Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=[O:11].C(N(CC)C(C)C)(C)C.[C:22]([O:25][CH2:26]Br)(=[O:24])[CH3:23].CCC(OBr)=O>C(#N)C>[C:22]([O:25][CH2:26][O:11][C:10](=[O:12])[CH2:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])(=[O:24])[CH3:23]
Reactant: CC(=O)OCBr
Reactant: O=C(O)Cc1ccc(I)cc1F
Agent: CCC(=O)OBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(=O)OCOC(=O)Cc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
A solution of 2-fluoro-4-iodo phenyl acetic acid (described in U.S. Pat. No. 6,252,090, incorporated herein by reference; 0.82 g, 2.93 mmol) in anhydrous acetonitrile (10 mL) was treated with N,N-diisopropyl ethyl amine (1.27 mL, 7.32 mmol) followed by acetoxy methyl bromide/bromo methylacetate (0.896 g, 5.86 mmol) and the resulting reaction mixture was stirred overnight at ambient temperature. The volatiles were evaporated in vacuo and the residue was diluted with water and extracted with diethyl ether (×2). The combined organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to an oil that was subjected to flash column chromatography over silica gel (230-400 mesh) using 10-20% ethyl acetate in hexane as the eluent to afford the title compound as an oil (0.75 g, 72%). 1H NMR (300 MHz, CDCl3): 7.42 (m, 2H), 6.97 (dd, J=8.0 & 8.0 Hz, 1H), 5.73 (s, 2H), 3.65 (s, 2H), 2.08 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:7][N:8]2[C:12](=[O:13])[O:11][N:10]=[C:9]2[C:14]2[C:18]([NH:19][CH2:20][CH2:21][OH:22])=[N:17][O:16][N:15]=2)[O:5][CH:6]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:23][S:24]([O:22][CH2:21][CH2:20][NH:19][C:18]1[C:14]([C:9]2[N:8]([CH2:7][C:4]3[O:5][CH:6]=[C:2]([Br:1])[CH:3]=3)[C:12](=[O:13])[O:11][N:10]=2)=[N:15][O:16][N:17]=1)(=[O:26])=[O:25]
Reactant: O=c1onc(-c2nonc2NCCO)n1Cc1cc(Br)co1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCNc1nonc1-c1noc(=O)n1Cc1cc(Br)co1
Reaction time: 0.08 h
Yield: 100 %

