Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:3]=1[C:4]([C:12]#[CH:13])([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[H][H]>CO>[CH3:1][C:2]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:3]=1[C:4]([CH2:12][CH3:13])([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C#CC(O)(c1ccccc1)c1cc(C)ccc1C
Reactant: [H][H]
Solvent: CO
Product: CCC(O)(c1ccccc1)c1cc(C)ccc1C

Procedure:
10 g. of 5% palladium-on-calcium-carbonate catalyst are added to a solution of 94.5 g. of 2,5-dimethyl-α-ethynyl-benzhydrol in 900 ml. of methanol, and the mixture is hydrogenated until the uptake of the calculated amount of hydrogen (about 30 to 40 minutes). The catalyst is filtered off, the filtrate is evaporated, and the obtained crystalline residue is recrystallized from n-heptane. This way 80.7 g. of 2,5-dimethyl-α-ethyl-benzhydrol are obtained, m.p.: 38°-39° C.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[CH2:32][NH2:33].C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:20][C:17]1[CH:18]=[CH:19][C:12]([N:10]2[CH2:9][CH2:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:33][CH2:32][C:23]4[CH:24]=[CH:25][C:26]5[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=5)[N:22]=4)[C:3]=3[CH2:11]2)=[C:13]([CH:16]=1)[C:14]#[N:15]
Reactant: NCc1ccc2ccccc2n1
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(N2CCc3ncnc(NCc4ccc5ccccc5n4)c3C2)c(C#N)c1

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (150 mg, 0.52 mmol) and quinolin-2-ylmethanamine hydrochloride (206.0 mg, 1.058 mmol) in acetonitrile (1 mL) and N,N-diisopropylethylamine (1 mL, 6 mmol) was subjected to microwave irradiation at 185° C. for 3.5 h. The reaction mixture was concentrated and the residue was purified by preparative HPLC (30-60% acetonitrile-water [10 mM DEA]) to afford a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].[CH:26]1([C:29]2[CH:33]=[C:32]([NH:34][C:35](=O)[O:36]C3C=CC=CC=3)[O:31][N:30]=2)[CH2:28][CH2:27]1.COC1C=C2C(=CC=1OC)N=CN=C2OC1C=C(NC(NC2ON=C(C(C)C)C=2)=O)C=CC=1>>[CH:26]1([C:29]2[CH:33]=[C:32]([NH:34][C:35]([NH:22][C:21]3[CH:23]=[CH:24][CH:25]=[C:19]([O:18][C:6]4[C:5]5[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:3]([O:2][CH3:1])[CH:4]=5)[N:9]=[CH:8][N:7]=4)[CH:20]=3)=[O:36])[O:31][N:30]=2)[CH2:28][CH2:27]1
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: O=C(Nc1cc(C2CC2)no1)Oc1ccccc1
Agent: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)C)no4)c3)c2cc1OC
Product: COCCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C5CC5)no4)c3)c2cc1OC
Yield: 52.4 %

Procedure:
Prepared from 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example 117B (90 mg, 0.264 mmol) and phenyl 3-cyclopropylisoxazol-5-ylcarbamate from Example 124A (78 mg, 0.317 mmol) according to the method described for 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropylisoxazol-5-yl)urea in Example 122B to afford 1-(3-cyclopropylisoxazol-5-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea as a colorless solid (68 mg, 52%). 1H NMR (300 MHz, DMSO-d6) δ 10.21 (brs, 1H), 9.08 (brs, 1H), 8.55 (s, 1H), 7.56 (s, 2H), 7.38-7.44 (m, 2H), 7.29 (m, 1H), 6.99 (m, 1H), 5.77 (s, 1H), 4.35 (m, 2H), 3.99 (s, 3H), 3.78 (m, 2H), 3.30 (s, 3H), 1.90 (m, 1H), 0.94-0.98 (m, 2H), 0.71-0.73 (m, 2H); LC-MS (ESI) m/z 492 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[O:11][C:10]2[CH:9]=[CH:8][N:7]=[C:6]([NH:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:5]=2[CH:4]=1)=O.[NH2:21][C:22]([CH:26]([F:28])[F:27])=[CH:23][C:24]#[N:25]>C(O)(=O)C.C(O)CCC>[C:24]([C:23]1[CH:1]([C:3]2[O:11][C:10]3[CH:9]=[CH:8][N:7]=[C:6]([NH:12][C:13](=[O:20])[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:5]=3[CH:4]=2)[C:23]([C:24]#[N:25])=[C:22]([CH:26]([F:28])[F:27])[NH:21][C:22]=1[CH:26]([F:28])[F:27])#[N:25]
Reactant: O=Cc1cc2c(NC(=O)c3ccccc3)nccc2o1
Reactant: N#CC=C(N)C(F)F
Solvent: CC(=O)O
Solvent: CCCCO
Product: N#CC1=C(C(F)F)NC(C(F)F)=C(C#N)C1c1cc2c(NC(=O)c3ccccc3)nccc2o1

