Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[N:14]=2)[CH:11]=1)CCC.[I:30]I.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[OH:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2[N:14]=[C:9]3[CH:8]=[N:7][C:6]([I:30])=[CH:11][N:10]3[CH:12]=2)=[CH:16][CH:17]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cc(-c3ccc(O)cc3)nc2cn1
Reactant: II
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Oc1ccc(-c2cn3cc(I)ncc3n2)cc1
Temperature: 0 °C
Reaction time: 30 h
Yield: 61.9 %

Procedure:
314 mg (corresponding to 0.628 mmol) of 6-tributylstannyl-2-[4′-hydroxyphenyl]imidazo[1,2-a]pyrazine obtained from Example II-2 was dissolved in 5.0 mL of dichloromethane, to which 114 mg (corresponding to 0.942 mmol) of iodine dissolved in 5.0 mL of dichloromethane was added. The reaction mixture was stirred at the temperature of 0° C. for 10 minutes and at room temperature for 30 hours. Then, a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium thiosulfate solution were added thereto. Precipitates were filtered and recovered, washed with water and ethyl acetate in this order, and dried under reduced pressure, to obtain 131 mg (corresponding to 0.389 mmol) of 2-(4′-hydroxyphenyl)-6-iodoimidazo[1,2-a]pyrazine (FIG. 12, Step 1).
Reaction SMILES: FC(S(O[C:9]1[CH2:14][CH2:13][C:12]([C:29]#[N:30])([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:16]=2)[CH2:11][CH:10]=1)(=O)=O)(F)F.C(N(CC)CC)C.[CH3:38][OH:39].CN(C)[CH:42]=[O:43]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:29]([C:12]1([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)[CH:16]=2)[CH2:13][CH2:14][C:9]([C:38]([O:43][CH3:42])=[O:39])=[CH:10][CH2:11]1)#[N:30]
Reactant: CO
Reactant: COc1ccc(C2(C#N)CC=C(OS(=O)(=O)C(F)(F)F)CC2)cc1OC1CCCC1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)C1=CCC(C#N)(c2ccc(OC)c(OC3CCCC3)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
To a solution of 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-1-cyclohexenyl trifluoromethylsulfonate (1.0 g, 2.24 mmol) in 1:1 methanol/N,N-dimethylformamide (8 mL) were added triethylamine (0.66 mL, 4.72 mmol) and tetrakis(triphenylphosphine)palladium (0.13 g, 0.11 mmol). The resulting mixture was stirred at room temperature in the dark under a carbon monoxide atmosphere for 3 h. The mixture was partitioned between water and ethyl acetate, the organic extract was washed three times with water, once with brine, was dried (potassium carbonate) and was evaporated. Purification by flash chromatography, eluting with 3:1 hexanes/ethyl acetate, provided an off-white solid (0.64 g, 80%): m.p. 128°-129° C.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:25]=[CH:24][C:12]([O:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[C:11]([C:26]([F:29])([F:28])[F:27])[CH:10]=2)O1.[NH2:31][C:32]1[C:33]([C:41]#[N:42])=[N:34][C:35](Cl)=[CH:36][C:37]=1[NH:38][CH3:39].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>O1CCOCC1.C(OCC)(=O)C.O>[NH2:31][C:32]1[C:37]([NH:38][CH3:39])=[CH:36][C:35]([C:9]2[CH:25]=[CH:24][C:12]([O:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[C:11]([C:26]([F:27])([F:28])[F:29])[CH:10]=2)=[N:34][C:33]=1[C:41]#[N:42]
Reactant: CC(C)(C)OC(=O)NCCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1C(F)(F)F
Reactant: CNc1cc(Cl)nc(C#N)c1N
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CNc1cc(-c2ccc(OCCNC(=O)OC(C)(C)C)c(C(F)(F)F)c2)nc(C#N)c1N