Procedure:
To a solution of 4-[(4-bromo-2-furyl)methyl]-3-{4-[(2-hydroxyethyl)amino]-1,2,5-oxadiazol-3-yl}-1,2,4-oxadiazol-5(4H)-one (7.7 g, 21 mmol, containing also some of the corresponding bromo-compound) in ethyl acetate (100 mL) was added methanesulfonyl chloride (0.96 mL, 12 mmol) in one portion. The reaction was stirred for 5 minutes and triethylamine (1.6 mL, 11 mmol) was added, also in one portion. After stirring for 30 minutes, additional methanesulfonyl chloride (0.4 mL, 5 mmol) was added, followed 5 minutes later by triethylamine (0.58 mL, 4.2 mmol). After 15 minutes, the reaction was quenched with the addition of water (100 mL). The product was extracted with ethyl acetate (3×50 mL) and the combined organic layers washed with brine (100 mL). After drying over sodium sulfate, the solvent was removed in vacuo to give the desired product (9.3 g, 100%). LCMS calculated for C12H13BrN5O7S (M+H)+: m/z=449.8, 451.8. 1H NMR (300 MHz, DMSO-d6): δ 7.88 (s, 1H), 6.73 (t, J=6.2 Hz, 1H), 6.68 (s, 1H), 5.08 (s, 2H), 4.37 (m, 2H), 3.59 (q, J=5.8 Hz, 2H), 3.16 (s, 3H).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[N-:5]=[C:6]=[O:7].C[N:9]1CCC[C:10]1=[O:14]>>[CH2:1]([NH:4][C:10]([NH2:9])=[O:14])[CH2:2][NH:3][C:6]([NH2:5])=[O:7]
Reactant: NCCN
Reactant: CN1CCCC1=O
Reactant: [N-]=C=O
Product: NC(=O)NCCNC(N)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.88 g of ethylenediamine (0.031 mol) were added dropwise at room temperature with stirring to 100 ml of a solution of 10 g of triethylammonum isocyanate (0.069 mol) in 100 ml of N-methylpyrrolidone, prepared according to the procedure described in example 1. After stirring at room temperature for 24 hours, the reaction mixture was heated to reflux for one hour, the solvent was evaporated and the residue was recrystallized from water. 3.4 g, i.e. 75% of theory, of ethylenediurea were obtained in this way.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]#[N:8].S(Cl)([Cl:12])(=O)=O>C1(C)C=CC=CC=1.CN(C)C=O>[Cl:12][C:3]1[C:2]([C:7]#[N:8])=[N:1][CH:6]=[CH:5][N:4]=1
Reactant: N#Cc1cnccn1
Reactant: O=S(=O)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: N#Cc1nccnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
Pyrazine-2-carbonitrile (26.36 g) is dissolved in toluene (187 ml)/N,N-dimethylformamide (19 ml), and thereto is added dropwise sulfuryl chloride (135 g) under ice-cooling. After completion of addition, the reaction solution is warmed to room temperature gradually and stirred overnight. The toluene layer is separated and the residual red oil is extracted with diethyl ether. The organic layers are combined, cooled with ice, and after pouring thereto ice-water, neutralized by adding saturated aqueous sodium hydrogen carbonate solution. The organic layer is separated, and aqueous layer is extracted with diethyl ether. The organic layers are combined, washed with water, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=4/1) to give the title compound (16.58 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:27])[CH2:17][CH2:16]4)[C@H:13]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:44][C:45]([F:60])([C:56]([F:59])([F:58])[F:57])[CH2:46][CH2:47][CH2:48][S:49][CH2:50][C@@H:51]1[CH2:55][CH2:54][CH2:53][NH:52]1>CCCCCC.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:27])[CH2:17][CH2:16]4)[C@H:13]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][N:52]3[CH2:53][CH2:54][CH2:55][C@H:51]3[CH2:50][S:49][CH2:48][CH2:47][CH2:46][C:45]([F:44])([F:60])[C:56]([F:57])([F:58])[F:59])[CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCCC[C@@H]2Cc3cc(OCc4ccccc4)ccc3[C@H]3CC[C@]4(C)C(=O)CC[C@H]4[C@H]23)cc1
Reactant: FC(F)(F)C(F)(F)CCCSC[C@@H]1CCCN1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4C[C@@H](CCCCCN4CCC[C@H]4CSCCCC(F)(F)C(F)(F)F)[C@H]3[C@@H]1CCC2=O
Yield: 72.5 %

Procedure:
Under the conditions of Example 23h, 4.58 g of 3-benzyloxy-7α-(5-tosyloxypentyl)-estra-1,3,5(10)-trien-17-one is reacted with 3.17 g of (2S)-2-(4,4,5,5,5-pentafluoropentylthiomethyl)-pyrrolidine, worked up, and the crude product is chromato-graphed on silica gel with hexane/ethyl acetate. 3.9 g of 3-benzyloxy-7α-{5-[(2S)-2-(4,4,5,5,5-pentafluoropentyl-thiomethyl)-pyrrolidin-1-yl]-pentyl}-estra-1,3,5(10)-trien-17-one is obtained as oil. [α]D22 =+32.5° (c=0.117 in chloroform).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([N:13]2[CH2:18][CH2:17][N:16](C(OCC3C=CC=CC=3)=O)[CH2:15][CH2:14]2)[S:11][CH:12]=1.B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([N:13]2[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]2)[S:11][CH:12]=1
Reactant: O=C(OCc1ccccc1)N1CCN(c2nc(-c3ccccc3F)cs2)CC1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Fc1ccccc1-c1csc(N2CCNCC2)n1
Temperature: -50 °C
Reaction time: 0.33 h