Procedure:
A solution of 200 mg (0.75 mmol) N-(2-formylfuro[3,2-c]pyridin-4-yl)benzamide (Example 3A) in acetic acid (1.3 ml) was treated with a solution of 200 mg (1.69 mmol) 3-amino-4,4-difluorobut-2-enenitrile [obtainable by Thorpe reaction of acetonitrile with 2,2-difluoroacetonitrile, cf. Org. React. 15, 1 (1967), ibid. 31, 1 (1984)] in 1-butanol (1.0 ml). The mixture was heated to reflux temperature for 2 h. Upon cooling, the reaction mixture was concentrated under reduced pressure, and the residue was treated with ethyl acetate and saturated aq. sodium bicarbonate solution. The organic layer was separated, washed with brine and with water, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative RP-HPLC (methanol/water+0.1% TFA gradient, final mixture 100% methanol) yielding 28 mg (8% of th.) of the title compound.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:11]([OH:12])=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1.[C:19]1([CH2:25][CH2:26][CH2:27][C:28](Cl)=[O:29])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>N1C=CC=CC=1>[C:16]([NH:15][CH2:14][CH2:13][CH:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([NH:2][C:28](=[O:29])[CH2:27][CH2:26][CH2:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]=2[OH:12])[CH2:7][CH2:8]1)(=[O:18])[CH3:17]
Reactant: O=C(Cl)CCCc1ccccc1
Reactant: CC(=O)NCCC1CCc2ccc(N)c(O)c21
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)NCCC1CCc2ccc(NC(=O)CCCc3ccccc3)c(O)c21
Reaction time: 0.25 h
Yield: 68.9 %

Procedure:
N-[2-(6-Amino-7-hydroxy-2,3-dihydro-1H-inden-1-yl)ethyl]acetamide hydrochloride (100 mg, 0.369 mmol) was dissolved in pyridine (4 mL), 4-phenylbutanoyl chloride (74.1 mg, 0.406 mmol) was added under ice-cooling, and the mixture was stirred for 15 min. Water was added to the reaction solution, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=80/20→100/0) to give the title compound (96.8 mg, yield 69%).
Reaction SMILES: Cl.Cl[C:3]1[N:8]2[N:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[N:11]=[C:7]2[CH:6]=[C:5]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:4]=1.Cl.Cl.[NH2:31][CH2:32][CH2:33][NH:34][C:35]1[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][N:36]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[C:5]1[N:4]=[C:3]([NH:31][CH2:32][CH2:33][NH:34][C:35]2[N:36]=[CH:37][C:38]([C:39]#[N:40])=[CH:41][CH:42]=2)[N:8]2[N:9]=[C:10]([CH:12]3[CH2:13][CH2:14][N:15]([CH:18]([CH3:19])[CH3:20])[CH2:16][CH2:17]3)[N:11]=[C:7]2[CH:6]=1
Reactant: N#Cc1ccc(NCCN)nc1
Reactant: CC(C)N1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)nc(Cl)n3n2)CC1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)nc(NCCNc4ccc(C#N)cn4)n3n2)CC1
Temperature: 130 °C

