Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])(=[O:3])[CH3:2].C(NC(C)C)(C)C.[Li]CCCC.[CH3:21][CH:22]([CH3:32])[C:23](=[O:31])[CH2:24][CH2:25][C:26]1[CH:30]=[CH:29][S:28][CH:27]=1>C1COCC1>[C:5]([O:4][C:1](=[O:3])[CH2:2][C:23]([OH:31])([CH2:24][CH2:25][C:26]1[CH:30]=[CH:29][S:28][CH:27]=1)[CH:22]([CH3:21])[CH3:32])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(=O)OC(C)(C)C
Reactant: CC(C)C(=O)CCc1ccsc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)C(O)(CCc1ccsc1)CC(=O)OC(C)(C)C

Procedure:
The title compound was prepared as described in General Method 9 using t-butyl acetate (42.6 mmol), diisopropyl amine (42.6 mmol), nBuLi (42.6 mmol), 4-methyl-1-thiophen-3-yl-pentan-3-one (Example C-5; 21.3 mmol), and THF (100 mL). The title compound was purified by flash chromatography over silica gel eluting with hexane:EtOAc 97:3. 1NMR (CDCl3): δ 0.95 (dd, 6H), 1.47 (s, 9H), 1.7-2.0 (m, 3H), 2.36-2.54 (AB q, 2H), 2.6-2.8 (m, 2H), 6.93-6.95 (m, 2H), 7.23-7.25 (m, 1H).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:16]2[CH:21]=[CH:20][C:19]([S:22](=[O:25])(=[O:24])[NH2:23])=[CH:18][CH:17]=2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C1(CNC2C=CC(S(=O)(=O)N)=CC=2)CCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:27]1([CH2:26][N:15]([C:16]2[CH:21]=[CH:20][C:19]([S:22](=[O:24])(=[O:25])[NH2:23])=[CH:18][CH:17]=2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:32])=[O:3])=[CH:8][N:9]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2ccc(S(N)(=O)=O)cc2)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Agent: NS(=O)(=O)c1ccc(NCC2CCCC2)cc1
Product: NS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2ncc(SCC(=O)O)s2)cc1

Procedure:
The title compound was prepared via {2-[3-cyclopentylmethyl-3-(4-sulfamoyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(4-sulfamoyl-phenyl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:14]1[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=1.[F:21][C:22]1[CH:23]=[C:24]([N:29]=[C:30]=[O:31])[CH:25]=[CH:26][C:27]=1[F:28]>C(Cl)Cl>[F:21][C:22]1[CH:23]=[C:24]([NH:29][C:30]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:20])=[C:8]([C:14]3[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=3)[CH:9]=2)=[O:31])[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: O=C=Nc1ccc(F)c(F)c1
Reactant: CN(C)CCCOc1ccc(N)cc1-c1ccnn1C
Solvent: ClCCl
Product: CN(C)CCCOc1ccc(NC(=O)Nc2ccc(F)c(F)c2)cc1-c1ccnn1C
Reaction time: 2 h
Yield: 55.7 %

Procedure:
To a solution of 4-(3-dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (61.1 mg, 0.223 mmol) in CH2Cl2 (2 mL) was added 3,4-difluorophenyl isocyanate (0.30 μL, 0.256 mmol) and stirred for two hours. The resulting material was purified by solid phase extraction (SCX, 1 gram cartridge), eluting with methanol (30 mL) followed by 2M NH3 in methanol (30 mL). The NH3 containing fractions were dried in vacuo to afford Compound 136 as a colorless solid (53.3 mg, 56%). LCMS m/z (%)=430 (M+H, 100), 1H NMR (400 MHz, DMSO-d6) δ: 8.93 (bs, 1H), 8.72 (bs, 1H), 7.71-7.61 (m, 1H), 7.49-7.42 (m, 2H), 7.37 (d, J=2.68 Hz, 1H), 7.35-7.28 (m, 1H), 7.14-7.06 (m, 1H), 7.09 (d, J=8.96 Hz, 1H), 6.23 (d, J=1.82 Hz, 1H), 3.97 (t, J=6.37 Hz, 2H), 3.65 (s, 3H), 2.19 (t, J=7.05 Hz, 2H), 2.07 (s, 6H), 1.77-1.68 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9](Br)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cu][C:15]#[N:16].CN1CCCC1=O>O>[NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([C:15]#[N:16])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Br)cc(C)c1N
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)c1cc(C#N)cc(C)c1N
Temperature: 120 °C