Procedure:
To a solution of benzyl 4-(4-(2-fluorophenyl)thiazol-2-yl)piperazine-1-carboxylate (0.85 g, 2.1 mmol) in CH2Cl2 (2 mL) cooled to −50° C. was added boron tribromide (1 M in CH2Cl2, 8.6 mL, 8.6 mmol). The reaction was stirred at −50° C. for 20 min and then carefully quenched with saturated aqueous NaHCO3. The mixture was extracted with CH2Cl2, and the combined extracts were washed with water, dried over Na2SO4, and concentrated under reduced pressure to yield 1-(4-(2-fluorophenyl)thiazol-2-yl)piperazine. LC/MS: m/z 264.1 (M+H)+ at 2.04 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]#[N:9].[Br:10][CH2:11][C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13].CCOCC>C(#N)C.CO>[Br-:10].[N:14]1([C:12](=[O:13])[CH2:11][N+:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[CH2:7][C:8]#[N:9])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C(CBr)N1CCCC1
Reactant: N#CCc1ccccn1
Solvent: CC#N
Solvent: CO
Solvent: CCOCC
Product: N#CCc1cccc[n+]1CC(=O)N1CCCC1
Product: [Br-]
Reaction time: 72 h
Yield: 34.3 %

Procedure:
2-Pyridineacetonitrile (0.8 g, 6.77 mmole) and 1-(bromoacetyl)pyrrolidine (1.3 g, 6.77 mmole) were warmed to melt the 1-(bromoacetyl)pyrrolidine, then stirred at room temp. for 3 days. The mixture was dissolved in acetonitrile (5 mL) and ether (2 mL) and stored at 4 C for 3 days. The crystals which separated were filtered out to yield a crude product which was dissolved in methanol, decolorized, evaporated, and the residue triturated with 30% ether-acetonitrile to obtain 0.72 g of the title compound, mp 150–152 C.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]1([C:11]2[C:19]3[C:18]([N:20]4[CH2:25][CH2:24][CH:23]([C:26](O)=[O:27])[CH2:22][CH2:21]4)=[N:17][CH:16]=[N:15][C:14]=3[S:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:29][N:30]1[CH2:34][CH2:33][CH2:32][CH:31]1[CH2:35][CH2:36][NH2:37].C(N(CC)CC)C>C(Cl)Cl>[CH3:29][N:30]1[CH2:34][CH2:33][CH2:32][CH:31]1[CH2:35][CH2:36][NH:37][C:26]([CH:23]1[CH2:22][CH2:21][N:20]([C:18]2[C:19]3[C:11]([C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)=[CH:12][S:13][C:14]=3[N:15]=[CH:16][N:17]=2)[CH2:25][CH2:24]1)=[O:27]
Reactant: CN1CCCC1CCN
Reactant: O=C(O)C1CCN(c2ncnc3scc(-c4ccccc4)c23)CC1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCCC1CCNC(=O)C1CCN(c2ncnc3scc(-c4ccccc4)c23)CC1
Reaction time: 0.5 h

Procedure:
Thionyl chloride (26 μL, 0.35 mmol) was added to (1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (100 mg, 0.294 mmol) in dry DCM at 0° C. The reaction was stirred for 30 min then 2-(1-methylpyrrolidin-2-yl)ethanamine (173 μL, 0.294 mmol) and triethylamine (82 μL, 0.588 mmol) were added and the reaction stirred for a further 10 min at 0° C. and then stirred at room temperature for 1 hr. The reaction was reduced to dryness in vacuo and the residue purified by prep HPLC (Basic, method F) to give the desired compound as an off-white solid. Yield=70 mg. LCMS [M+H]+=450; RT=3.01 min
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([O:16][CH2:17][CH3:18])[CH2:5][C:6]1[C:11]2[S:12][CH:13]=[CH:14][C:10]=2[C:9]([OH:15])=[CH:8][CH:7]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:29][C:30]([CH3:36])=[C:31]([CH2:33][CH2:34]O)[N:32]=2)=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([O:16][CH2:17][CH3:18])[CH2:5][C:6]1[C:11]2[S:12][CH:13]=[CH:14][C:10]=2[C:9]([O:15][CH2:34][CH2:33][C:31]2[N:32]=[C:28]([C:25]3[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=3)[O:29][C:30]=2[CH3:36])=[CH:8][CH:7]=1
Reactant: COc1ccc(-c2nc(CCO)c(C)o2)cc1
Reactant: CCOC(Cc1ccc(O)c2ccsc12)C(=O)OC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(Cc1ccc(OCCc2nc(-c3ccc(OC)cc3)oc2C)c2ccsc12)C(=O)OC

