13])=O>C(Cl)(Cl)Cl>[S:1]1[CH:5]=[CH:4][C:3]([CH:6]([CH3:10])[C:7]([Cl:13])=[O:8])=[CH:2]1
Reactant: CC(C(=O)O)c1ccsc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(C(=O)Cl)c1ccsc1
Reaction time: 0.5 h

Procedure:
The 2-(3-thienyl)propionic acid (22.9 g) was dissolved in chloroform (60 ml), to which was added thionyl chloride (20 g), followed by 30 minutes refluxing. The reaction was carried out in a similar manner to the foregoing Example 9 to obtain 2-(3-thienyl)propionic acid chloride with bp 76°-78° C./2.0 torr.
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5]([C:7]1[C:36](=[O:37])[N:35]([CH:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)[C:10]2[N:11]=[C:12]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[CH:18][N:17]=3)[N:13]=[CH:14][C:9]=2[C:8]=1[CH3:43])=[O:6])[CH3:3].C(OCC)C>C(Cl)Cl.CCO>[ClH:1].[CH2:2]([O:4][C:5]([C:7]1[C:36](=[O:37])[N:35]([CH:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)[C:10]2[N:11]=[C:12]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)=[CH:18][N:17]=3)[N:13]=[CH:14][C:9]=2[C:8]=1[CH3:43])=[O:6])[CH3:3]
Reactant: CCOC(=O)c1c(C)c2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1c(C)c2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n(C2CCCC2)c1=O
Reaction time: 24 h

Procedure:
Anhydrous HCl gas was bubbled through a solution of 2-[5-(4-tert-butoxycarbonyl-piperazin-1-yl)-pyridin-2-ylamino]-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (50 mg, 0.086 mmol, prepared as in Example 30) in CH2Cl2/EtOH at room temperature and the reaction was stirred for 24 h. Diethyl ether was added to the reaction mixture and a solid precipitated which was isolated and dried to 8-cyclopentyl-5-methyl-7-oxo-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester hydrochloride as a yellow solid (12 mg, 29%). mp 216–218° C. M++1:. Calc'd. 478.6, Found 478.1. HPLC, retention time: 5.77 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6]([OH:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:18]([F:23])([F:22])C([O-])=O.[Na+]>CN(C=O)C.O>[Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6]([O:8][CH:18]([F:23])[F:22])[CH:7]=1
Reactant: N#Cc1ncc(O)cc1Cl
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ncc(OC(F)F)cc1Cl
Temperature: 100 °C

Procedure:
To a solution of 3-chloro-5-hydroxy-pyridine-2-carbonitrile (314 mg, 2.03 mmol) in DMF (10 ml) was added K2CO3 (841 mg, 6.09 mmol) and sodium chlorodifluoroacetate (1.29 g, 8.11 mmol) and the reaction mixture was heated at 100° C. for 10 min. The reaction mixture was diluted with H2O and extracted with TBME. Combined extracts were washed with brine, dried over MgSO4, filtered and concentrated. The title compound was obtained as a yellow oil after chromatography on silica gel (hexane-EtOAc 20:1 to 1:1) to provide the title compound as a light yellow oil: TLC (hexane-EtOAc 2:1): Rf=0.54;
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])OC1C=CC=CC=1.Cl.[CH2:20]([O:22][C:23](=[O:26])[CH2:24][NH2:25])[CH3:21]>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:25][CH2:24][C:23]([O:22][CH2:20][CH3:21])=[O:26])=[O:18]
Reactant: CCOC(=O)CN
Reactant: O=C(Nc1ccc(F)cc1F)Oc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)CNC(=O)Nc1ccc(F)cc1F
Temperature: 80 °C
Yield: 88.4 %