Procedure:
Methyl 2-amino-5-bromo-3-methylbenzoate (100 g, 0.393 mol, 96% of quantitative NMR), copper(I) cyanide (36.3 g, 0.401 mol) and N-methyl-2-pyrrolidinone (NMP) (206 g, 200 mL, 2.084 mol) are heated to 170° C. for 4 hours under agitation. The reaction batch is cooled down to 120° C., 350 mL of H2O (90° C.) are added dropwise in the course of 30 minutes and the suspension obtained is filtered. The solid obtained is washed twice with ammonia (200 g, 12% in H2O) and 2 times with 100 ml of water. Following drying in a vacuum drying cabinet at 50° C., methyl 2-amino-5-cyano-3-methylbenzoate is obtained as a grey solid. Yield: 69.0 g, 88.2% of theory, purity: 95.6% quantitative NMR, 1500 ppm Cu).
Reaction SMILES: [CH2:1]([N:5]1[CH:9](P(=O)(OCC)OCC)[C:8](=[O:18])[NH:7][C:6]1=[O:19])[CH2:2][CH2:3][CH3:4].[Cl-].[Li+].C1CCN2C(=NCCC2)CC1.[CH2:33]([C:37]1[N:38]([CH2:44][C:45]2[CH:54]=[CH:53][C:48]([C:49]([O:51][CH3:52])=[O:50])=[CH:47][C:46]=2[Cl:55])[C:39]([CH:42]=O)=[CH:40][N:41]=1)[CH2:34][CH2:35][CH3:36]>C(#N)C>[CH2:33]([C:37]1[N:38]([CH2:44][C:45]2[CH:54]=[CH:53][C:48]([C:49]([O:51][CH3:52])=[O:50])=[CH:47][C:46]=2[Cl:55])[C:39](/[CH:42]=[C:9]2\[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6](=[O:19])[NH:7][C:8]\2=[O:18])=[CH:40][N:41]=1)[CH2:34][CH2:35][CH3:36]
Reactant: CCCCN1C(=O)NC(=O)C1P(=O)(OCC)OCC
Reactant: CCCCc1ncc(C=O)n1Cc1ccc(C(=O)OC)cc1Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCCCc1ncc(/C=C2/C(=O)NC(=O)N2CCCC)n1Cc1ccc(C(=O)OC)cc1Cl
Reaction time: 0.08 h

Procedure:
To a solution of diethyl 3-butyl-2,5-dioxo-4-imidazolylphosphonate (0.49 g, 1.72 mmol) in acetonitrile (5 mL) was added lithium chloride (0.15 g, 3.47 mmol) and then DBU (0.52 mL, 3.47 mmol). This mixture was stirred for 5 minutes under N2. Methyl 4-[(2-butyl-5-formyl-1H-imidazol-1-yl)methyl]-3-chlorobenzoate (0.48 g, 1.43 mmol) in acetonitrile (5 mL) was added and the mixture stirred for 4 days. The solvent was removed in vacuo and the isomers separated by chromatography eluting with (1-5)% methanol in chloroform.
Reaction SMILES: [C:1]12([C:11]3[CH:30]=[CH:29][C:14]([O:15][CH2:16][C:17]([NH:19][C:20]4[CH:21]=[N:22][CH:23]=[C:24]([CH:28]=4)[C:25](O)=[O:26])=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:31][CH2:32][CH2:33][CH2:34][N:35]1[CH:39]=[CH:38][N:37]=[CH:36]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CO>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:1]12([C:11]3[CH:30]=[CH:29][C:14]([O:15][CH2:16][C:17]([NH:19][C:20]4[CH:21]=[N:22][CH:23]=[C:24]([CH:28]=4)[C:25]([NH:31][CH2:32][CH2:33][CH2:34][N:35]4[CH:39]=[CH:38][N:37]=[CH:36]4)=[O:26])=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cncc(C(=O)O)c1
Reactant: NCCCn1ccnc1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cncc(C(=O)NCCCn2ccnc2)c1
Yield: 73.5 %