Procedure:
tert-Butyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)-phenoxy)ethylcarbamate (4.34 mmol, 1.87 g), 3-amino-6-chloro-4-(methylamino)-picolinonitrile (4.34 mmol, 0.792 g), potassium phosphate (13.01 mmol, 2.76 g), tricyclohexylphosphine (0.520 mmol, 0.146 g), and tris(dibenzylacetone)dipalladium (0) (0.217 mmol, 0.199 g) were dissolved in Dioxane (20 ml) and Water (10.00 ml) and stirred under nitrogen at 100° C. for 2 hrs. The mixture was diluted with ethyl acetate and filtered through celite. Organic layer was washed with water and separated from the aqueous layer, the organic layer was concentrated in vacuo. This was purified by silica chromatography, eluting with heptane—50/50 heptane/EtOAc to afford tert-butyl 2-(4-(5-amino-6-cyano-4-(methylamino)pyridin-2-yl)-2-(trifluoro-methyl)phenoxy)ethylcarbamate. (0.51 g)
Reaction SMILES: [OH-].[K+].[F:3][C:4]([F:22])([F:21])[C:5]1[CH:6]=[C:7]2[CH:13]=[CH:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[C:8]2=[N:9][CH:10]=1.CC[C:25]([O-:27])=[O:26]>O.C(O)C>[F:22][C:4]([F:21])([F:3])[C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:25]([OH:27])=[O:26])[N:11]([CH2:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[C:8]2=[N:9][CH:10]=1
Reactant: FC(F)(F)c1cnc2c(ccn2Cc2ccncc2)c1
Reactant: CCC(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc2cc(C(F)(F)F)cnc2n1Cc1ccncc1
Reaction time: 4 h
Yield: 73.4 %

Procedure:
A solution of 0.39 g (6.87 mmol) of potassium hydroxide in 2 mL of water is added to a solution, in 30 mL of ethanol, of 0.8 g (2.29 mmol) of 5-trifluoromethyl-1-[(4-pyridyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-ethyl carboxylate, obtained in Stage 9.1. The mixture is stirred for four hours under reflux. After this time the reaction mixture is concentrated at reduced pressure, and is then taken up in 40 mL of water. The reaction mixture is acidified to pH 5 by successive additions of concentrated hydrochloric acid. The precipitate is collected by filtration, washed with water and then dried at reduced pressure. In this way we isolate 0.54 g of the expected product, in the form of a white powder, which is used as it is in the next stage.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH2:11])[C:7]=1[C:8](O)=[O:9].[OH-].[Na+].[O-:14][C:15]#[N:16].[Na+].C(O)(=O)C.Cl>O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:7]=1[C:8](=[O:9])[NH:16][C:15](=[O:14])[NH:11]2
Reactant: N#C[O-]
Reactant: Nc1cccc(Cl)c1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c(=O)c2c(Cl)cccc2[nH]1
Reaction time: 9 h
Yield: 72.2 %

Procedure:
To a solution of 6-chloroanthranilic acid (1.72 g, 10 mmol) and NaOH (0.40 g, 10 mmol) in water (15 mL) was added sodium cyanate (0.72 g, 11 mmol), followed by acetic acid (0.66 g, 11 mmol). The solution was stirred for 9 h, and then acidified with conc. HCl. The precipitate was filtered off and washed with water. The wet solid was added to a solution of NaOH (8.0 g, 200 mmol) in water (60 mL) and stirred for 20 h. The precipitate was filtered off and suspended in water (80 mL), then heated to boiling and acidified with 50% H2SO4. The cooled mixture was filtered, the solid washed well with water and dried to give 5-chloroquinazolin-2,4-dione (1.42 g, 72%).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][C:3]=1[CH2:15][NH:16][CH3:17].[CH2:18]([O:25][C:26]([NH:28][CH2:29][C:30](O)=[O:31])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1C=CC2N(O)N=NC=2C=1.O.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.C(Cl)Cl>[F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:11])([CH3:12])[CH3:10])=[O:7])=[CH:4][C:3]=1[CH2:15][NH:16][CH2:17][C:30](=[O:31])[CH2:29][NH:28][C:26]([O:25][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:27]
Reactant: CNCc1cc(C(=O)OC(C)(C)C)ccc1F
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(F)c(CNCC(=O)CNC(=O)OCc2ccccc2)c1
Yield: 101 %