Procedure:
In analogy to the procedure described in example 17 a], [rac]-2-ethoxy-3-(4-hydroxy-benzo[b]thiophen-7-yl)-propionic acid methyl ester was reacted with 2-[2-(4-methoxy-phenyl)-5-methyl-oxazol-4-yl]-ethanol [J. Med. Chem. (1998), 41(25), 5037-5054] in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-2-ethoxy-3-(4-{2-[2-(4-methoxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-benzo[b]thiophen-7-yl)-propionic acid methyl ester, which was further saponified in analogy to the procedure described in example 91 e] to yield [rac]-2-ethoxy-3-(4-{2-[2-(4-methoxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy]-benzo[b]thiophen-7-yl)-propionic acid as colorless amorphous solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[S:6].[Br:7][CH2:8][C:9]([C:11]1([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[CH2:14][CH2:13][CH2:12]1)=[O:10]>CC(C)=O>[BrH:7].[Cl:22][C:17]1[CH:16]=[C:15]([C:11]2([C:9](=[O:10])[CH2:8][S:6][C:2]3[NH:1][CH2:5][CH2:4][N:3]=3)[CH2:14][CH2:13][CH2:12]2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: S=C1NCCN1
Reactant: O=C(CBr)C1(c2ccc(Cl)c(Cl)c2)CCC1
Solvent: CC(C)=O
Product: Br
Product: O=C(CSC1=NCCN1)C1(c2ccc(Cl)c(Cl)c2)CCC1
Temperature: 25 °C
Yield: 87.2 %

Procedure:
A solution of imidazolidine-2-thione (4.5 g) in acetone (750 ml ) was added to a solution of 2-bromo-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethanone (15 g) in acetone (125 ml), then the stirred mixture was heated under reflux for 10 minutes, and allowed to cool to ambient temperature. The resulting solid was collected by filtration, washed with ethanol (50 ml) and dried in vacuo at 60° C. for 4 hours to give 1-[1-(3,4-dichlorophenyl)cyclobutyl]-2-(2-imidazolin-2-ylthio)ethanone hydrobromide as a white solid (16.3 g), m.p. 156-158° C.
Reaction SMILES: [CH2:1]([OH:6])[CH:2]([OH:5])[CH2:3][CH3:4].[CH3:7][CH:8](O)[CH:9]([OH:11])[CH3:10].ClC(Cl)(Cl)C(C(Cl)(Cl)Cl)=O.[C:23]([O-:26])([O-:25])=[O:24].[K+].[K+]>>[C:9]1(=[O:11])[O:5][CH:2]([CH2:3][CH3:4])[CH2:1][O:6]1.[C:23]1(=[O:26])[O:25][CH:9]([CH3:10])[CH:8]([CH3:7])[O:24]1
Reactant: CCC(O)CO
Reactant: O=C([O-])[O-]
Reactant: CC(O)C(C)O
Agent: O=C(C(Cl)(Cl)Cl)C(Cl)(Cl)Cl
Agent: [K+]
Product: CC1OC(=O)OC1C
Product: CCC1COC(=O)O1