Procedure:
50 mg (0.12 mmol) of 5-chloro-7-(2,4-dichlorophenyl)-2-[1-(propan-2-yl)piperidin-4-yl][1,2,4]-triazolo[1,5-c]pyrimidine hydrochloride (Example 40A), 28 mg (0.14 mmol) of 6-[(2-aminoethyl)-amino]pyridine-3-carbonitrile dihydrochloride (Example 2A) and 0.125 ml (3.5 mmol) of N,N-diisopropylethylamine were initially charged in 1 ml of DMSO. The mixture was heated in the microwave at 130° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 48 mg (74% of theory) of the product as a solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@@H:4]1[CH2:8][C@@H:7](O)[CH2:6][N:5]1[C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(S(F)(F)[F:25])CC)C.N1C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3](=[O:18])[C@@H:4]1[CH2:8][C@H:7]([F:25])[CH2:6][N:5]1[C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)c1ccccc1
Reactant: CCN(CC)S(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](F)CN1C(=O)c1ccccc1
Temperature: -45 °C
Yield: 64 %

Procedure:
A solution of (trans)-1-benzoyl-4-hydroxy-L-proline methyl ester prepared as described in Example 1 Part A(2) (6 g, 24.1 mmole) was dissolved in dichloromethane and cooled to -45° C. under an argon atmosphere. To the above solution diethylaminosulfur trifluoride (5.2 ml, 42 mmole) was added dropwise. The resulting solution was stirred and warmed to -35° C. To the above solution pyridine was added dropwise (9 ml, 116 mmole). The reaction was allowed to stir overnight while warming to room temperature. The solvent was removed in vacuo and the oily residue treated with ethyl acetate and 1N HCl. The mixture was transferred to a separatory funnel, the aqueous layer removed, and the organic layer washed with additional 1N HCl, then water and saturated sodium bicarbonate solution. The organic solution was dried over sodium sulfate, filtered and concentrated to a yellow oil. The crude product was chromatographed on silica gel using 1:1 ethyl acetate:hexane as eluent. Combination and concentration of product containing fractions produced 3.9 gm (64%) of title compound as an oil.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].CO.Cl>O1CCCC1>[Br:1][CH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4]
Reactant: O=C(CBr)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: O[C@@H](CBr)c1ccccc1
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
(R)-2-amino-2-cyclohexyl-1,1-bis(2-naphthyl)ethanol (79.1 mg, 0.2 mmol) and dry tetrahydrofuran (2 mL) and trimethylboroxine (27.2 μL, 0.24 mmol) were added to a dry flask under an atmosphere of nitrogen, then stirred for 1 hour to form a solution of (R)-4-cyclohexyl-5,5-bis(2-naphthyl)-2-methoxy-1,3,2-oxazaborolidine. Borane dimethylsulfide complex (100 μL, 1.0 mmol) was added and the reaction was stirred for 30 minutes. Then, a solution of bromoacetophenone (199 mg, 1.0 mmol) in dry tetrahydrofuran (3 mL) was added at the rate of 9 mL/hr by means of a syringe pump. After 2 hours, methanol was added to quench the reaction, followed by 0.5 N ethanolic HCl (0.4 mL). The solvent was removed by evaporation under vacuum and the resulting residue was chromatographed on silica gel (hexane/ethyl acetate 25:2). Combination of the like fractions, followed by removal of the solvent gave (R)-2-bromo-1-phenylethanol (130 mg, 93% yield, 98.3% ee). The enantiomeric excess was measured by HPLC (Chiralcel OD-H column, mobile phase, hexane/2-propanol 9:1, flow rate=0.7 mL/min).
Reaction SMILES: C1CCCCC1.C([Li])(CC)C.Br[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][N:14]=1.CN(C)[C:22](=[O:24])[CH3:23]>C(OCC)C>[C:22]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][N:14]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)N(C)C
Reactant: Clc1ccc(Br)nc1
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: CCOCC
Product: CC(=O)c1ccc(Cl)cn1
Temperature: -74 °C
Reaction time: 1.5 h
Yield: 65 %