Procedure:
To solution of 5-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-nicotinic acid (40 mg, 0.098 mmol), 1-(3-aminopropyl)-imidazole (24.65 mg, 0.196 mmol) and DMAP (24.06 mg, 0.196 mmol) in DMF was added PyBOP (102.47 mg, 0.196 mmol) at room temperature, and stirred. Reaction mixture was poured onto ice cold water, diluted by methanol/MC mixture (10%). The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The resultant crude product was purified by PLC (MeOH:MC=1:9) to afford 5-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-N-(3-imidazole-1-yl-propyl)nicotinamide as a colorless solid (37 mg, 49% yield).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]([CH:14]2[S:19][CH:18](C(OCC)=O)[C:17](=[O:25])[CH2:16][S:15]2)[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O>O.Cl>[CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]([CH:14]2[S:19][CH2:18][C:17](=[O:25])[CH2:16][S:15]2)[N:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1SC(c2ncn(Cc3ccccc3)c2C)SCC1=O
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1c(C2SCC(=O)CS2)ncn1Cc1ccccc1
Temperature: 100 °C

Procedure:
A mixture of 2-(1-benzyl-5-methyl-4-imidazolyl)-4-carbethoxy-1,3-dithian-5-one (15.5 g., 0.041 mole) in water (40 ml.) containing concentrated sulfuric acid (3.0 ml.) is heated at 100° C. for 4-5 hours. The mixture is cooled, diluted with 10% hydrochloric acid, washed with diethyl ether and filtered through a charcoal pad. The filtrate is made basic with sodium carbonate solution and extracted into methylene chloride. The solvent is dried and evaporated to give a dark brown oil (11.2 g.), 2-(1-benzyl-5-methyl-4-imidazolyl)-1,3-dithian-5-one, which is used as is in subsequent steps.
Reaction SMILES: [O:1]=[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=[C:3]1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]#[N:17])[CH2:11][CH2:10]1.[OH-:18].[NH4+]>S(=O)(=O)(O)O>[O:1]=[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=[C:3]1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][C:16]([NH2:17])=[O:18])[CH2:13][CH2:14]1
Reactant: [OH-]
Reactant: N#CCN1CCN(c2cccccc2=O)CC1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: NC(=O)CN1CCN(c2cccccc2=O)CC1
Reaction time: 72 h

Procedure:
A solution of 4-(2-oxo-3,5,7-cycloheptatrien-1-yl)-1-piperazine-acetonitrile (3.0 g; described in Example 3) in conc. sulfuric acid (30 ml) was allowed to stay at room temperature for 3 days. The reaction mixture was poured over ice and conc. ammonium hydroxide slowly while stirring, then extracted with chloroform. Evaporation of the solvent left 2.7 g crude product, which was recrystallized from methanol to yield 2.2 g of the title compound: mp 169°-171° C.; ir(CHCl3) 3500, 3430, 3370, 1685 and 1563 cm-1 ; uv max(MeOH) 351 (ε=9920), 254 (ε=14810) and 221 nm(ε=12090); nmr(CDCl3)δ2.75 (t, 4H), 3.09 (s, 2H), 3.35 (t, 4H), 6.00 (2H) and 6.8 (m, 5H); and Anal. Calcd for C13H17N3O2 : C, 63.14% H, 6.93% N, 16.99% and Found: C, 63.24% H, 7.00% N, 16.99%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[C:8]([C:13]([OH:15])=O)=[N:9][CH:10]=[CH:11][CH:12]=1.[CH3:16][C:17]1([NH:23][C:24]2[N:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=2)[CH2:21][CH2:20][CH2:19][CH:18]1[NH2:22].N1C2C(=NC=CC=2)N(O)N=1.C(Cl)CCl.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:16][C:17]1([NH:23][C:24]2[N:25]=[CH:26][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:28][N:29]=2)[CH2:21][CH2:20][CH2:19][CH:18]1[NH:22][C:13]([C:8]1[C:7]([C:2]2[N:1]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:15]
Reactant: O=C(O)c1ncccc1-c1ncccn1
Reactant: CC1(Nc2ncc(C(F)(F)F)cn2)CCCC1N
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClCCCl
Product: CC1(Nc2ncc(C(F)(F)F)cn2)CCCC1NC(=O)c1ncccc1-c1ncccn1

