Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:19])[C:5]2[C:11](=[O:12])[N:10]([CH3:13])[C:9]3[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=3[NH:7][C:6]=2[N:18]=1.[H-].[Na+].Br[CH2:23][CH2:24][CH2:25][Cl:26].C(Cl)Cl>CN(C)C=O>[Cl:26][CH2:25][CH2:24][CH2:23][N:7]1[C:8]2[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=2[N:10]([CH3:13])[C:11](=[O:12])[C:5]2[C:4]([CH3:19])=[CH:3][C:2]([CH3:1])=[N:18][C:6]1=2
Reactant: ClCCCBr
Reactant: Cc1cc(C)c2c(n1)Nc1ccccc1N(C)C2=O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(C)c2c(n1)N(CCCCl)c1ccccc1N(C)C2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.47 gm of 6,11-dihydro-2,4,6-trimethyl-5H-pyrido-[2,3-b][1,5]benzodiazepin-5-one were dissolved in 15 ml of dimethyl formamide, 0.76 gm of 50% sodium hydride in mineral oil was added, and the mixture was stirred at room temperature for one hour. Then, 1.7 ml of 1-bromo-3-chloro-propane were added, and the mixture was stirred at room temperature for 5 hours. After standing overnight, 100 ml of methylene chloride were added and the reaction mixture was washed three times with water. The organic phase was dried over sodium sulfate and evaporated in vacuo at room temperature. The crystalline residue was digested with a mixture of 7 ml of chloroform and 7 ml of ethyl acetate, and the mixture was suction-filtered. The filter cake was recrystallized from absolute ethanol, yielding 52% of theory of 11-(3-chloro-propyl)-6,11-dihydro-2,4,6-trimethyl-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one having a melting point of 161°-163° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]23[CH2:24][CH:16]([C:17]4[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][C:22]=42)[C:15]2[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:3]1.Cl[C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1.C(N(CC)CC)C.CO>CN1CCCC1=O>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]2[CH:16]3[CH2:24][C:9]([CH2:8][N:5]4[CH2:6][CH2:7][CH:2]([NH:1][C:26]5[N:31]=[CH:30][CH:29]=[CH:28][N:27]=5)[CH2:3][CH2:4]4)([C:10]4[C:15]3=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:22]=2[CH:21]=1
Reactant: NC1CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Reactant: Clc1ncccn1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Solvent: CO
Product: Clc1ccc2c(c1)C1(CN3CCC(Nc4ncccn4)CC3)CC2c2ccccc21

Procedure:
4-amino-1-(2-chloro-9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)piperidine (0.500 g, 1.48 mmol, prepared as described in Example 7b) was heated to 100° C. for 5 hours in 1.5 mL N-methylpyrrolidinone with 2-chloropyrimidine (0.212 g, 1.85 mmol, commercial grade purified by extraction into petroleum ether) and triethylamine (0.300 g, 2.96 mmol) under a nitrogen atmosphere. Aqueous methanol (3 mL, 50% v/v) was added to the warm (50° C.) reaction mixture to give a white precipitate. The solid was collected by filtration and washed with fresh aqueous methanol (5 mL, 50% v/v) to give the title compound as a white solid. The solid was dissolved in methanolic hydrogen chloride, evaporated to dryness on a rotary evaporator, redissolved in a minimum volume of fresh methanol (2 mL) and added at a slow dropwise rate to rapidly stirring ethyl ether (80 mL) to precipitate the hydrochloride salt as a white solid (0.414 g, 0.99 mmol, 67%), mp 212°-214° C.; MS(CI) 417 (M+H); NMR (250 MHz, DMSO-d6): 10.17(br s, 1H), 8.38-8.33(m, 2H), 7.67(br m, 1H), 7.52`7.49(m, 1H), 7.38-7.31(m, 3H), 7.05-6.96(m, 3H), 6.70-6.63(m, 1H), 4.47(s, 1H), 4.35-4.29(m, 2H), 4.16(br m, 1H), 3.57-3.36(m, 4H), 2.76(m, 2H), 2.12-1.90(m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].[B-](F)(F)(F)F.[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.[I:33]I.O>CC#N>[F:1][C:2]1[CH:9]=[C:8]([I:33])[C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1ccc(F)c(C=O)c1
Reactant: II
Agent: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: O
Product: COc1cc(C=O)c(F)cc1I
Temperature: 80 °C
Yield: 82 %