Procedure:
Similarly, 1,2-butanediol and 2,3-butanediol were heated with equivalent quantities of hexachloroacetone in the presence of K2CO3 or other such basic catalyst as previously defined to produce comparable yields of 1,2-butylene carbonate and 2,3-butylene carbonate, respectively. Also, 3-chloro-1,2-propanediol was reacted in this way with hexachloroacetone to make 4-(chloromethyl)-1,3-dioxol-2-one (chloromethylethylene carbonate). In the same way, styrene glycol (1-phenyl-1,2-ethanediol) is reacted with hexachloroacetone in the presence of a basic catalyst to produce 1-phenylethylene carbonate (4-phenyl-1,3-dioxol-2-one), 1,2-hexanediol is reacted with hexachloroacetone to produce 1,2-hexylene carbonate (4-butyl-1,3-dioxol-2-one), and 1-cyclohexyl-1,2-ethanediol is reacted with hexachloroacetone to make 4-cyclohexyl-1,3-dioxol-2-one (cyclohexylethylene carbonate).
Reaction SMILES: [CH3:1][C:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([CH3:25])[CH:17]=2)=[N:4][N:3]=1.[C:26](Cl)(=[O:28])[CH3:27]>>[C:26]([N:3]1[C:2]([CH3:1])=[CH:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([CH3:25])[CH:17]=2)=[N:4]1)(=[O:28])[CH3:27]
Reactant: CC1=NN=C(c2ccc([N+](=O)[O-])c(C)c2)c2cc3c(cc2C1)OCO3
Reactant: CC(=O)Cl
Product: CC(=O)N1N=C(c2ccc([N+](=O)[O-])c(C)c2)c2cc3c(cc2C=C1C)OCO3
Yield: 69 %

Procedure:
A mixture of 3.37 g (10.0 millimoles) of 8-methyl-5-(3-methyl-4-nitro-phenyl)-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepine and 25 ml acetyl chloride is stirred under boiling for 3 hours, whereupon the acid chloride is distilled off in vacuo. The residue is taken up in 100 ml of dichloro methane, washed with 50 ml of a saturated sodium carbonate solution and 50 ml of water. The organic phase is dried over magnesium sulfate and evaporated in vacuo. The crude product obtained is recrystallized from 50 ml of acetonitrile. Thus 2.62 g of the desired compound are obtained, yield 69%, mp.: 115–116° C.
Reaction SMILES: [CH:1]1[C:6](=CN=O)[CH:5]=[CH:4][NH:3][CH:2]=1.Cl[N:11]1[C:15](=O)[CH2:14][CH2:13][C:12]1=O.[CH2:18]([O:20]CC)[CH3:19].O>CN(C=O)C>[N:11]1([C:6]2[CH2:1][CH2:2][N:3]([C:18](=[O:20])[CH3:19])[CH2:4][CH:5]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOCC
Reactant: O=NC=C1C=CNC=C1
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N1CC=C(N2CCCC2)CC1
Temperature: 25 °C

Procedure:
Pyridine-4-carbaldoxime (1 g, 8.19 mmol) was dissolved in DMF (10 ml), a solution of N-chlorosuccinimide (1.31 g, 9.83 mmol) in DMF (5 ml) was slowly added dropwise and the reaction mixture was stirred at room temperature. When the reaction was complete (thin layer chromatography control, here 6 h), diethyl ether (50 ml) and water (20 ml) were added, phase separation, extraction of the aqueous phase with diethyl ether (5×30 ml). The combined organic phases were washed with water (50 ml) and saturated sodium chloride solution (50 ml), dried (MgSO4) and concentrated in vacuo. The crude yield was reacted without further purification and analysis. The yield was 0.74 g (>99%).
Reaction SMILES: C([C:4]1[CH:9]=[C:8]([CH:10]([NH2:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[O:20][CH3:21])C=C.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=O)[CH3:30])=[C:25]([F:32])[CH:24]=1>>[F:32][C:9]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[O:20][CH3:21])[CH:6]=[CH:7][C:8]=1[CH:10]([NH2:12])[CH3:11].[Br:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]([NH2:12])[CH3:30])=[C:25]([F:32])[CH:24]=1
Reactant: C=CCc1cc(C(C)N)ccc1-c1cc(F)ccc1OC
Reactant: CC(=O)c1ccc(Br)cc1F
Product: CC(N)c1ccc(Br)cc1F
Product: COc1ccc(F)cc1-c1ccc(C(C)N)c(F)c1

