Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[S:23][N:22]=[C:21]([N:24]4[CH2:29][CH2:28][CH:27]([NH:30]C(=O)OC(C)(C)C)[CH2:26][CH2:25]4)[N:20]=3)[CH2:15][CH2:14]2)=[O:12])=[N:2]1.[ClH:38]>O1CCCC1.CO.C(OCC)(=O)C>[ClH:38].[ClH:38].[NH2:30][CH:27]1[CH2:28][CH2:29][N:24]([C:21]2[N:20]=[C:19]([N:16]3[CH2:15][CH2:14][N:13]([C:11]([NH:10][C:3]4[C:4]5[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=5[O:1][N:2]=4)=[O:12])[CH2:18][CH2:17]3)[S:23][N:22]=2)[CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2nsc(N3CCN(C(=O)Nc4noc5ccccc45)CC3)n2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: NC1CCN(c2nsc(N3CCN(C(=O)Nc4noc5ccccc45)CC3)n2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.5 %

Procedure:
To a solution of tert-butyl [1-(5-{4-[(1,2-benzisoxazol-3-ylamino)carbonyl]piperazin-1-yl}-1,2,4-thiadiazol-3-yl)piperidin-4-yl]carbamate (200 mg, 0.378 mmol) in tetrahydrofuran (10 ml) and methanol (10 ml) was added a solution of 4 N hydrogen chloride in ethyl acetate (10 ml), and the mixture was stirred at room temperature for 5 hours. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of methanol and diethyl ether to give 181 mg (95.5%) of the desired product as a solid.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])([CH3:3])[CH3:2].[I:22]Cl.C([O-])(O)=O.[Na+]>CC(O)=O.O>[I:22][C:7]1[CH:6]=[C:5]([S:12]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)(=[O:13])=[O:14])[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][C:8]=1[O:10][CH3:11]
Reactant: ClI
Reactant: COc1ccc(S(=O)(=O)c2ccc(C)cc2)c(C(C)C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(C(C)C)c(S(=O)(=O)c2ccc(C)cc2)cc1I
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.8 %

Procedure:
To a solution of 2-Isopropyl4-methoxy-1-(toluene4-sulfonyl)-benzene (10 g, 31.25 mmol) in HOAc (10 ml) was added a solution of ICl (9.6 g, 59.26 mmol) in HOAc (10 ml) and H2O (5 ml). The reaction mixture was stirred at room temperature for 16 hrs and basified by saturated NaHCO3 solution. The aqueous solution was extracted into EtOAc which was washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo to give 1-Iodo4-isopropyl-2-methoxy-5-(toluene4-sulfonyl)-benzene (12.35 g, 89%).
Reaction SMILES: [Cl-:1].[Cl-].C([N:10]1[CH2:14][CH2:13][C:12]([OH:18])([CH2:15][NH:16][CH3:17])[CH2:11]1)C1C=CC=CC=1>CO.[Pd]>[ClH:1].[ClH:1].[OH:18][C:12]1([CH2:15][NH:16][CH3:17])[CH2:13][CH2:14][NH:10][CH2:11]1
Reactant: CNCC1(O)CCN(Cc2ccccc2)C1
Reactant: [Cl-]
Agent: [Pd]
Solvent: CO
Product: CNCC1(O)CCNC1
Product: Cl

Procedure:
6.9 g (23.5 mmol) of 1-benzyl-3-hydroxy-3-methylaminomethylpyrrolidine dichloride in 100 ml of methanol are hydrogenated on 2 g of palladium/active carbon (10%) at 80° C. and 100 bar. The catalyst is filtered off with suction, the solution is concentrated and the residue is triturated with butanol. The crystalline salt is filtered off with suction, washed with acetone and dried.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][CH:19]=2)=[O:17])[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C=CNC(=O)C=1)C1C=CC=CC=1.BrCC(C1C=CC(CO)=C([F:54])C=1)=O>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([C:18]2[CH:19]=[CH:20][C:21]([CH2:24][OH:25])=[C:22]([F:54])[CH:23]=2)=[O:17])[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CO)cc1
Reactant: O=C(CBr)c1ccc(CO)c(F)c1
Agent: O=c1cc(OCc2ccccc2)cc[nH]1
Product: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CO)c(F)c1