Procedure:
Phenyl 2,4-difluorophenylcarbamate (5.0 g) and 4.2 g of glycine ethyl ester hydrochloride were dissolved in 30 ml of pyridine and the solution was heated at 80° C. for 14 hours. The reaction solution was concentrated under reduced pressure and to the residue were added 80 ml of ethyl acetate and 20 ml of water. The ethyl acetate layer was washed with 10 ml of an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Hexane (50 ml) was added to the residue and the solid separated out was collected by filtration to give 4.58 g of N-(2,4-difluorophenyl)-N'-ethoxycarbonylmethylurea as a colorless powder.
Reaction SMILES: COCCOC[O:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([O:29]CC4C=CC=CC=4)=[CH:25][CH:24]=3)[CH:20]=[C:19]([C:37]3[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][CH2:45][O:46]COCCOC)=[CH:39][CH:38]=3)[CH:18]=2)=[CH:13][CH:12]=1>C1COCC1>[OH:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:18]=[C:19]([C:37]3[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][CH2:45][OH:46])=[CH:39][CH:38]=3)[CH:20]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[CH:22]=2)=[CH:15][CH:16]=1
Reactant: COCCOCOCCCc1ccc(-c2cc(-c3ccc(CCCOCOCCOC)cc3)cc(-c3ccc(OCc4ccccc4)cc3)c2)cc1
Solvent: C1CCOC1
Product: OCCCc1ccc(-c2cc(-c3ccc(O)cc3)cc(-c3ccc(CCCO)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.50 g (3.55 mmol) 4,4″-bis-[3-(2-methoxy-ethoxymethoxy)-propyl]-5′-(4-benzyloxyphenyl)-[1,1′;3′,1″]terphenyl are hydrogenated in 70 ml THF on Pd/activated charcoal until the reaction is completed. The catalyst is filtered off, the solvent is removed in vacuo, the residue is dissolved in 20 ml THF, 5 ml 25% hydrochloric acid are added dropwise under cooling and the mixture is stirred overnight at RT. After addition of 100 ml MTB ether the solution is washed with water and sat. aq. sodium chloride solution and dried over sodium sulfate. The solvent is removed in vacuo and the residue is filtered through silica gel with dichloromethane/MTB ether (9:1), to give 3-[4″-(3-hydroxy-propyl)-5′-(4-hydroxyphenyl)-[1,1′;3′,1″]terphenyl-4-yl]-propane-1-ol as colourless oil.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4](NC(=O)OC(C)(C)C)=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C:14]23[O:21][CH:18]([CH2:19]C2)[CH:17]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:16][CH2:15]3)[N:6]=1.[F:40][C@H]1[C@H](NC(=O)OC(C)(C)C)CC[C@@H](C2N(C)N=CC=2[N+]([O-])=O)OC1.BrC1SC=C(C(O)=O)N=1>>[Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@H:14]2[O:21][CH2:19][C@@H:18]([F:40])[C@H:17]([NH:22][C:23](=[O:24])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:16][CH2:15]2)=[O:31])[N:6]=1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1C12CCC(NC(=O)OC(C)(C)C)C(CC1)O2
Agent: O=C(O)c1csc(Br)n1
Product: Cn1ncc(NC(=O)c2csc(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1

Procedure:
Following the procedure for Intermediate 65, starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 80) and replacing 2-bromo-5-(tert-butoxycarbonylamino)thiazole-4-carboxylic acid with 2-bromothiazole-4-carboxylic acid (commercial) gave tert-butyl ((3S,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:2].[C:9](Cl)(=[O:12])[CH:10]=[CH2:11].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:12])[CH:10]=[CH2:11])=[CH:5][CH:4]=1)[CH3:2]
Reactant: C=CC(=O)Cl
Reactant: CCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C=CC(=O)c1ccc(CC)cc1

Procedure:
Ethylbenzene (0.5 mL), acryloyl chloride (120 mg), and aluminium chloride (199 mg) were reacted in dichloromethane (1.5 mL) at from 0° C. to room temperature for 4 hours. The resultant was treated in the same manner as described in Example 1 to obtain the title compound (110 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[OH-].[Na+].Cl[C:15]([F:20])([F:19])C([O-])=O.[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([O:11][CH:15]([F:20])[F:19])[CH:3]=1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: O=[N+]([O-])c1cc(O)cc(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Br)cc(OC(F)F)c1
Temperature: 55 °C
Yield: 4.2 %