Procedure:
A solution of 3-(pyrimidin-2-yl)pyridine-2-carboxylic acid (CAS number 1228431-21-7; 80 mg, 0.40 mmol), 1-methyl-1-N-[5-(trifluoromethyl)pyrimidin-2-yl]cyclopentane-1,2-diamine (Intermediate 50; 103 mg, 0.40 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (81 mg, 0.60 mmol), EDC (114 mg, 0.60 mmol) and DIPEA (0.208 ml, 1.19 mmol) in DCM (4 ml) was stirred at room temperature for 4 days. The reaction was diluted with DCM (5 ml) and a saturated solution of sodium bicarbonate (5 ml), filtered through a hydrophobic frit and concentrated in vacuo. The crude product was purified by reverse phase chromatography (C18 silica, 5-95% water (0.05% ammonia)/acetonitrile) to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1[N:14]=[C:15]([NH2:24])[C:16]2[C:21]([CH2:22]Cl)=[CH:20][O:19][C:17]=2[N:18]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[NH2:12][C:13]1[N:14]=[C:15]([NH2:24])[C:16]2[C:21]([CH2:22][NH:1][C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH:5]=[CH:4][CH:3]=3)=[CH:20][O:19][C:17]=2[N:18]=1
Reactant: Nc1cccc2ccccc12
Reactant: Nc1nc(N)c2c(CCl)coc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Nc1nc(N)c2c(CNc3cccc4ccccc34)coc2n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 32.5 %

Procedure:
To a 50 ml three neck round bottom flask was added sequentially anhydrous DMSO (5 ml), 1-aminonaphthalene (0.66 g), Compound 117 (0.50 g) and anhydrous potassium carbonate (0.69 g). The reaction mixture was stirred at 50° C. for 8 h under nitrogen in the dark. The reaction was then quenched with distilled water (15 ml) and the resultant suspension stirred at room temperature for 4 h, cooled to 5° C. and filtered. The residue was washed with cold water (2×5 ml) and then dissolved in hot MeOH, and the solution mixed with silica gel (2 g). The mixture was evaporated under reduced pressure and then dried in vacuo. The residue was ground into a fine powder and poured on top of a dry column of silica gel (40 g). The column was washed with MeOH in CHCl3: 200 ml (0.5%), 100 ml (1%), 100 ml (2%). The column then eluted with 3% MeOH in CHCl3. Fractions corresponding to a single spot of the product (TLC) were pooled and evaporated. The residue was washed with ether and air dried to afford 0.25 g (33%) of compound 423 as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([O:18][CH:19]2[CH2:23][CH2:22][NH:21][CH2:20]2)[CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][C:12](=[O:32])[N:13]2[C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:31].C=O.[C:35]([BH3-])#N.[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([O:18][CH:19]2[CH2:23][CH2:22][N:21]([CH3:35])[CH2:20]2)[CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][C:12](=[O:32])[N:13]2[C:24]1[C:25]([Cl:31])=[CH:26][CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: [BH3-]C#N
Reactant: O=C1CCc2c(-c3ccccc3Cl)cc(OC3CCNC3)cc2N1c1c(Cl)cccc1Cl
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CCC(Oc2cc(-c3ccccc3Cl)c3c(c2)N(c2c(Cl)cccc2Cl)C(=O)CC3)C1
Reaction time: 48 h