Procedure:
4-Benzyloxy-1-[2-(3-fluoro-4-hydroxymethyl-phenyl)-2-oxo-ethyl]-1H-pyridin-2-one is prepared following preparation 15b from 193 mg (0.93 mmol) 4-benzyloxy-1H-pyridin-2-one and 230 mg (0.93 mmol) 2-bromo-1-(3-fluoro-4-hydroxymethyl-phenyl)-ethanone (preparation 16f).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([CH:18]=1)[CH2:7][C:8]1[CH:17]=[CH:16][C:11]2[O:12][CH2:13][CH2:14][O:15][C:10]=2[CH:9]=1.C([Li])CCC.[CH2:25]([O:32][C@@H:33]1[C@@H:38]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@H:37]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C@@H:36]([CH2:55][O:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[S:35][C:34]1=[O:64])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1>[CH2:25]([O:32][C@@H:33]1[C@@H:38]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@H:37]([O:47][CH2:48][C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[C@@H:36]([CH2:55][O:56][CH2:57][C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=2)[S:35][C:34]1([C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([CH2:7][C:8]2[CH:17]=[CH:16][C:11]3[O:12][CH2:13][CH2:14][O:15][C:10]=3[CH:9]=2)[CH:18]=1)[OH:64])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Clc1ccc(Br)cc1Cc1ccc2c(c1)OCCO2
Reactant: O=C1S[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2ccc(Cl)c(Cc3ccc4c(c3)OCCO4)c2)S[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a solution of 6-(5-bromo-2-chlorobenzyl)-2,3-dihydrobenzo[b][1,4]dioxine (124, 384 mg, 1.1 mmol) in tetrahydrofuran (5 mL) at −78° C. under an atmosphere of nitrogen was added dropwise n-butyllithium (2.5M in hexane, 0.45 mL, 1.1 mmol), and the mixture was stirred for 0.5 h at the same temperature. Then a solution of (3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-thiopyran-2-one (123, 300 mg, 0.54 mmol, This compound was synthesized by reference to H. Driguez and B. Henrissat, Tetrahedron Lett. 1981, 22, 5061-5062, Kakinuma, H., et al., J. Med. Chem. 2010, 53, 3247-3261) in tetrahydrofuran (5 mL) was added dropwise, and the mixture was stirred for 15 min at the same temperature. The reaction mixture was quenched by addition of saturated ammonium chloride solution. After complete addition, the solution was gradually raised to room temperature. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (silica gel, 3 to 30% tetrahydrofuran in hexane) to yield (3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-2-(4-chloro-3-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)phenyl)tetrahydro-2H-thiopyran-2-ol (125, 416 mg, 0.51 mmol, 95%) as a white solid.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[O:6][C:5]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][C:3]=1[OH:22].[CH:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[SH:32])([CH3:25])[CH3:24].N1CCCCC1>ClCCl>[OH:22][C:3]1[CH2:4][C:5]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6][C:7](=[O:8])[C:2]=1[S:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)c1ccccc1S
Reactant: O=C(O)CCCCC1(c2ccccc2)CC(O)=C(Br)C(=O)O1
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CC(C)c1ccccc1SC1=C(O)CC(CCCCC(=O)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared as described in General Method 6 from 1.1 mmol of 5-[5-bromo-3,6-dihydro-4-hydroxy-6-oxo-2-phenyl-2H-pyran-2-yl]pentanoic acid (prepared in example DDD), 1.3 mmol of 2-isopropylbenzenethiol, and 1.3 mmol of piperidine in 20 mL of dichloromethane. The crude product was chromatographed on silica gel, eluting first with 5% methanol in chloroform and then with 9:1:0.5 chloroform:methanol:acetic acid, to give the title compound, (m.p. 145°-146° C.). 1H NMR (DMSO-d6) δ 1.07-1.19 (t plus m, 7 H), 1.25 (m, 1 H), 1.43 (m, 2 H), 1.91 (m, 2 H), 2.15 (t, 2 H), 3.19 (m, 1 H), 3.41 (2 H+H2O), 5.81 (d, 1 H), 6.54 (t, 1 H), 6.93 (t, 1 H), 7.12 (d, 1 H), 7.29-7.44 (m, 5 H).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(N1CCC(CC2C=CC=CC=2)([C:20](=[O:29])[C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)C1)=O)(C)(C)C.[OH-].[Na+]>C(Cl)Cl.O>[Cl:28][C:23]1[CH:22]=[C:21]([CH:20]=[O:29])[CH:26]=[CH:25][C:24]=1[Cl:27]
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccccc2)(C(=O)c2ccc(Cl)c(Cl)c2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (0.3 mL) was added at room temperature to a solution of 3-benzyl-3-(3,4-dichloro-benzoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (40 mg, 0.092 mmol) in DCM (3 mL). The reaction mixture was stirred at room temperature for 1 hour, then poured into aqueous NaOH (1.0 M), diluted with water and extracted with DCM. The combined organic extracts were dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (3% to 10% of MeOH in DCM+0.5% of NH4OH) to give 15 mg (48% yield) of 3-benzyl-pyrrolidin-3-yl)-(3,4-dichloro-phenyl)-methanone as a yellow oil. This material was dissolved in DCM and a solution of HCl (1.0 M in Et2O, 1.1 equivalents) was added, the resulting mixture was concentrated under reduced pressure and the residue was triturated with Et2O to give 17 mg of 3-benzyl-pyrrolidin-3-yl)-(3,4-dichloro-phenyl)-methanone hydrochloride as a white solid; MS=334 [M+H]+.
Reaction SMILES: [CH3:1][C@H:2]([CH2:7][CH2:8][O:9][Si](C(C)(C)C)(C)C)[CH2:3][CH:4]=[CH:5][CH3:6].[H][H]>[OH-].[OH-].[Pd+2].CO>[CH3:1][C@@H:2]([CH2:3][CH2:4][CH2:5][CH3:6])[CH2:7][CH2:8][OH:9]
Reactant: [H][H]
Reactant: CC=CC[C@H](C)CCO[Si](C)(C)C(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCCC[C@H](C)CCO