Procedure:
A solution of 2-fluoro-5-methoxybenzaldehyde (Oakwood, 6.000 g, 38.9 mmol) and Selectfluor (13.79 g, 38.9 mmol) in 40 mL MeCN was treated with iodine (10.87 g, 42.8 mmol) and was heated to 80° C. for one hour. LC/MS showed mostly product, so the reaction mixture was poured into water and was extracted with DCM. The organic were dried over MgSO4 and concentrated. Purification of the crude residue by silica gel column chromatography (0-20% EtOAc/heptane) gave 2-fluoro-4-iodo-5-methoxybenzaldehyde (8.92 g, 31.9 mmol, 82% yield) as a 3:1 mixture with starting material. (M+H)+=281.0.
Reaction SMILES: C[O-].[Na+].C([NH:12][C:13]([NH:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1F)=[S:14])(=O)C1C=CC=CC=1>CO>[N+:22]([C:20]1[CH:19]=[CH:18][C:17]2[S:14][C:13]([NH2:12])=[N:15][C:16]=2[CH:21]=1)([O-:24])=[O:23]
Reactant: O=C(NC(=S)Nc1cc([N+](=O)[O-])ccc1F)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Nc1nc2cc([N+](=O)[O-])ccc2s1

Procedure:
To a solution of methanol (1.6 L) was added sodium methoxide (8.64 g). While stirring, 1-benzoyl-3-(2-fluoro-5-nitro-phenyl)-thiourea (16 g) was added as a solid and the mixture stirred at room temperature for 17 hours. After this time, the reaction mixture was cooled in an ice bath and then filtered. The precipitate was washed with water (7.10 g, 86%). 1H-NMR δ: 8.05 (d, 1H, J=2.2 Hz), 7.97 (brs, 2H), 7.93 (s, 1H), 7.90 (d, 1H, J=2.2 Hz); MS (ESI) 195.8 (M+1, 100%).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[C:3]3[N:4]([N:8]=[C:9]([NH2:11])[N:10]=3)[CH:5]=[CH:6][CH:7]=2)=[CH:15][CH:14]=1
Reactant: Nc1nc2c(Br)cccn2n1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Nc1nc2c(-c3ccc(Cl)cc3)cccn2n1

Procedure:
A mixture of 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (500 mg, 2.35 mmol), 4-chlorophenyl boronic acid (757 mg, 4.69 mmol), dichloro[1,1′-bis(diphenylphosphino)-ferrocene]palladium(II) dichloromethane adduct (153 mg, 0.188 mmol) and an aqueous solution of Na2CO3 (2 N, 2.35 mL, 4.69 mmol) in dioxane (10 mL) was stirred at 110° C. for 2 hours. The reaction mixture was diluted with a 2 N aqueous solution of sodium carbonate and extracted with diethyl ether, the combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue purified by silica gel chromatography using pentane/diethyl ether as eluent. The title compound was obtained as a white solid (572 mg, 99%).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10](B2OC(C)(C)C(C)(C)O2)=[CH:9][N:8]=1)=[O:5])[CH3:2].[Br:22]C1N=C(N)C=CC=1.C(N=C=O)C>>[Br:22][C:9]1[N:8]=[C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])[CH:12]=[CH:11][CH:10]=1
Reactant: Nc1cccc(Br)n1
Reactant: CCNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: CCN=C=O
Product: CCNC(=O)Nc1cccc(Br)n1