Procedure:
According to the procedure of Preparation 4(c), except using tert-butyl 4-fluoro-3-(methylaminomethyl)benzoate (4.00 g, 16.7 mmole), N-(benzyloxycarbonyl)glycine (3.50 g, 16.7 mmole), HOBt H2O (2.3 g, 17 mmole), DCC (2.4 g, 11.6 mmole), and 1:1 DMF/CH2Cl2 (100 mL), the title compound (7.26 g, 100%) was prepared as a thick yellow oil following flash chromatography on silica gel (30% EtOAc/hexanes): MS (ES) m/e 431.02 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][CH2:9][C:8]([C:14]#N)=[CH:7]2.[OH-:18].[Na+].[OH2:20].Cl>>[F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][CH2:9][C:8]([C:14]([OH:20])=[O:18])=[CH:7]2
Reactant: O
Reactant: N#CC1=Cc2cc(OC(F)(F)F)ccc2OC1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: O=C(O)C1=Cc2cc(OC(F)(F)F)ccc2OC1
Temperature: 150 °C

Procedure:
To a microwave vial was added 6-trifluoromethoxy-2H-chromene-3-carbonitrile (100 mg, 0.4 mmol) and 10 M of sodium hydroxide in water (2 mL, 20 mmol). The reaction mixture was heated at 150° C. for 10 minutes in the microwave. The reaction mixture was acidified with conc. HCl then extracted with EtOAc (3×30 mL). The combined organics were washed with brine (3×30 mL), dried (MgSO4), filtered and concentrated, to give the product (42 mg) as a solid. m/z=258.9 (M−1), r.t.=3.43 mins. 1H NMR (400 MHz; CDCl3) δ 7.50 (1H, s), 7.11 (1H, dd), 7.04 (1H, d), 6.84 (111, d), 5.02 (2H, d).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[O:7])[N:3]=[CH:2]1.[H-].[Na+].[CH:10]1([CH2:16][CH2:17]Br)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>O1CCCC1>[CH:10]1([CH2:16][CH2:17][N:1]2[CH:5]=[C:4]([CH:6]=[O:7])[N:3]=[CH:2]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=Cc1c[nH]cn1
Reactant: BrCCC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1cn(CCC2CCCCC2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Imidazole-4-carboxaldehyde (4.8 g, 50 mmol) was added portionwise to a suspension of sodium hydride (2.20 g, 60% dispersion in mineral oil, 55 mmol) in tetrahydrofuran (150 ml), and the mixture was then stirred at room temperature for 1 hour. 2-Cyclohexylethyl bromide (8.6 ml, 55 mmol) was added, and the mixture was heated under reflux for 18 hours. The cooled mixture was evaporated under reduced pressure and the residue was partitioned between water (500 ml) and dichloromethane (500 ml). The layers were separated, and the organic phase was dried (MgSO4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of toluene:ethyl acetate (100:0 to 96:4) to afford the title compound, 1.78 g. 1H-NMR (CDCl3, 400 MHz) δ: 0.98 (m, 2H), 1.20 (m, 4H), 1.68 (m, 7H), 4.00 (t, 2H), 7.4 (s, 1H), 7.60 (s, 1H), 9.80 (s, 1H). LRMS: m/z (TSP+) 207.2 [MH+].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[N:10]=[C:11]([C:15]([O:17]C)=[O:16])[N:12]([CH3:14])[CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.O.O>[C:1]([O:5][C:6]([NH:8][C:9]1[N:10]=[C:11]([C:15]([OH:17])=[O:16])[N:12]([CH3:14])[CH:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1nc(NC(=O)OC(C)(C)C)cn1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(NC(=O)OC(C)(C)C)nc1C(=O)O
Reaction time: 8 h
Yield: 81.5 %