Procedure:
To a solution of 74.8 g. of 5-(S)-methyl-7-(t-butyldimethylsilyloxy)-2-heptene in 500 ml. of methanol was added 7.5 g. of 10% palladium hydroxide on carbon and the mixture shaken in a hydrogen atmosphere for 1.5 hours at 50 psi. The catalyst was filtered and the solvent removed under vacuum, 30 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]#[N:11])=[CH:4][CH:3]=1.[OH:12][NH2:13]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][C:10]([NH:13][OH:12])=[NH:11])=[CH:6][CH:7]=1
Reactant: N#CC=Cc1ccc(Cl)cc1
Reactant: NO
Solvent: CCO
Product: N=C(C=Cc1ccc(Cl)cc1)NO
Yield: 50.9 %

Procedure:
A solution of 3-(4-chloro-phenyl)-acrylonitrile (1.63 g, 10 mmol) and hydroxyamine (0.74 ml, 12 mmol) in ethanol (10 ml) was stirred at room temperature overnight. The solvent was evaporated, and the residue was purified by column chromatography (EtOAc: Hexane=1:3) to give 1.0 g (51%) of 3-(4-chloro-phenyl)-N-hydroxy-acrylamidine.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[CH:11]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=3)[C:10](=[O:27])[N:9]2[CH3:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br-].[Br-].[Br-].C1([N+](CC)(CC)CC)C=CC=CC=1.C1([N+](CC)(CC)CC)C=CC=CC=1.C1([N+](CC)(CC)CC)C=CC=CC=1>C1(C)C=CC=CC=1.CN(C=O)C>[CH:1]1([CH2:7][N:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=3)[C:10](=[O:27])[N:9]2[CH3:28])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN1C(=O)C(c2ccc(Cl)c(Cl)c2)C(c2ccncc2)N1CC1CCCCC1
Agent: CC[N+](CC)(CC)c1ccccc1
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cn1c(=O)c(-c2ccc(Cl)c(Cl)c2)c(-c2ccncc2)n1CC1CCCCC1