Procedure:
1-(3,5′-Difluoro-2′-methoxy-biphenyl-4-yl)-ethylamine was prepared in a similar manner to 1-(2-allyl-5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethylamine (Example 34) using 4′-bromo-2′-fluoroacetophenone to give 1-(4-bromo-2-fluoro-phenyl)-ethylamine. To a solution of 1-(3,5′-difluoro-2′-methoxy-biphenyl-4-yl)-ethylamine (20.0 mg, 0.08 mmol) in dichloromethane (1 ml) was added triethylamine (8.1 mg, 0.08 mmol) and 1-methyl-3-trifluoromethyl-1H-pyrazole-4-sulfonyl chloride (14.2 mg, 0.06 mmol). The solution was stirred overnight then the solvent evaporated and the residue purified by flash chromatography over silica gel eluting with dichloromethane. Evaporation of solvent under reduced pressure gave the title compound (20 mg). 1H NMR (400 MHz, CDCl3): δ 7.51 (s, 1H), 7.21-7.16 (m, 2H), 7.14-7.09 (m, 1H), 7.05-6.95 (m, 2H), 6.93-6.88 (m, 1H), 5.11 (d, 1H), 4.76 (dq, 1H), 3.81 (s, 3H), 3.73 (s, 3H), 1.55 (d, 3H) ppm; MS (ESI) m/z: 498.3 [M+Na]+.
Reaction SMILES: [BH4-].[Na+].FC(F)(F)C(O)=O.C(O)(=O)C.[CH3:14][O:15][C:16]1[C:17]([CH3:31])=[C:18]2[C:23](=[CH:24][C:25]=1[CH3:26])[NH:22][C:21]1([CH2:29][CH2:28][CH2:27]1)[CH2:20][CH:19]2O>C1COCC1>[CH3:14][O:15][C:16]1[C:17]([CH3:31])=[C:18]2[C:23](=[CH:24][C:25]=1[CH3:26])[NH:22][C:21]1([CH2:27][CH2:28][CH2:29]1)[CH2:20][CH2:19]2
Reactant: COc1c(C)cc2c(c1C)C(O)CC1(CCC1)N2
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: COc1c(C)cc2c(c1C)CCC1(CCC1)N2
Reaction time: 0.5 h

Procedure:
To a mixture of NaBH4 (1 g) added in portions to a solution of cooled trifluoroacetic acid and acetic acid (30 mL, v/v: 1/1), was added 6′-methoxy-5′,7′-dimethyl-3′,4′-dihydro-1′H-spiro[cyclobutane-1,2′-quinolin]-4′-ol in 10 mL THF. After 30 minutes, the reaction mixture was quenched with water and extracted with ethyl acetate (3×20 mL). The organic layer was dried with Na2SO4, evaporated, and purified by column chromatography (1-2% methanol in CH2Cl2), to give 6′-methoxy-5′,7′-dimethyl-3′,4′-dihydro-1′H-spiro[cyclobutane-1,2′-quinoline] as a brown oil (500 mg).
Reaction SMILES: CC1C=CC(S)=CC=1.C(N(CC)CC)C.[Cl:16][C:17]1[S:18][C:19]([S:23](Cl)(=[O:25])=[O:24])=[CH:20][C:21]=1[Cl:22].O>ClCCl>[Cl:16][C:17]1[S:18][C:19]([S:23]([OH:25])=[O:24])=[CH:20][C:21]=1[Cl:22]
Reactant: O=S(=O)(Cl)c1cc(Cl)c(Cl)s1
Agent: Cc1ccc(S)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=S(O)c1cc(Cl)c(Cl)s1
Temperature: 78 °C
Reaction time: 2 h
Yield: 66.9 %