Procedure:
The title compound was synthesized by a method analogous to Intermediate 1 synthesis starting with 6-bromopyridin-2-amine and ethyl isocyanate. The crude residue was purified by flash chromatography (EtOAc/hexanes as eluent). MS (ESP): 245 (M+H+) for C8H10BrN3O; NMR: 1.08 (t, 3H), 3.16 (m, 2H), 7.26 (d, 1H), 7.64 (s, 1H), 7.75 (s, 1H), 8.08 (d, 1H), 9.29 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]2[O:22][CH:21]=[C:20](Br)[C:15]=2[CH:16]=[N:17][C:18]=1[NH2:19])[CH3:11].[CH3:24][N:25]1[CH:30]2[CH2:31][CH2:32][CH:26]1[CH:27]=[C:28]([Sn](C)(C)C)[CH2:29]2.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CN(C=O)C>C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CO.C(N(CC)CC)C>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]2[O:22][CH:21]=[C:20]([C:28]3[CH2:29][CH:30]4[N:25]([CH3:24])[CH:26]([CH2:32][CH2:31]4)[CH:27]=3)[C:15]=2[CH:16]=[N:17][C:18]=1[NH2:19])[CH3:11]
Reactant: CN1C2C=C([Sn](C)(C)C)CC1CC2
Reactant: C[C@@H](Oc1c(N)ncc2c(Br)coc12)c1c(Cl)ccc(F)c1Cl
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](Oc1c(N)ncc2c(C3=CC4CCC(C3)N4C)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 115 °C

Procedure:
In a two necked RB flask (50 mL), equipped with a N2 inlet, a water condenser and a magnetic stirrer, were placed 7-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-3-bromofuro[3,2-c]pyridine-6-amine (200 mg, 0.48 mmol), 8-methyl-3-(trimethylstannyl)-8-azabicyclo[3.2.1]oct-2-ene (216 mg, 0.75 mmol), tris(dibenzylideneacetone)dipalladium (100 mg, 0.11 mmol), tri-o-tolylphosphine (26 mg, 0.085 mmol), DMF (10 mL) and triethylamine (1.0 mL). This reaction mixture was heated at 114-116° C. for 4 h. TLC (10% MeOH in DCM) indicated that the starting material was consumed. DMF was removed under reduced pressure; water was added to the residue and extracted with DCM (3×10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude material was purified on silica gel column chromatography eluting with 2-5% methanol in dichloromethane to give the title compound. 1H NMR (CDCl3, 300 MHz): δ=1.2 (m, 1H), 2.85 (d, J=6.6 Hz, 3H), 2.31 (m, 2H), 2.58 (br, m, 2H), 2.70 (s, 3H), 3.10 (br, d, 1H), 3.90 (d, br, 2H), 4.77 (br, 2H), 6.40 (d, J=6.0 Hz, 1H), 6.55 (m, 1H), 7.01 (t, J=6.6 Hz, 1H), 7.30 (t, J=6.6 Hz, 1H), 7.40 (s, 1H), 8.21 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH:27]([NH:30][C:31]([CH2:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1)=[O:32])([CH3:29])[CH3:28]>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:39][CH2:38][C:37]1[CH:40]=[CH:41][C:34]([CH2:33][C:31](=[O:32])[NH:30][CH:27]([CH3:28])[CH3:29])=[CH:35][CH:36]=1
Reactant: CC(C)NC(=O)Cc1ccc(CN)cc1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Product: CC(C)NC(=O)Cc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Yield: 63.9 %

Procedure:
Use a method similar to the General Procedure 1-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (162 mg, 0.38 mmol) and 4-(iso-propylcarbamoyl-methyl)-benzylamine (157 mg, 0.76 mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1, 4:1, 2:1 and 1:1) to obtain 7-chloro-6-[4-(iso-propylcarbamoyl-methyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an oil (117 mg, 64%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]12[CH2:17][CH2:16][CH2:15][C:13]3[C:14]1=[C:9]([CH:10]=[CH:11][CH:12]=3)[N:8]([CH3:18])[C:7]2=[O:19].[CH2:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][NH:21]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[CH2:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][N:21]1[CH2:2][CH2:3][CH2:4][CH2:5][C:6]12[CH2:17][CH2:16][CH2:15][C:13]3[C:14]1=[C:9]([CH:10]=[CH:11][CH:12]=3)[N:8]([CH3:18])[C:7]2=[O:19]
Reactant: c1ccc2c(c1)CCNC2
Reactant: CN1C(=O)C2(CCCCBr)CCCc3cccc1c32
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)C2(CCCCN3CCc4ccccc4C3)CCCc3cccc1c32