Procedure:
The solution of 1-Cyclohexylmethyl-4-(3,4-dichloro-phenyl)-2-methyl-5-pyridin-4-yl-pyrazolidin-3-one 0.16 g in toluene 20 mL and DMF 2 mL was treated with phenyltriethylammonium tribromide 0.22 g at room temperature, The reaction mixture was refluxed for 4 h. The reaction was quenched with sat. Na2SO3 25 mL at 0° C. The reaction mixture was extracted with dichloromethane, 3×25 mL. The combined organic phase was washed with brine, dried over anhydrous Na2SO4. After purification by flash chromatography, the title compound was obtained as light yellow solid 80 mg. MS (ES+): 416 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][NH:4][CH2:5][CH2:6][NH:7][CH2:8][CH2:9][NH2:10].[CH:25]([CH:27]([CH3:33])[C:28](OCC)=O)=[O:26]>>[OH:1][CH:2]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][NH:4][CH2:5][CH2:6][N:7]1[C:25](=[O:26])[CH:27]([CH3:33])[CH:28]=[N:10][CH2:9][CH2:8]1
Reactant: CCOC(=O)C(C)C=O
Reactant: CCCCCCCCCCCCCCC(O)CNCCNCCN
Product: CCCCCCCCCCCCCCC(O)CNCCN1CCN=CC(C)C1=O

Procedure:
Into an apparatus similar to that in Example 1, were charged 339.5 g (1 mole) of N-(2-hydroxy)hexadecyldiethylenetriamine and 130.1 g of ethyl 2-formylpropionate. At 140° to 150° C., 18 g of water and 46 g of ethanol were distilled off to obtain 4-(2-hydroxyhexadecyl)aminoethyl-6-methyl-3,6-dihydro-2H-1,4-diazepin-5-one.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.[C:32]([O:35][C:36]1[CH:43]=[CH:42][C:39]([CH:40]=[CH2:41])=[CH:38][CH:37]=1)(=[O:34])[CH3:33].C(N(CC)C(C)C)(C)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:41]=[CH:40][C:39]1[CH:42]=[CH:43][C:36]([O:35][C:32](=[O:34])[CH3:33])=[CH:37][CH:38]=1
Reactant: C=Cc1ccc(OC(C)=O)cc1
Reactant: O=[N+]([O-])c1ccccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(=O)Oc1ccc(C=Cc2ccccc2N)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of 1-bromo-2-nitrobenzene (2.0 g), palladium(II) acetate (112 mg) and 2-(di-tert-butylphosphino)biphenyl (150 mg) in acetonitrile (20 ml) were sequentially added 4-acetoxystyrene (1.7 ml) and N,N-diisopropylethylamine (5 ml) under a nitrogen atmosphere, and the solution was stirred for 3 hours at 80° C. The solution was extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. Obtained by purifying the residue by silica gel column chromatography (hexane-ethyl acetate system), acetic acid 4-[2-(2-nitrophenyl)vinyl]phenyl ester (840 mg) was used according to an analogous synthetic method to Example 57 to provide the title compound (330 mg).
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:25]([OH:27])=O.Cl.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2([NH2:42])[CH2:41][CH2:40]2)[N:34]=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[C:7]2[C:8]([C:18]([NH:19][CH3:20])=[O:21])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([C:25](=[O:27])[NH:42][C:39]2([C:35]3[N:34]=[N:33][CH:38]=[CH:37][CH:36]=3)[CH2:41][CH2:40]2)[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: NC1(c2cccnn2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)c(F)c12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5cccnn5)CC4)ccc3C)c(F)c12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture 3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.04 g, 0.095 mmol, 1 eq), 1-(pyridazin-3-yl)cyclopropanamine HCl salt (0.017, 0.095 mmol, 1 eq) and Py-Bop (0.064 g, 0.12 mmol, 1.3 eq) in DMF at ambient temperature under nitrogen was added triethylamine (0.029 g, 0.28 mmol, 3 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by preparative HPLC. Yield: 0.029 g (57%). 1H NMR (400 MHz, CD3OD): δ 9.14 (d, J=3.6 Hz, 1H), 7.97-7.85 (m, 6H), 7.56 (d, J=8.4 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.34-7.28 (m, 3H), 2.96 (s, 3H), 2.30 (s, 3H), 1.89-1.86 (m, 2H), 1.62-1.59 (m, 2H). 19F NMR (376.57 MHz, CD3OD): δ −77.63 (TFA), −112.22, −112.77 LCMS: (ES+) m/z=539.2 (M+H)+
Reaction SMILES: [C:1]1([C:7]2[S:11][CH:10]=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:21])=[C:17]([CH:20]=1)[CH:18]=O>>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:21])=[C:17]([CH2:18][C:10]2[S:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][N:9]=2)[CH:20]=1
Reactant: O=Cc1cc(Br)ccc1Cl
Reactant: c1ccc(-c2cncs2)cc1
Product: Clc1ccc(Br)cc1Cc1ncc(-c2ccccc2)s1