Procedure:
Methyl 4-(tert-butoxycarbonylamino)-1-methyl-1H-imidazole-2-carboxylate (5.0 g, 19.59 mmol) in 120 ml of 1:1 THF/H2O was added 8 g of NaOH in 30 ml of water. The mixture was stirred overnight, concentrated, diluted with water, extracted with EtAc/Hexane (1:1). The aqueous solution was adjusted to pH 4.0 with 20% H3PO4 and extracted with EtAc (4×60 ml). The organic solutions were combined, dried over MgSO4, filtered, evaporated and crystallized with ethanol/EtAc/Hexane to afford 3.85 g (81%) of the title product. 1H NMR (DMSO) 9.32 (s, 1H), 7.29 (s, 1H), 3.57 (s, 3H), 1.42 (s, 9H); 13C NMR 172.45, 159.78, 136.93, 135.44, 132.85, 79.50, 35.57, 28.07; MS m/z−240.8 (M−H).
Reaction SMILES: Cl/[C:2](=[C:4]1\[C@H:5]2[C@@H:7]([CH2:8][C:9]\1=O)[C:6]2([CH3:12])[CH3:11])/[CH3:3].[C:13]([CH2:15][S:16]C(=O)C)#[N:14]>C1COCC1.[OH-].[Na+]>[CH3:11][C:6]1([CH3:12])[C@@H:7]2[CH2:8][C:9]3[C:4]([C@H:5]12)=[C:2]([CH3:3])[S:16][C:15]=3[C:13]#[N:14]
Reactant: C/C(Cl)=C1\C(=O)C[C@@H]2[C@H]1C2(C)C
Reactant: CC(=O)SCC#N
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1sc(C#N)c2c1[C@H]1[C@@H](C2)C1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.2 %

Procedure:
A solution of (1S, 5R)-2-(1-chloro-(E)-ethylidene)-6,6-dimethyl-bicyclo[3.1.0]hexan-3-one (997 mg, 5.40 mmol) and thioacetic acid S-cyanomethyl ester (746 mg, 6.48 mmol) in THF (37 mL) is treated with 2 N aq. NaOH (10.8 mL). The resulting mixture is stirred vigorously at rt for 2 h. Another portion of thioacetic acid S-cyanomethyl ester (100 mg, 0.87 mmol) and 2 N aq. NaOH (2 mL) is added and stirring is continued for 1 h. The reaction mixture is diluted with 2 N aq. NaOH and extracted twice with DCM. The organic extracts are dried over Na2SO4 and evaporated. The remaining brown oil is dissolved in THF (30 mL) and treated with 2 N aq. NaOH (3 mL). The mixture is heated to 90° C. for 4 h before it is diluted with 2 N aq. NaOH and extracted with DCM. The organic extracts are dried over Na2SO4 and evaporated. The crude product is purified by prep. HPLC (Phenomenex Aqua 30×75 mm, gradient 10 to 95% acetonitrile in water containing 0.5% formic acid) to give (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopro-pa[a]pentalene-4-carbonitrile (650 mg) as a brown oil; LC-MS: tR=1.06 min, [M+1+CH3CN]+=245.11; 1H NMR (CDCl3): δ 2.90 (dd, J=5.9, 18.8 Hz, 1H), 2.68 (d, J=18.8 Hz, 1H), 2.38 (s, 3H), 1.96-1.88 (m, 2H), 1.13 (s, 3H), 0.72 (s, 3H).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:24][N:25]=[C:20]2[C@H:19]([NH2:31])[CH2:18][CH2:17]1.Cl[C:33](OC1C=CC([N+]([O-])=O)=CC=1)=[O:34].[N:45]1[C:49]2([CH2:54][CH2:53][NH:52][CH2:51][CH2:50]2)[C:48](=[O:55])[NH:47][CH:46]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.C(Cl)(Cl)Cl>[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:28])[F:29])=[CH:24][N:25]=[C:20]2[C@H:19]([NH:31][C:33]([N:52]2[CH2:51][CH2:50][C:49]3([N:45]=[CH:46][NH:47][C:48]3=[O:55])[CH2:54][CH2:53]2)=[O:34])[CH2:18][CH2:17]1
Reactant: N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)cnc21
Reactant: O=C1NC=NC12CCNCC2
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)cnc21)N1CCC2(CC1)N=CNC2=O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 68.8 %