Procedure:
2a-(4-Bromobutyl)-1-methyl-2a,3,4,5-tetrahydro-1H-benz[cd]indol-2-one (120 mg, 0.37 mmol), 1,2,3,4-tetrahydroisoquinoline (55 mg, 0.41 mmol) and potassium carbonate (77 mg, 0.56 mmol) were stirred at room temperature for 18 hours in anhydrous N,N-dimethylformamide (1 ml). The reaction solution was mixed with ethyl acetate, washed with water and saturated brine and dried with anhydrous magnesium sulfate, the solvent was removed by evaporation under a reduced pressure, and then the thus obtained material was separated and purified by a silica gel column chromatography to obtain 130 mg (0.34 mmol, 90% in yield) of the title compound.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:35])[CH:12]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:6][CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH:14]1([CH2:13][CH:12]([C:19]2[CH:20]=[CH:21][C:22]([C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([CH2:3][OH:2])=[CH:5][N:6]=2)=[O:35])[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: COC(=O)c1ccc(NC(=O)C(CC2CCCC2)c2ccc(-c3cccc4ccccc34)cc2)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: O=C(Nc1ccc(CO)cn1)C(CC1CCCC1)c1ccc(-c2cccc3ccccc23)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
A solution 6-[3-cyclopentyl-2-(4-naphthalen-1-yl-phenyl)-propionylamino]-nicotinic acid methyl ester (prepared in Example 25B-a, 140 mg, 0.29 mmol) in diethyl ether (2 mL) was cooled to 0° C. and then slowly treated with lithium aluminum hydride powder (17 mg, 0.44 mmol). The reaction mixture was stirred at 0° C. for 30 min and then allowed to warm to 25° C. where it was stirred for 3.5 h. The reaction mixture was then slowly quenched by the dropwise addition of water (5 mL). The resulting mixture was partitioned between water (25 mL) and ethyl acetate (25 mL), and the layers were separated. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-N-(5-hydroxymethyl-pyridin-2-yl)-2-(4-naphthalen-1-yl-phenyl)-propionamide (47 mg, 37%) as a light yellow foam: mp 72-75° C.; EI-HRMS m/e calcd for C30H30N2O2 (M+) 450.2307, found 450.2312.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[F:24])=[CH:10][C:11]1[N:15]([CH3:16])[N:14]=[N:13][N:12]=1.C([Li])CCC.[CH:30](OCC)=[O:31]>O1CCCC1>[F:24][C:18]1[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=1[C:9]([C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[F:1])=[C:10]([C:11]1[N:15]([CH3:16])[N:14]=[N:13][N:12]=1)[CH:30]=[O:31]
Reactant: Cc1ccc(C(=Cc2nnnn2C)c2ccc(C)cc2F)c(F)c1
Reactant: CCOC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C(=C(C=O)c2nnnn2C)c2ccc(C)cc2F)c(F)c1
Reaction time: 0.25 h
Yield: 37.3 %

Procedure:
To a solution of 1,1-bis(2-fluoro-4-methylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethene (1.6 g, 5.0 mmoles) in tetrahydrofuran (20 mL) at -78° C. was added butyl lithium (2.3 mL of a 2.2 M solution, 5 mmoles). After stirring for 15 minutes, ethyl formate (0.44 g, 6.0 mmoles) was added and the solution stirred with cooling for 2 hours. The reaction was quenched with 1N hydrochloric acid and the mixture extracted with diethyl ether. The extracts were dried (MgSO4) and evaporated. The residue was crystallized from isopropyl acetate to give 0.66 g of the title compound; m.p.=154°-155° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9]C(=O)OC(C)(C)C>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH2:9]
Reactant: Cc1cccc(F)c1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(F)c1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The crude carbamate from step 2 (7.2 g, 32 mmol) was treated with trifluoroacetic acid (30 mL). The resulting solution was stirred at room temperature for 30 minutes, then most of trifluoroacetic acid was evaporated under vacuum. The residue was diluted with CH2Cl2 and poured into a slurry of solid Na2CO3 in CH2Cl2. The resulting slurry was carefully treated with EtOAc to increase product solubility, then filtered through a pad of silica gel and the product washed off with EtOAc. The filtrate and washings were concentrated under vacuum to afford 2-fluoro-6-methylaniline as a yellow solid.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH:13]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[O:15][CH2:14]2)(=O)=O)=CC=1.[ClH:24].[CH3:25][O:26][C:27]([CH2:29][CH2:30][NH2:31])=[O:28].C(N(C(C)C)C(C)C)C>CN(C)C=O>[ClH:24].[O:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:22][CH:13]([CH2:12][CH2:11][NH:31][CH2:30][CH2:29][C:27]([O:26][CH3:25])=[O:28])[CH2:14]1
Reactant: COC(=O)CCN
Reactant: Cc1ccc(S(=O)(=O)OCCC2COc3ccccc3C2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CCNCCC1COc2ccccc2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
33.2 g (0.1 mol) of 3-[2-(p-toluenesulphonyloxy)ethyl]chroman, 14.0 g of N-(2-methoxycarbonylethyl)-amine hydrochloride and 39 g of N-ethyl-N,N-diisopropylamine are dissolved under nitrogen in 750 ml of dimethylformamide and the solution is stirred for 16 hours at room temperature. The reaction mixture is subsequently concentrated to approximately 200 ml under reduced pressure, 500 ml of water are then added and the whole is extracted by shaking three times with 150 ml of dichloromethane each time. The combined organic phases are dried over sodium sulphate and concentrated to dryness by evaporation. By adding ethanolic hydrochloric acid and cooling, N-[2-(chroman-3-yl)ethyl]-N-(2-methoxycarbonylethyl)-amine hydrochloride having a melting point of 190°-192° is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[NH2:19][C@H:20]([C:23]([NH2:25])=[O:24])[CH2:21][OH:22]>>[C:23]([C@@H:20]([NH:19][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][N:17]=[CH:18][C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])[CH2:21][OH:22])(=[O:24])[NH2:25]
Reactant: NC(=O)[C@@H](N)CO
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Product: NC(=O)[C@H](CO)NC(=O)c1ccncc1Nc1ccc(I)cc1F