Procedure:
A solution of thiazole (10.0 g), iodobenzene (2.63 ml), tetrakis(triphenylphosphine)palladium (0) (1.36 g) and potassium acetate (3.46 g) in N,N-dimethylacetamide (100 ml) was stirred under heating at 100° C. overnight. The solvent was evaporated under reduced pressure, and added to the residue was ethyl acetate. The mixture was washed successively with water and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-90:10) to give 5-phenylthiazole (1.50 g) as a pale yellow solid. APCI-Mass m/Z 162 (M+H). (2) The above 5-phenylthiazole and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) were treated in a manner similar to Reference Example 100 to give 5-bromo-2-chloro-1-(5-phenyl-2-thiazolylmethyl)benzene as a yellow solid. APCI-Mass m/Z 364/366 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.FC(F)(F)S(O[CH2:33][CH:34]([O:37][CH3:38])[CH2:35][CH3:36])(=O)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][CH:34]([O:37][CH3:38])[CH2:35][CH3:36])[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: CCC(COS(=O)(=O)C(F)(F)F)OC
Product: CCC(CC(C(=O)OC(C)(C)C)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O)OC

Procedure:
1.00 g (2.67 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate in the presence of 2.94 ml (2.94 mmol, 1.1 eq.) of bis(trimethylsilyl)lithium amide (1M in tetrahydrofuran) and 945 mg (4.00 mmol, 1.5 eq.) of 2-methoxybutyl trifluoromethanesulphonate (racemate) were reacted according to General Method 7B. Yield: 669 mg (54% of theory)
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[S:13]([NH2:16])(=[O:15])=[O:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:17][I:18]>C(#N)C>[I-:18].[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[S:13]([NH:16][CH3:17])(=[O:14])=[O:15])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NS(=O)(=O)c1ccccc1CN1CCCC1
Reactant: CI
Solvent: CC#N
Product: CNS(=O)(=O)c1ccccc1CN1CCCC1
Product: [I-]

Procedure:
A solution of 2-(pyrrolidinomethyl)benzenesulfonamide (0.8 g) in acetonitrile (10 ml) was contacted with methyl iodide (3 ml) and heated to reflux for 2.0 hrs. Solvent was removed and the residue was treated with acetone and ether. The solid was filtered, digested with acetone (20 ml), chilled and collected. There was obtained 1.00 g of white solid. 1H nmr δDMSO-d6TMS 8.15-7.30 (m), 5.07 (s, 2H), 3.9-3.3 (m, 4H), 2.90 (s, 3H), 2.4-1.8 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[N:7]([CH:9]([C:11](=[O:38])[NH:12][CH:13]([C:18]([N:20]1[CH2:24][CH2:23][CH:22]2[NH:25][CH2:26][CH:27]([CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=3)[CH:21]12)=[O:19])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:10])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:40](O)(=[O:44])[C:41]([CH3:43])=[O:42].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:39])[N:7]([CH:9]([C:11](=[O:38])[NH:12][CH:13]([C:18]([N:20]1[CH2:24][CH2:23][CH:22]2[N:25]([C:40](=[O:44])[C:41](=[O:42])[CH3:43])[CH2:26][CH:27]([CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=3)[CH:21]12)=[O:19])[C:14]([CH3:16])([CH3:17])[CH3:15])[CH3:10])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C(=O)NC(C(=O)N1CCC2NCC(COc3ccc(F)c(F)c3)C21)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Reactant: CC(=O)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)C(=O)N1CC(COc2ccc(F)c(F)c2)C2C1CCN2C(=O)C(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.6 %