Procedure:
Triethylamine (42 μL, 0.30 mmol) was added to a solution of the hydrochloride salt of (6S,9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-amine (25 mg, 0.061 mmol) and 4-nitrophenyl chloroformate (14 mg, 0.070 mmol) in tetrahydrofuran (5 mL) at 0° C. After 40 min, the hydrochloride salt of 1,3,8-triazaspiro[4.5]dec-1-en-4-one (21 mg, 0.091 mmol), triethylamine (34 μL, 0.24 mmol) and chloroform (5 mL) were added and the mixture allowed to warm to ambient temperature. After 18 h, saturated aqueous sodium carbonate was added and the mixture was extracted with dichloromethane. The organic extracts were washed with saturated aqueous sodium bicarbonate (3×), saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→85% dichloromethane/methanol) gave the title compound (22 mg). MS 525.2000 (M+1).
Reaction SMILES: [S:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[OH:11].[CH2:12]([CH:14]1[O:16][CH2:15]1)Cl>>[O:16]1[CH2:15][CH:14]1[CH2:12][O:11][CH:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[S:1]1
Reactant: OC1CCc2ccccc2S1
Reactant: ClCC1CO1
Product: c1ccc2c(c1)CCC(OCC1CO1)S2
Yield: 65 %

Procedure:
The procedure of Step A of Example 1 is followed, starting from 1.72 g (10.34 mmol) of thiochromanol and 7.653 g (82.72 mmol) of epichlorohydrin. 1.5 g (6.721 mmol) of 2,3-epoxypropoxy-thiochroman are obtained.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:10]#[C:11][CH2:12][Si](C)(C)C)[C:5]([NH2:9])=[N:6][C:7]=1[Cl:8].CC([O-])(C)C.[K+].Cl>C(O)(C)(C)C.O>[Br:1][C:2]1[N:3]=[C:4]2[CH:10]=[C:11]([CH3:12])[NH:9][C:5]2=[N:6][C:7]=1[Cl:8]
Reactant: C[Si](C)(C)CC#Cc1nc(Br)c(Cl)nc1N
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1cc2nc(Br)c(Cl)nc2[nH]1
Temperature: 60 °C