Procedure:
N-(1-(S)-Carbamoyl-2-hydroxy-ethyl)-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.30 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.45 mmol of L-serinamide. LC/MS [5.09 min; 445 (M+1)]
Reaction SMILES: O=O.[CH2:3]([OH:12])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-:14].[K+].[K+]>[Pt].O>[C:3]([OH:14])(=[O:12])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OCC=Cc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [Pt]
Agent: O=O
Agent: [K+]
Solvent: O
Product: O=C(O)C=Cc1ccccc1
Yield: 96.3 %

Procedure:
In an ambient pressure oxygen atmosphere, 40.3 mg of cinnamyl alcohol, 105.3 mg of the platinum catalyst obtained in Example 1 and 40.2 mg of potassium carbonate were agitated for eighteen hours at 60° C. in 3 ml of water. The aqueous layer was subsequently washed using tert-butyl methyl ether and was extracted using ethyl acetate after neutralizing the layer with a HCl solution. The ethyl acetate solution was dried using magnesium sulfate, filtered and concentrated to obtain 41.5 mg (93% yield) of cinnamic acid. The reaction equation and the analytical results of the product are shown below.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C@H:11]1[C:16]2[CH:17]=[CH:18][C:19]([N:21]=[C:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:20][C:15]=2[CH2:14][CH2:13][O:12]1)(C(C)(C)C)(C)C.OCC[C@H]1C2C=CC(C(N)=O)=CC=2CCO1>C(O)(=O)C>[C:29]1([C:22](=[N:21][C:19]2[CH:18]=[CH:17][C:16]3[C@H:11]([CH2:10][CH2:9][OH:8])[O:12][CH2:13][CH2:14][C:15]=3[CH:20]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)[Si](C)(C)OCC[C@@H]1OCCc2cc(N=C(c3ccccc3)c3ccccc3)ccc21
Agent: NC(=O)c1ccc2c(c1)CCO[C@H]2CCO
Solvent: CC(=O)O
Product: OCC[C@@H]1OCCc2cc(N=C(c3ccccc3)c3ccccc3)ccc21