Procedure:
A solution of amine 84 (480 mg, 0.87 mmol) in DCM (8 mL) was cooled to 0° C. and treated with pyruvic acid (0.06 mL, 0.91 mmol), EDC (200 mg, 1.04 mmol), HOBt (141 mg, 1.04 mmol), and DIPEA (0.47 mL, 2.69 mmol). The reaction mixture was allowed to warm to ambient temperature. After 16 h, the reaction mixture was diluted with DCM, washed successively with 1M HCl, saturated aqueous NaHCO3, and brine, dried over anhydrous Na2SO4, filtered and concentrated to afford 87 (529 mg, 97%) as a white foam that was used with out further purification. 1H NMR (CDCl3, 300 MHz): δ7.10-7.01 (m, 1H), 6.88 (br s, 1H), 6.71-6.64 (m, 1H), 6.56-6.53 (m, 1H), 4.72-4.68 (m, 1H), 4.62-4.53 (m, 2H), 4.44 (d, J=6.3 Hz, 1H), 4.15-3.97 (m, 2H), 3.89-3.81 (m, 1H), 3.72-3.61 (m, 1H), 3.53-3.36 (m, 1H), 2.88-2.79 (m, 4H), 2.49-2.00 (m, 5H), 1.49 (s, 9H), 1.32 (d, J=6.9 Hz, 3H), 0.98 (s, 9H) ppm.
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:10]([CH3:20])=[C:9]([C:21]([O:23][CH3:24])=[O:22])[C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.[CH:25]1([CH2:28][O:29][C:30]2[CH:35]=[C:34]([F:36])[C:33]([O:37][CH3:38])=[CH:32][C:31]=2B2OC(C)(C)C(C)(C)O2)[CH2:27][CH2:26]1>>[CH:25]1([CH2:28][O:29][C:30]2[CH:35]=[C:34]([F:36])[C:33]([O:37][CH3:38])=[CH:32][C:31]=2[C:2]2[C:3]3[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:10]([CH3:20])=[C:9]([C:21]([O:23][CH3:24])=[O:22])[C:4]=3[N:5]=[C:6]([CH3:8])[N:7]=2)[CH2:26][CH2:27]1
Reactant: COC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(Cl)nc(C)nc12
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)c(OCC2CC2)cc1F
Product: COC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(-c3cc(OC)c(F)cc3OCC3CC3)nc(C)nc12

Procedure:
Starting from methyl 4-chloro-2,6-dimethyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example A.11) and 2-(2-cyclopropylmethoxy-4-fluoro-5-methoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane e (example B.c2) the title compound is obtained as off white solid.
Reaction SMILES: C1C2C(COC([NH:18][C@H:19]3[CH2:23][N:22]([C:24]([O:26]C(C)(C)C)=O)[C@H:21]([CH2:31][O:32][C:33](=[O:43])[NH:34][C:35]4[CH:40]=[CH:39][C:38]([CH2:41][CH3:42])=[CH:37][CH:36]=4)[CH2:20]3)=O)C3C(=CC=CC=3)C=2C=CC=1.Cl.CCN(C(C)C)C(C)C.[Cl:54][C:55]1[CH:64]=[CH:63][CH:62]=[CH:61][C:56]=1[CH2:57][N:58]=C=O>CO>[CH2:41]([C:38]1[CH:37]=[CH:36][C:35]([NH:34][C:33](=[O:43])[O:32][CH2:31][C@@H:21]2[CH2:20][C@@H:19]([NH2:18])[CH2:23][N:22]2[C:24](=[O:26])[NH:58][CH2:57][C:56]2[CH:61]=[CH:62][CH:63]=[CH:64][C:55]=2[Cl:54])=[CH:40][CH:39]=1)[CH3:42]
Reactant: CCc1ccc(NC(=O)OC[C@@H]2C[C@@H](NC(=O)OCC3c4ccccc4-c4ccccc43)CN2C(=O)OC(C)(C)C)cc1
Reactant: O=C=NCc1ccccc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CCc1ccc(NC(=O)OC[C@@H]2C[C@@H](N)CN2C(=O)NCc2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of crude (2S,4R)-tert-butyl 4-(((9H-fluoren-9-yl)methoxy)carbonylamino)-2-((4-ethylphenylcarbamoyloxy)methyl)pyrrolidine-1-carboxylate in MeOH was added HCl (4 N in dioxane). The reaction was stirred at rt for 1 h and concentrated. The residue was dissolved in THF (10 mL). To this solution were added DIEA (469 μL, 2.7 mmol) and 2-chlorobenzylisocyanate. The mixture was stirred at rt for 1 h and concentrated. The residue was dissolved in 10 ml of 20% piperidine in DCM. The reaction mixture was stirred at rt for 15 min, concentrated and purified on RP-HPLC using a mixture of acetonitrile and H2O to give ((2S,4R)-4-amino-1-(2-chlorobenzylcarbamoyl)pyrrolidin-2-yl)methyl 4-ethylphenylcarbamate (210 mg, 53% for 4 steps). LRMS (M+H+) m/z 431.1.