Procedure:
5-Bromo-6-chloro-3-(3-(trimethylsilyl)prop-1-ynyl)pyrazin-2-amine (step 2)(280 mg, 0.879 mmol) in tert-butanol (4 ml) at RT was treated with KOtBu (217 mg, 1.933 mmol) and heated at 60° C. for 2 hours. The reaction mixture was cooled to room temperature, diluted with water and the pH adjusted to pH 1 using 2M HCl. The aqueous was extracted with DCM (×3) and the organic solvent removed under reduced pressure to afford the titled compound:
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].C(N(CC)CC)C.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH:25]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[NH:24][C:23]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=3[O:41][CH3:42])=[N:22]2)=[CH:17][CH:16]=1>C(Cl)Cl>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([CH:21]2[CH:25]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)[N:24]([C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[C:23]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=3[O:41][CH3:42])=[N:22]2)=[CH:19][CH:20]=1
Reactant: CC(C)C(=O)Cl
Reactant: COc1ccc(C2=NC(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2)c(OC)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C2=NC(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2C(=O)C(C)C)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Isobutyryl chloride (19 μL, 0.18 mmol) was added to a solution of triethylamine (25 μL, 0.18 mmol) and 4,5-bis-(4-chloro-phenyl)-2-(2,4-dimethoxy-phenyl)-4,5-dihydro-1H-imidazole (70 mg, 0.164 mmol). The reaction mixture was stirred at room temperature for 2 h. It was diluted with methylene chloride and washed with water and brine, and dried over sodium sulfate. The solvents were removed under reduced pressure and chromatography of the residue over silica gel using 0.5-1% methanol in methylene chloride gave 1-[4,5-bis-(4-chloro-phenyl)-2-(2,4-dimethoxy-phenyl)-4,5-dihydro-imidazole-1-yl]-2-methyl-propan-1-one. HR-MS (EI, m/z) calculated for C27H26N2O3Cl2 (M+) 496.1320, observed 496.1319.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23](O)=[O:24])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.Cl.[NH2:27][C@@H:28]([CH3:36])[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>O1CCCC1.C(#N)C>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][C:23]([NH:27][C@@H:28]([CH3:36])[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:24])=[CH:19][CH:20]=2)=[CH:11][CH:10]=1
Reactant: C[C@@H]1CCCN1CCc1ccc(-c2ccc(CCC(=O)O)cc2)cc1
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CC#N
Product: C[C@H](NC(=O)CCc1ccc(-c2ccc(CCN3CCC[C@H]3C)cc2)cc1)C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-3-(4′-(2-(2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)propanoic acid (40 mg, 0.119 mmol), (S)-tert-butyl 2-aminopropanoate hydrochloride (25.8 mg, 0.142 mmol), and TEA (0.050 mL, 0.356 mmol) in tetrahydrofuran (1 mL) and acetonitrile (1 mL) was added HATU (54.1 mg, 0.142 mmol). The reaction was stirred at 60° C. for 2 h. The mixture was added 1M HCl (1 mL) and purified by HPLC to give the title compound. LCMS m/z=465.5 [M+H]+; 1H NMR (400 MHz, CD3CN) δ ppm 1.27 (d, J=6.7 Hz, 0.4H), 1.28 (d, J=7.2 Hz, 3H), 1.44 (s, 9H), 1.46 (d, J=6.6 Hz, 2.6H), 1.70-1.82 (m, 1H), 2.01-2.12 (m, 2H), 2.23-2.33 (m, 1H), 2.51 (t, J=7.8 Hz, 2H), 2.95 (t, J=7.7 Hz, 2H), 3.05-3.21 (m, 4H), 3.37-3.48 (m, 1H), 3.49-3.62 (m, 1H), 3.73-3.83 (m, 1H), 4.20-4.29 (m, 1H), 6.64 (d, 7.1 Hz, 1H), 7.34 (d, J=8.1 Hz, 2H), 7.39 (d, J=8.1 Hz, 2H), 7.58 (d, J=8.1 Hz, 2H), 7.63 (d, J=8.1 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+].Br[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([F:29])[CH:22]=1>CN1CCCC1=O.O>[F:29][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[O:27][CH3:28])[CH2:20][CH2:19][N:7]1[C:8]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=2[C:5]2[CH2:14][N:13]([CH3:15])[CH2:12][CH2:11][C:6]1=2
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: COc1ccc(CCBr)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc(CCn2c3c(c4cc(Cl)ccc42)CN(C)CC3)cc1F
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 4.6 %

Procedure:
8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.5 g, 0.0022 mol) was dissolved in N-methyl 2-pyrolidone (4.0 mL). Powdered potassium hydroxide (1 g, 0.008 mol) was added and heated at 100° C. for 2 h. 4-(2-Bromo-ethyl)-2-fluoro-1-methoxy-benzene (0.520 g, 0.0022 mol) was added at the room temperature and stir for 0.5 h at RT (TLC showed incomplete reaction). Reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (3×100 mL). Organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator. The crude was purified through column chromatography (4% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch) to provide the desired compound as light yellow oil (0.038 g, 4% yield). 8-Chloro-5-[2-(3-fluoro-4-methoxy-phenyl)-ethyl]-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.038 g, 0.00010 mol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.012 g, 0.00010 mol) in THF (1.0 mL) was added and stirred for 30 min at RT. The precipitate was filtered and dried to give oxalate salt as off white solid (0.016 g, 34% yield).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[CH:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[C:7]1([CH:6]([OH:13])[C@@H:2]([C:3]([OH:5])=[O:4])[NH2:1])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=Cc1ccccc1
Reactant: NCC(=O)O
Product: N[C@H](C(=O)O)C(O)c1ccccc1

Procedure:
In 10.0 mL of buffer was dissolved glycine (25.4 mg, 0.338 mmol) and benzaldehyde (35 μL, 0.344 mmol). This solution (100 μL) was added to 100 μL of the SHMT solution (0.1 mg enzyme). Aliquots were taken at incubation times of 1.0, 5.25, and 7.0 hours.