Procedure:
(1S)-1-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-N-(diphenylmethylene)-3,4-dihydro-1H-2-benzopyran-6-amine was deprotected with aqueous acetic acid, as described for the preparation of (1S)-1-(2-hydroxyethyl)-3,4-dihydro-1H-2-benzopyran-6-carboxamide, to yield 2-{(1S)-6-[(diphenylmethylene)amino]-3,4-dihydro-1H-2-benzopyran-1-yl}ethanol.
Reaction SMILES: [NH2:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]([O:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)=[O:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.Br[CH2:20][C:21]([N:23]1[CH2:27][C@@H:26]([F:28])[CH2:25][C@H:24]1[C:29]#[N:30])=[O:22]>>[O:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH:13]1[O:12][C:10]([C:5]12[CH2:6][CH2:7][C:2]([NH:1][CH2:20][C:21]([N:23]3[CH2:27][C@@H:26]([F:28])[CH2:25][C@H:24]3[C:29]#[N:30])=[O:22])([CH2:9][CH2:8]1)[CH2:3][CH2:4]2)=[O:11]
Reactant: NC12CCC(C(=O)OC3CCCCO3)(CC1)CC2
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CBr
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)OC3CCCCO3)(CC1)CC2
Yield: 79.6 %

Procedure:
In a similar manner to Example 2, 2-tetrahydropyranyl 4-aminobicyclo[2.2.2]octane-1-carboxylate (62.9 mg) and (2S,4S)-1-(2-bromoacetyl)-4-fluoropyrrolidine-2-carbonitrile (53.1 mg) were used to obtain (2S,4S)-1-[[N-[4-(2-tetrahydropyranyl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (73.3 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:11]=2[C:12]([O:14]C(C)(C)C)=[O:13])[CH:5]=[N:6][C:7]=1[F:8]>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:11]=2[C:12]([OH:14])=[O:13])[CH:5]=[N:6][C:7]=1[F:8]
Reactant: Cc1ccc(Nc2cnc(F)c(F)c2)c(C(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(Nc2cnc(F)c(F)c2)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15 %

Procedure:
The solid residue obtained in step A was dissolved in 0.78 ml of trifluoroacetic acid and stirred for 1 hour at room temperature. The solvent was evaporated and the solid residue was triturated with an isopropyl ether/hexane mixture. The solid was filtered off affording 0.01 g (yield 15%) of the expected product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:9]([O:10][CH2:11][O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=[C:6]([O:16][CH2:17][O:18][CH3:19])[C:5]=1[O:20][CH3:21].[H-].[Na+].O1CCCC1.I[CH2:30][CH2:31][CH2:32][C:33]1[C:38]([O:39][CH2:40][O:41][CH3:42])=[C:37]([O:43][CH3:44])[CH:36]=[C:35]([O:45][CH2:46][O:47][CH3:48])[C:34]=1[O:49][CH3:50]>CN(C)C=O.C(OCC)C>[CH3:50][O:49][C:34]1[C:35]([O:45][CH2:46][O:47][CH3:48])=[CH:36][C:37]([O:43][CH3:44])=[C:38]([O:39][CH2:40][O:41][CH3:42])[C:33]=1[CH2:32][CH2:31][CH2:30][O:1][CH2:2][CH2:3][C:4]1[C:9]([O:10][CH2:11][O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=[C:6]([O:16][CH2:17][O:18][CH3:19])[C:5]=1[O:20][CH3:21]
Reactant: COCOc1cc(OC)c(OCOC)c(CCCI)c1OC
Reactant: COCOc1cc(OC)c(OCOC)c(CCO)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCOc1cc(OC)c(OCOC)c(CCCOCCc2c(OC)c(OCOC)cc(OC)c2OCOC)c1OC
Temperature: 50 °C

Procedure:
374 Milligrams of 1-(2-hydroxyethyl)-2,5-dimethoxy-3,6-bis(methoxymethoxy)benzene was dissolved in 3 ml of dimethylformamide, under ice-cooling conditions, 80 mg of sodium hydride (60% dispersion) was added thereto, then 2 ml of tetrahydrofuran solution containing 527 mg of 1-(3-iodopropyl)-2,5-dimethoxy-3,6-bis(methoxymethoxy)benzene was added. The reaction mixture was heated at 50° C. in an oil bath. 6 Hours later, ice water and 100 ml of diethyl ether were added to the reaction mixture. The ether layer was washed twice with 50 ml of water, then washed twice with 50 ml of a saturated sodium chloride aqueous solution, then dried over anhydrous magnesium sulfate. This solution was concentrated under reduced pressure, and the residue obtained was purified by means of a silica gel column chromatography (diameter 3 cm×length 15 cm, eluent: 40% ethyl acetate-n-hexane mixed solvent, adsorbent: "Wakogel C-200") to obtain 484 mg of 2-[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]ethyl 3 -[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]propyl ether.