Procedure:
A two liter 4 neck flask was equipped with a stirrer, a thermometer and a 250 mL addition funnel. The reaction setup was flushed with nitrogen overnight. A 1.3 M cyclohexane solution of sec-butyllithium (222 mL, 0.289 mol) was charged to the addition funnel with a cannula. 2-Bromo-5-chloropyridine (57.72 g, MW=192.4, 0.30 mol) and 600 mL of ethyl ether were charged to the flask and then cooled in an acetone/dry ice bath. The temperature of the resultant slurry was -76° C. The sec-butyllithium was added dropwise at a rate to maintain the temperature at -74° C. or lower. The addition took 1.5 hours. When the addition was complete the addition funnel was rinsed with 20 mL of ethyl ether, then charged with 30.7 mL of N,N-dimethylacetamide (MW=87.12, d=0.937, 0.330 mol) and 30 mL of ethyl ether. Ten minutes after the completion of the sec-butyllithium addition, the N,N-dimethylacetamide solution was added dropwise to the reaction mixture, again maintaining the temperature at -74° C. or less. This addition took about 40 minutes. The reaction mixture was held at -76° C. for one hour after the N,N-dimethylacetamide addition was complete, then the bath was removed and the temperature allowed to warm to -30° C. At this temperature the cold bath was replaced and the reaction was quenched with 200 mL of 3 N HCl. The reaction mixture was allowed to warm to room temperature and held overnight. The phases were separated, the ethyl ether phase washed with water and saturated brine and then dried over anhydrous MgSO4. The ethyl ether was stripped, the crude product dissolved in methylene chloride and then treated with one weight equivalent of silica gel. The resulting slurry was filtered through Celite and stripped. The product was recrystallized from hexane to give 29.35 g of 2-acetyl-5-chloropyridine (65% yield based on sec-butyllithium, the limiting reagent).
Reaction SMILES: C(O[C:4](=[O:17])[CH2:5][O:6][C:7]1[C:8]([N+:14]([O-])=O)=[N:9][C:10](Br)=[CH:11][CH:12]=1)C.BrC1N=C([N+]([O-])=O)[C:22]([OH:28])=CC=1.C([O-])([O-])=O.[K+].[K+].BrCC(OCC)=O>CC(C)=O.CCOCC>[O:17]=[C:4]1[CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH:22]=[O:28])=[N:9][C:8]=2[NH:14]1
Reactant: O=[N+]([O-])c1nc(Br)ccc1O
Reactant: CCOC(=O)COc1ccc(Br)nc1[N+](=O)[O-]
Agent: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: O=Cc1ccc2c(n1)NC(=O)CO2
Temperature: 25 °C
Reaction time: 20 h
Yield: 74 %

Procedure:
(6-Bromo-2-nitro-pyridin-3-yloxy)-acetic acid ethyl ester. To a suspension of 6-bromo-2-nitro-pyridin-3-ol (3.07 g, 14.0 mmol) in acetone (20 mL) was added K2CO3 (3.93 g, 28.0 mmol) and ethyl bromoacetate (1.55 mL, 14.0 mmol). The mixture was heated to reflux and stirred for 20 h. The resulting suspension was cooled to RT, diluted with Et2O (100 mL) and filtered. The filtrate was concentrated to afford 3.14 g (74%) of the title compound, which was used without further purification. MS (ESI): exact mass calculated for C9H9BrN2O5, 303.97; m/z found, 305.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.67 (d, J=8.6, 1H), 7.35 (d, J=8.7, 1H), 4.78 (s, 2H), 4.27 (q, J=7.1, 2H), 1.30 (t, J=8.5, 3H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:16]=[CH:17][C:18]([C:19]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:21])=[CH:22][CH:23]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: C1CCNC1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N2CCCC2)cn1
Yield: 98 %