Procedure:
To a solution of 3-bromo-5-nitrophenol (3.1 g, 14.4 mmol) and powdered sodium hydroxide (0.63 g, 15.8 mmol) in DMF (14 mL), sodium chlorodifluoroacetate (4.4 g, 28.7 mmol) was added in five portions every 0.5 hour to the warmed reaction mixture at to 55° C. The reaction was maintained at to 55° C. for 1 day and then allowed to cool to room temperature. The reaction mixture was partitioned between EtOAc and water, the layers separated, and the aqueous portion was extracted (2×25 mL) EtOAc and the combined organic layers were washed with aqueous 1.0 M NaOH solution (3×25 mL), water (3×25 mL) and brine (50 mL). The organic layer was dried (MgSO4), and concentrated. The resulting residue was purified by flash chromatography (SiO2, 0-50% EtOAc in hexanes) to afford 1-bromo-3-(difluoromethoxy)-5-nitrobenzene (160 mg, 0.6 mmol). 1H NMR (400 MHz, CDCl3) δ 6.61 (t, J=71.6 Hz, 1H) 7.65 (s, 1H) 7.96 (s, 1H) 8.21-8.31 (m, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[CH:2]1.[CH3:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:13]=1)(=[O:11])=[O:10].N1CCCCC1>C1(C)C=CC=CC=1>[CH3:8][S:9]([C:12]1[CH:13]=[CH:14][C:15](/[C:18](=[CH:6]\[C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)/[C:19]([OH:21])=[O:20])=[CH:16][CH:17]=1)(=[O:10])=[O:11]
Reactant: CS(=O)(=O)c1ccc(CC(=O)O)cc1
Reactant: O=Cc1ccsc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CS(=O)(=O)c1ccc(/C(=C\c2ccsc2)C(=O)O)cc1
Reaction time: 16 h

Procedure:
A mixture of 3-thiophenecarboxaldehyde (1.40 mL, 15.0 mmol), (4-methanesulfonylphenyl)acetic acid (3.23 g, 15.0 mmol), and piperidine (0.45 mL, 4.5 mmol) in PhMe (21 mL) was heated under reflux with stirring for 16 h. On cooling, the PhMe was decanted off from the oily solid that had settled at the bottom of the reaction vessel. This solid was partitioned between 1M HCl (60 mL) and EtOAc (400 mL), then the aqueous phase was extracted further with EtOAc (60 mL). The combined organic layers were washed with H2O (60 mL), before being shaken with saturated aqueous Na2CO3 (100 mL). The resulting emulsion was filtered through Celite. The organic layer was extracted further with saturated aqueous Na2CO3 (2×100 mL). The combined aqueous layers were washed with Et2O (80 mL), before being filtered through Celite and carefully acidified with AcOH to adjust the pH to 4. The off-white precipitate formed was collected, washed thoroughly with H2O, and air dried to furnished the title compound: m/z (ES+)=634.2 [2M+NH4]+.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12](=[O:25])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:14]=1)[CH2:8]2.[CH3:26][O:27][C:28](=[O:32])[CH2:29][CH2:30]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:13]1[N:14]=[C:15]([N:19]3[CH2:20][CH2:21][N:22]([CH2:30][CH2:29][C:28]([O:27][CH3:26])=[O:32])[CH2:23][CH2:24]3)[CH:16]=[CH:17][CH:18]=1)=[O:25])[CH2:8]2
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1cccc(N2CCNCC2)n1
Reactant: COC(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCN1CCN(c2cccc(C(=O)NC3C4CC5CC(C4)CC3C5)n2)CC1
Temperature: 100 °C
Reaction time: 24 h
Yield: 96.1 %