Procedure:
To a solution of 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-7-(pyrrolidin-3-yloxy)-3,4-dihydroquinolin-2(1H)-one (0.046 g) in 5 mL of methanol was added formaldehyde (50 μL) and sodium cyanoborohydride (0.012 g). The reaction mixture was stirred for 48 h, then washed with 1N HCl (5 mL), extracted with 5×5 mL of ethyl acetate, washed with brine (5 mL), dried with sodium sulfate, and concentrated. Purification was achieved by preparative thin layer chromatography eluting with 10% ethanol/dichloromethane to yield product. Mass spectrum (ESI) 501.1 (M+1). 1H NMR (500 MHz, CDCl3): δ 7.50-7.48 (m, 3H), 7.36-7.30 (m, 4H) 6.38 (s, 1H), 5.85 (s, 1H), 4.66 (m, 1H), 2.87-2.65 (m, 8H), 2.36 (s, 3H), 2.18-2.15 m, 1H), 1.94-1.91 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[C:11]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=3)[N:10]=[C:9]2[CH3:22])[CH:5]=[CH:4][N:3]=1.[OH-:23].[K+]>C(O)(C)(C)C>[Cl:21][C:17]1[CH:16]=[C:15]([C:14]#[C:13][C:11]2[N:10]=[C:9]([CH3:22])[N:8]([C:6]3[CH:5]=[CH:4][NH:3][C:2](=[O:23])[CH:7]=3)[CH:12]=2)[CH:20]=[CH:19][N:18]=1
Reactant: [OH-]
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1ccnc(Cl)c1
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1cc[nH]c(=O)c1

Procedure:
The title compound, white crystalline solid, MS: m/e=311.2, 313.2 (M+H+), was prepared in accordance with the general method of example 1a by treatment of 2-chloro-4-[4-(2-chloro-pyridin-4-ylethynyl)-2-methyl-imidazol-1-yl]-pyridine with 50% KOH in tert-butanol
Reaction SMILES: [C:1]1([O:7][C:8]([N:10]2[CH:23]([C:24]#[C:25]/[CH:26]=[CH:27]\[C:28]#[C:29][Si](C)(C)C)[C:22]34[O:34][C:17]3([C:18](=[O:35])[CH2:19][CH2:20][CH2:21]4)[C:16]3[CH:15]=[C:14]([O:36][CH3:37])[CH:13]=[CH:12][C:11]2=3)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C-]#N.[K+]>O.CCO.C1COCC1.[N+]([O-])([O-])=O.[Ag+]>[C:1]1([O:7][C:8]([N:10]2[CH:23]([C:24]#[C:25]/[CH:26]=[CH:27]\[C:28]#[CH:29])[C:22]34[O:34][C:17]3([C:18](=[O:35])[CH2:19][CH2:20][CH2:21]4)[C:16]3[CH:15]=[C:14]([O:36][CH3:37])[CH:13]=[CH:12][C:11]2=3)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc2c(c1)C13OC1(CCCC3=O)C(C#C/C=C\C#C[Si](C)(C)C)N2C(=O)Oc1ccccc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [C-]#N
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: C#C/C=C\C#CC1N(C(=O)Oc2ccccc2)c2ccc(OC)cc2C23OC12CCCC3=O
Reaction time: 0.25 h
Yield: 87 %