Procedure:
As described for example 191, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.64 mmol) was converted, using pyrrolidine instead of 2-aminoethyl isopropylether, to the title compound (229 mg, 98%) which was obtained as a colourless. MS: m/e=364.3 [M+H]′.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[CH:16][N:17]2[CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27].[C:30](Cl)(=[O:34])[C:31](Cl)=[O:32]>>[CH3:27][Si:26]([CH3:29])([CH3:28])[CH2:25][CH2:24][O:23][CH2:22][N:17]1[C:18]2[C:14](=[C:13]([N:12]3[C:3]4[CH:4]=[CH:5][C:6]5[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=5[C:2]=4[NH:1][C:31](=[O:32])[C:30]3=[O:34])[CH:21]=[CH:20][CH:19]=2)[CH:15]=[CH:16]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: C[Si](C)(C)CCOCn1ccc2c(Nc3ccc4c(c3N)CCCC4)cccc21
Product: C[Si](C)(C)CCOCn1ccc2c(-n3c(=O)c(=O)[nH]c4c5c(ccc43)CCCC5)cccc21

Procedure:
1-Amino-2-[1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-4-yl]amino-5,6,7,8-tetrahydronaphthalene and oxalyl chloride were used in a process similar to Example 1(3) to give the titled compound.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[C:3]=1[CH3:9].C(=O)([O-])[O-].[Na+].[Na+].[I:16]I.S([O-])([O-])=O.[Na+].[Na+].S([O-])([O-])=O>C1COCC1.CO>[NH2:1][C:2]1[CH2:7][CH2:6][CH:5]([I:16])[C:4](=[O:8])[C:3]=1[CH3:9]
Reactant: CC1=C(N)CCCC1=O
Reactant: II
Agent: O=C([O-])[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC1=C(N)CCC(I)C1=O
Temperature: 10 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
50 g (0.4 mol, 1 eq) of 3-amino-2-methyl-2-cyclohexen-1-one and 106 g (1 ml, 2.5 eq) of sodium carbonate are dispensed into the reactor. 480 mL of MeOH is added. The mixture is cooled in an ice bath to 10° C. A solution of iodine in THF, made by dissolving 253 g (1 mol, 2.5 eq) of iodine in 300 ml of THF, is added to above suspension slowly so that the temperature does not exceed 25° C. The resulting dark suspension is stirred for ˜1 h at room temperature and HPLC shows the ending point of reaction (product area percentage at 265 nm was larger than 70%). To the reaction mixture in the ice bath, is added an aqueous saturated solution of sodium sulfite slowly, until the peroxide level is below 3 ppm (by peroxide test strips), and at same time, the sulfite level is below 50 ppm (by sulfite test strips). Approximately 1.5 q of sodium sulfite is used. The suspension is filtered through a celite pad and the pad is washed with 150 mL×3 of THF (washings not optimized). The combined filtrate and washes are concentrated under vacuum until solid crashes out. 250 mL of MTBE is added and the two layer mixture is concentrated again under vacuum until all upper layer evaporates. 250 mL of MTBE and 100 mL of H2O are added and the mixture is stirred at room temperature for 30 minutes. A dark yellow solid crashes out upon stirring and is filtered and washed with water to give 3-amino-6-iodo-2-methyl-2-cyclohexen-1-one 65 g (65% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10]\[CH:11]=[CH:12]\[C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.[N+:21]([C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1)([O-:23])=[O:22].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9](\[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)/[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:26][CH:25]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCCCC/C(=C/C=C/C(=O)O)c1ccc(OC)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCC/C(=C/C=C/C(=O)Oc1ccc([N+](=O)[O-])cc1)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.1 %