Procedure:
After N-(adamantan-2-yl)-6-(piperazin-1-yl)picolinamide (34 mg, 0.100 mmol) was dissolved in DMF (2 ml), 3-bromopropanoic acid methyl ester (25 mg, 0.150 mmol) and potassium carbonate (41 mg, 0.300 mmol) were added thereto, and then the resulting mixture was stirred at 100° C. under nitrogen stream for 24 hours. The resulting reaction liquid was filtered and concentrated under reduced pressure, and then the residue thus obtained was subjected to MPLC (60% EtOAc/Hexanes), to obtain 41 mg of white solid (96%). MS (ESI): 427 [M+H]+
Reaction SMILES: [OH:1][CH:2]1[CH2:25][NH:24][CH2:23][CH2:22][C:3]21[C:7](=[O:8])[N:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH3:21])[C:17]([F:20])([F:19])[F:18])=[CH:11][CH:10]=1)[CH2:5][CH2:4]2.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33](Cl)(=[O:35])=[O:34]>>[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33]([N:24]1[CH2:23][CH2:22][C:3]2([C:7](=[O:8])[N:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH3:21])[C:17]([F:20])([F:18])[F:19])=[CH:11][CH:10]=3)[CH2:5][CH2:4]2)[CH:2]([OH:1])[CH2:25]1)(=[O:35])=[O:34]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: CC(Oc1ccc(N2CCC3(CCNCC3O)C2=O)cc1)C(F)(F)F
Product: CC(Oc1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4Cl)CC3O)C2=O)cc1)C(F)(F)F

Procedure:
The title compound was prepared in analogy to example 2 step B from a mixture of (5SR,6RS)-6-hydroxy-2-[4-((rac)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one and 2-chloro-benzenesulfonyl chloride. Light yellow solid. MS (ESI): 533.1 (MH+)
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[CH:7][C:8]([N:11]2[CH2:15][C@@:14]3([CH2:20][CH2:19][CH2:18][C@@:17]([CH2:22][N:23]4[C:27]5[CH:28]=[C:29]([C:32]#[N:33])[CH:30]=[CH:31][C:26]=5[N:25]=[CH:24]4)([CH3:21])[CH2:16]3)[O:13][C:12]2=[O:34])=[N:9][CH:10]=1)([CH3:4])[CH3:3].[H-].[Na+].[CH3:37]I>CN(C)C=O>[CH3:37][O:1][C:2]([C:5]1[N:6]=[CH:7][C:8]([N:11]2[CH2:15][C@@:14]3([CH2:20][CH2:19][CH2:18][C@@:17]([CH2:22][N:23]4[C:27]5[CH:28]=[C:29]([C:32]#[N:33])[CH:30]=[CH:31][C:26]=5[N:25]=[CH:24]4)([CH3:21])[CH2:16]3)[O:13][C:12]2=[O:34])=[N:9][CH:10]=1)([CH3:3])[CH3:4]
Reactant: CI
Reactant: CC(C)(O)c1cnc(N2C[C@@]3(CCC[C@](C)(Cn4cnc5ccc(C#N)cc54)C3)OC2=O)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(C)(C)c1cnc(N2C[C@@]3(CCC[C@](C)(Cn4cnc5ccc(C#N)cc54)C3)OC2=O)cn1
Reaction time: 0.17 h
Yield: 58.2 %

Procedure:
To a solution of 1-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (75 mg, 0.163 mmol) in N,N-Dimethylformamide (DMF) (1 mL) was added sodium hydride (9.77 mg, 0.244 mmol) at RT. After 10 minutes, MeI (0.020 mL, 0.326 mmol) was added. The mixture stirred for an hour and was purified by reverse phase HPLC (Waters Sunfire 30×150 mm Acetonitrile:Water 0.1% TFA 30-70%, 50 mL/min, 15 min). The product was free based with PL-HCO3 resin SPE to yield 1-(((5S,7S)-3-(5-(2-methoxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile as a white powder (45 mg, 58%). 1H NMR (400 MHz, DMSO-d6) δ 9.25 (d, J=1.51 Hz, 1H), 8.47-8.53 (m, 2H), 8.39 (d, J=1.00 Hz, 1H), 7.84 (d, J=8.78 Hz, 1H), 7.60 (dd, J=8.53, 1.51 Hz, 1H), 4.17 (s, 2H), 3.88 (dd, J=23.09, 10.29 Hz, 2H), 3.09 (s, 3H), 2.00 (d, J=14.05 Hz, 1H), 1.89 (d, J=14.56 Hz, 1H), 1.59-1.78 (m, 3H), 1.30-1.56 (m, 9H), 1.08 (s, 3H). MS (m/z) 443.2 (M-OMe).