Procedure:
Silver nitrate (1.43 g, 8.44 mmol) was added to a solution of Compound 315 (1.08 g, 2.11 mmol) in 48 mL of H2O-EtOH-THF (1:1:1) at 25° C. followed by stirring for 15 minutes. Potassium cyanide (0.962 g, 14.8 mmol) was then added and the mixture was stirred for one hour, concentrated in vacuo to 20 mL, poured into saturated aqueous sodium bicarbonate (30 mL), and extracted with dichloromethane (3×40 mL). The combined organic layers were dried (MgSO4) and evaporated in vacuo, and the residue was purified by flash column chromatography (silica, 35 percent ethyl ether in petroleum ether) to give 0.807 g (88 percent) of Compound 316: white foam Rf =0.22 (silica, 40 percent ethyl ether in petroleum ether); IR (CHCl3) νmax 3299, 2947, 1716, 1609, 1590, 1501, 1493, 1380, 1299, 1253 cm-1 ; 1H NMR (500 MHz, CDCl3 ) 7.96 (d, J=2.9 Hz, 1 H, aromatic), 7.38-7.07 (m, 6 H, aromatic), 6.89 (dd, J=8.9, 2.9 Hz, 1 H, aromatic), 5.88 (s, 1 H, H6), 5.77 and 5.74 (ABq, J=11.2 Hz, 2 H, olefinic), 3.81 (s, 3 H, OCH3), 3.16 (d, J=1.5 Hz, 1 H, C≡CH), 2.74 (dt, J=15.3, 5.0 Hz, 1 H, H9), 2.67 (ddd, J=15.3, 10.1, 6.1 Hz, 1 H, H9), 2.36-2.26 (m, 2 H, H7), 1.99-1.89 (m, 2 H, H8); 13C NMR (125 MHz, CDCl3) δ 201.5, 157.2, 154.1, 151.0, 129.3, 128.7, 128.5, 125.7, 124.1, 121.4, 120.4, 120.3, 114.8, 114.7, 90.6, 85.1, 82.7, 80.3, 74.9, 57.4, 55.5, 48.3, 38.8, 23.8, 18.6; MS (FAB+) m/e (rel intensity) 439 (M+, 100), 364 (8), 176 (19), 120 (10); HRMS for C27H21NO5 (M+), calcd 439.1420, found 439.1434.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:22])=[C:6]([C@:8]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)([CH3:11])[CH2:9][OH:10])[CH:7]=1.C(N(CC)CC)C.[C:30]([Si:34]([CH3:37])([CH3:36])Cl)([CH3:33])([CH3:32])[CH3:31]>ClCCl.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:22])=[C:6]([C@:8]([NH:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)([CH3:11])[CH2:9][O:10][Si:34]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:37])[CH3:36])[CH:7]=1
Reactant: COc1ccc(CN[C@@](C)(CO)c2cc(Br)ccc2F)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CN[C@@](C)(CO[Si](C)(C)C(C)(C)C)c2cc(Br)ccc2F)cc1

Procedure:
A solution of (R)-2-(5-bromo-2-fluoro-phenyl)-2-(4-methoxy-benzylamino)-propan-1-ol (6.95 g, 18.9 mmol) in dichloromethane (170 ml) was treated at room temperature with triethylamine (5.78 ml, 41.5 mmol), 4-dimethylaminopyridine (1.15 g, 9.43 mmol), and tert-butyldimethylchlorosilane (1.15 g, 37.7 mmol). After 16 hours at room temperature the reaction mixture was consecutively extracted with saturated sodium hydrogen carbonate solution (100 ml), water (100 ml), and brine (100 ml). The aqueous layers were re-extracted with dichloromethane (100 ml). The combined organic layers were dried over sodium sulfate and evaporated at reduced pressure. After chromatography on Silicycle-Si-amine column using heptane as the eluent, [(R)-1-(5-bromo-2-fluoro-phenyl)-2-(tert-butyl-dimethyl-silanyloxy)-1-methyl-ethyl]-(4-methoxy-benzyl)-amine (intermediate C8A) was obtained as a colourless oil (8.0 g, 88% of theory). MS (ISP): m/z=482.2, 484.3 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[NH2:11])=[CH:4][CH:3]=1.[CH:12]([CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)=O.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:10][C@H:9]2[NH:11][CH2:12][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:16][CH2:15]2)=[CH:6][CH:7]=1
Reactant: N[C@@H]1C[C@H]1c1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(CN[C@@H]2C[C@H]2c2ccc(I)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.1 %