Procedure:
As in Example 115. (2E,4Z)-5-(4-methoxyphenyl)-2,4-decadienoic acid (2.8 g) and 4-nitrophenol (1.71 g) in 20 mL of dichloromethane was reacted with 1,3-dicyclohexylcarbodiimide (2.1 g). The mixture was stirred at room temperature for 18 hours and the usual work up furnished 4.0 g of (2E,4Z)-5-(4-methoxyphenyl)-2,4-decadienoic acid 4-nitrophenyl ester as an oil.
Reaction SMILES: Cl.[NH2:2][C:3](=[NH:15])[N:4]1[CH2:9][CH2:8][CH:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5]1.[Cl:16][C:17]([SH:20])(Cl)Cl.[OH-].[Na+]>ClCCl.O>[Cl:16][C:17]1[S:20][N:2]=[C:3]([N:4]2[CH2:5][CH2:6][CH:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:8][CH2:9]2)[N:15]=1
Reactant: CCOC(=O)C1CCN(C(=N)N)CC1
Reactant: SC(Cl)(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C1CCN(c2nsc(Cl)n2)CC1
Temperature: 25 °C
Yield: 62.7 %

Procedure:
To a solution of ethyl 1-[amino(imino)methyl]piperidine-4-carboxylate hydrochloride (1.50 g, 6.36 mmol) and perchloromethyl mercaptan (1.37 ml, 12.7 mmol) in dichloromethane (40 ml) was added dropwise a solution of sodium hydroxide (2.04 g, 50.9 mmol) in water (6 ml) under ice-cooling. Then, the reaction mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give 1.10 g (62.9%) of the desired product as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]=O)[CH:23]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:12]2[CH2:13][CH2:14][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:10][CH2:11]2)[CH:23]=1
Reactant: O=Cc1cccc(-c2ccccc2Cl)c1
Reactant: COc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: COc1ccccc1N1CCN(Cc2cccc(-c3ccccc3Cl)c2)CC1

Procedure:
61 mg of the target compound (0.16 mmol, 33.7%) was obtained using 1-(2-methoxyphenyl)piperazine (177 mg, 0.92 mmol), 2′-chlorobiphenyl-3-carbaldehyde (100 mg, 0.46 mmol) and NaBH(OAc)3 (297 mg, 1.38 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:9](=[O:10])[O:8][CH2:7]2)([OH:3])=[O:2].[C:14]1([CH3:24])[CH:19]=CC(S(Cl)(=O)=O)=C[CH:15]=1.C(O)(C)(C)C>N1C=CC=CC=1>[C:14]([O:2][C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:9](=[O:10])[O:8][CH2:7]2)=[O:3])([CH3:24])([CH3:19])[CH3:15]
Reactant: O=C(O)c1ccc2c(c1)COC2=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CC(C)(C)O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)c1ccc2c(c1)COC2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5-Carboxyphthalid (100 g, 0.56 mole) is suspended in pyridine (1200 mL). p-toluenesulfonyl chloride (211 g, 1.12 mole) is added and the mixture is stirred for 30 minutes at room temperature. Tert.Butanol (54 g, 0.73 mole) is added and the reaction mixture is left at room temperature with efficient stirring for 3 days. The clear solution is poured into ice water and the precipitated crystals are filtered off. The product is recrystallized from 2-propanol (500 mL). Yield: 123 g, 94%. DSC onset: 151.5° C.
Reaction SMILES: [CH2:1]([C@H:8]1[C@H:12]([CH2:13][CH:14]([NH:29][C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=3)=[CH:18][CH:17]=2)[O:11]C(C)(C)[N:9]1C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.Cl>C1COCC1>[NH2:9][C@@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@@H:12]([OH:11])[CH2:13][CH:14]([NH:29][C:30](=[O:31])[O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=2)=[CH:20][CH:21]=1
Reactant: Cc1ccc(-c2ccc(CC(C[C@@H]3OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]3Cc3ccccc3)NC(=O)OCc3ccccc3)cc2)nc1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc(CC(C[C@H](O)[C@@H](N)Cc3ccccc3)NC(=O)OCc3ccccc3)cc2)nc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A solution containing the product from Example 128C (0.322 g, 0.496 mmol) in a mixture of THF (5 mL), methanol (5 mL), and aqueous HCl (5 mL, 1 N) was stirred at 60° C. for 16 hours. The solvent was removed under reduced pressure to give the title compound as the hydrochloride salt.