Procedure:
A solution of p-thiocresol (4.94 g, 39.8 mmol), triethylamine (5.55 mL, 39.8 mmol) in dichloromethane (30 mL) was added dropwise over 12 minutes to a solution of 2,3-dichlorothiophene-5-sulfonyl chloride (5.0 g, 19.9 mmol) in dichloromethane (50 mL) at -78° C. under a dry nitrogen atmosphere. An additional 10 mL of dichloromethane was added and the reaction mixture was stirred at-78° C. for 2 h and then warmed to room temperature over 20 minutes. The reaction mixture was poured into water (400 mL) and the layers were separated. The dichloromethane phase was washed with water (2×200 mL) and the combined aqueous phase was acidified with concentrated HCl. Solid NaCl was also added to the aqueous phase which was then extracted with ether (4×200 mL). The extracts were combined and dried (Na25SO4) and concentrated to afford 2,3-dichlorothiophene-5-sulfinic acid as a white solid (2.89 g, 67%): NMR (DMSO, d 6): δ 9.1 (broad s, 1H, O H), 7.54 (s, 1H, thiophene H); MS(EI): 216, 218, 220 (70, 50, 10%, MI), 199, 201, 203 (60, 50, 10%,--OH), 169 (50%), 167 (70%), 154 (70%), 152 (100%).This ulfinic acid (2.33 g, 10.73 mmol) was dissolved in a solution of sodium hydroxide (0.42 g, 10.73 mmol) in methanol (25 mL) at room temperature. The methanol was removed and residual water was removed by azeotroping with benzene to provide 2,3-dichlorothiophene-5-sulfinic acid, sodium salt of formula (IV) as a whir solid (2.57 g, 100%): NMR (DMSO, d6): δ 6.89 (s, 1H, thiophene H); Anal. Calc. for C4HCl2O2S2 : C, 20.09; H, 0.41; Found: C, 19.80; H, 0.52. This sulfinic acid, sodium salt of formula (IV) (2.12 g, 8.87 mmol) was mixed with 5-bromo-thiazolidine-2,4-dione (1.58 g, 8.06 mmol) and Aliquat 336 (tricaprylylmethylammonium chloride, 0.45 mL) and allowed to stand overnight. Dilute aqueous HCl (100 mL) was added and the aqueous reaction mixture was extracted with ethyl acetate (2×100 mL). The combined extracts were washed with brine and concentrated. The crude product was purified by flash chromatography using acid washed (2% H3PO4 in methanol) silica gel and 82:18 ethyl acetate: petroleum ether as eluant to provide the title compound of formula (V) as a white solid: mp 176°-177° C: NMR (DMSO, d 6): δ 13.0 (broad s, 1H,N H), 8.10 (s, 1H, thiophene H); 6.85 (s, 1H, C H); MS(E1): 331,333, 335 (30, 20, 5%, MI), 215, 217, 219 (100, 70, 15%); Anal. Calc. for C7H3Cl2NO4S3 : C, 25.31; H, 0.91; N, 4.22; Found: C, 25.83; H, 1.00; N, 4.23.
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([CH:10]([C:12]2[CH:25]=[C:24]3[C:15]([O:16][CH2:17][CH2:18][N:19]4[C:23]3=[N:22][C:21]([C:26]3[N:30]([CH:31]([CH3:33])[CH3:32])[N:29]=[CH:28][N:27]=3)=[CH:20]4)=[CH:14][CH:13]=2)[CH3:11])[CH2:7]1)(=O)=O.[CH3:34][NH:35][CH3:36]>O1CCOCC1>[CH:31]([N:30]1[C:26]([C:21]2[N:22]=[C:23]3[C:24]4[CH:25]=[C:12]([CH:10]([N:8]5[CH2:7][CH:6]([N:35]([CH3:36])[CH3:34])[CH2:9]5)[CH3:11])[CH:13]=[CH:14][C:15]=4[O:16][CH2:17][CH2:18][N:19]3[CH:20]=2)=[N:27][CH:28]=[N:29]1)([CH3:32])[CH3:33]
Reactant: CC(c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)cn1CCO2)N1CC(OS(C)(=O)=O)C1
Reactant: CNC
Solvent: C1COCCO1
Product: CC(c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)cn1CCO2)N1CC(N(C)C)C1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of 1-(1-{4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaen-13-yl}ethyl)azetidin-3-yl methanesulfonate from Example 162 (70 mg, 0.15 mmol) and dimethylamine (68 mg, 1.5 mmol) in 1,4-dioxane (4 mL) was stirred at 80° C. for 16 h under nitrogen atmosphere. After concentration, the residue was purified by reverse phase Combiflash eluting with a 0-50% gradient of CH3CN in 0.3% NH4HCO3 to give 168. The enantiomers were separated by chiral HPLC (OJ-H column, 2% EtOH (0.1% DEA) in n-hexane isocratic) to give: 9 mg of one enantiomer and 5 mg of the other (23% total yield).