Procedure:
To a solution of trans-2-(4-iodophenyl)cyclopropanamine (1.0 g, 3.86 mmol) in methanol (15 mL) were added tert-butyl 4-formylpiperidine-1-carboxylate (0.741 g, 3.47 mmol), acetic acid (0.066 mL, 1.158 mmol), and the mixture was stirred at rt for 1 h. Sodium cyanoborohydride (0.364 g, 5.79 mmol) was added and the mixture was stirred at room temperature for 18 h. The mixture was concentrated and the residue was treated with water (2 mL) and extracted with DCM (3×). The extract was dried (Na2SO4) and concentrated. The residue was purified using column chromatography (silica gel, 0 to 100% EtOAc/hexanes) to give 730 mg of product as pale yellow oil. MS: (M+H)+=457.2. 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.99-1.18 (m, 3H), 1.45-1.51 (m, 9H), 1.69-1.81 (m, 3H), 1.87-1.94 (m, 1H), 2.29-2.37 (m, 1H), 2.62-2.90 (m, 3H), 4.00-4.20 (m, 2H), 6.86-6.88 (m, 2H), 7.57-7.59 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[F:27][CH:28]([F:37])[O:29][C:30]1[CH:31]=[CH:32][C:33](Cl)=[N:34][CH:35]=1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:33]5[CH:32]=[CH:31][C:30]([O:29][CH:28]([F:37])[F:27])=[CH:35][N:34]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Reactant: FC(F)Oc1ccc(Cl)nc1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccc(OC(F)F)cn5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 5-difluoromethoxy-2-chloro-pyridine following a procedure analogous to that described for Intermediate 12. LC (method 2): tR=1.18 min; Mass spectrum (ESI+): m/z=502 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][C:15]=2[CH3:21])[CH:7]=1)[CH3:2].[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([C:14]2[CH:19]=[CH:18][C:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:16][C:15]=2[CH3:21])=[O:22])[CH:7]=1)[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)Cc1cccc(NC(=O)c2ccc(Br)cc2C)c1
Product: CCOC(=O)Cc1cccc(NC(=O)c2ccc(-c3ccccc3)cc2C)c1
Temperature: 80 °C

Procedure:
[3-(4-Bromo-2-methyl-benzoylamino)-phenyl]-acetic acid ethyl ester (188 mg, 0.50 mmol) was coupled to phenylboronic acid using Method E, except that the reaction mixture was heated at 80° C. The crude residue was purified by column chromatography using 20% EtOAc in heptane to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1N.S(=O)(=O)(O)[OH:11].S(O)(O)(=O)=O.ClC1C=CC(Cl)=CC=1N>>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[OH:11]
Reactant: O=S(=O)(O)O
Reactant: Nc1cc(Cl)ccc1Cl
Product: Oc1cc(Cl)ccc1Cl

Procedure:
40 Grams of 2,5-dichloroaniline and 250 g of 75% aqueous sulfuric acid solution were charged into a ceramic ball mill having one liter capacity. A suspension of fine particles of 2,5-dichloroaniline sulfate was prepared by a method similar to that described in Example 5. The suspension was transferred into a beaker having one liter capacity. The ceramic ball mill used was washed with 77 g of 75% aqueous sulfuric acid solution and the washings were transferred into the beaker. Diazotization of 2,5-dichloroaniline sulfate in the form of suspension of fine particles was carried out by a method similar to that described in Example 5 except that 18.2 g of sodium nitrite powder was added in 15 minutes. The diazotized solution was hydrolyzed by a method similar to that described in Example 5. 35.5 Grams of 2,5-dichlorophenol (100° - 105° C/20 mmHg) was obtained. The yield was found to be 88.3%.