Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:14]=[CH:13][N:12]([CH3:15])[N:11]=1.Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([OH:27])[CH:25]=2)[N:20]=[CH:19][N:18]=1>>[F:8][C:5]1[CH:6]=[CH:7][C:2]([O:27][C:24]2[CH:25]=[C:26]3[C:21](=[CH:22][CH:23]=2)[N:20]=[CH:19][N:18]=[C:17]3[NH:9][C:10]2[CH:14]=[CH:13][N:12]([CH3:15])[N:11]=2)=[N:3][CH:4]=1
Reactant: Oc1ccc2ncnc(Cl)c2c1
Reactant: Fc1ccc(F)nc1
Reactant: Cn1ccc(N)n1
Product: Cn1ccc(Nc2ncnc3ccc(Oc4ccc(F)cn4)cc23)n1

Procedure:
The compound of Example 115 was manufactured by the same method as in Example 95, by a similar method thereto or by a combination of such a method with a conventional method using 2,5-difluoropyridine, 3-amino-1-methyl-pyrazole and 4-chloro-6-hydroxy-quinazoline.
Reaction SMILES: [F:1]/[C:2](=[C:14](/[F:22])\[C:15]1[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=1)/[C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH3:13])=[CH:7][CH:6]=1.C(N)CCC.[C:28]1([CH3:36])[CH:33]=[CH:32][C:31]([C:34]#[CH:35])=[CH:30][CH:29]=1.C([O-])(O)=O.[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1>[F:1]/[C:2](=[C:14](/[F:22])\[C:15]1[CH:20]=[CH:19][C:18]([C:35]#[C:34][C:31]2[CH:32]=[CH:33][C:28]([CH3:36])=[CH:29][CH:30]=2)=[CH:17][CH:16]=1)/[C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH3:13])=[CH:7][CH:6]=1
Reactant: C#Cc1ccc(C)cc1
Reactant: CCCc1ccc(C#C/C(F)=C(\F)c2ccc(Br)cc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCN
Product: CCCc1ccc(C#C/C(F)=C(\F)c2ccc(C#Cc3ccc(C)cc3)cc2)cc1
Temperature: 25 °C
Yield: 64.9 %

Procedure:
Into a 100 ml three-necked flask, 2.86 g of cuprous iodide, 4.33 g (0.012 mol) of (E)-3,4-difluoro-1-(4-propylphenyl)-4-(4-bromophenyl)-3-buten-1-yne obtained in Example 4 and 30 ml of dry THF were charged under an argon atmosphere, followed by stirring at room temperature. Then, 1.42 g of n-butylamine and 1.53 g of p-toluylacetylene were added thereto. Then, 10 ml of a dry THF solution containing 0.69 g of (Ph3P)4Pd was added thereto, and the mixture was stirred at room temperature for 2 hours. After an addition of 30 ml of a saturated NaHCO3 aqueous solution, the mixture was subjected to liquid separation, and then extracted with methylene chloride. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 3.09 g (yield: 65%) of (E)-3,4-difluoro-1-(4-propylphenyl)-4-[4-(2-p-toluylethynyl)phenyl]-3-buten-1-yne.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1([CH3:20])[CH2:11][O:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[CH3:19])=[N:8]1.Cl[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([CH3:31])[CH:24]=1>C1COCC1>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][CH2:19][C:13]2[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:12]=2[C:9]2[O:10][CH2:11][C:7]([CH3:20])([CH3:6])[N:8]=2)=[CH:24][C:25]=1[CH3:31]
Reactant: Cc1ccc(C2=NC(C)(C)CO2)c(C)c1
Reactant: COc1ccc(CCl)cc1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(CCc2cc(C)ccc2C2=NC(C)(C)CO2)cc1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
n-Butyllithium (14.4 ml, 2.5M solution in hexane) was added dropwise to a stirred solution of the product from step (i) (6.9 g) in THF (100 ml) at 0° C. The solution was stirred at 0° C. for 1 hour and then transferred by cannula into a solution of 4-chloromethyl-1-methoxy-2-methylbenzene (J. Chem. Soc. 1956, 2455) (5.86 g) in THF (60 ml) at -30° C. The mixture was stirred for 1 hour and allowed to warm to room temperature. After 30 minutes the reaction was quenched with water. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with water, dried (MgSO4) and evaporated. Purification was by chromatography eluting with 5% ethyl acetate in isohexane. Yield 2.16 g.
Reaction SMILES: [NH2:1][CH2:2][C:3]1(O)[C:12]2[C:7](=[C:8]([O:15]C)[C:9]([O:13]C)=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1.B(Br)(Br)[Br:19]>>[BrH:19].[NH2:1][CH2:2][C:3]1[C:12]2[C:7](=[C:8]([OH:15])[C:9]([OH:13])=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH:4]=1
Reactant: BrB(Br)Br
Reactant: COc1ccc2c(c1OC)CCCC2(O)CN
Product: Br
Product: NCC1=CCCc2c1ccc(O)c2O

Procedure:
1-Aminomethyl-5,6-dimethoxy-1-hydroxy-1,2,3,4-tetrahydronaphthalene is treated with BBr3 according to the method of Example 4 to obtain 1-aminomethyl-5,6-dihydroxy-3,4-dihydronaphthalene HBr identical to that obtained in Example 4.
Reaction SMILES: O[CH2:2][CH2:3][CH:4]([C:11]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]2[C:12]=1[C:13]([C:22]#[N:23])=[CH:14][NH:15]2)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:24][NH:25]CCC(C1C=C2C(=CC=1)NC=C2C#N)C1C=CC=CC=1>>[CH3:21][O:20][C:18]1[CH:17]=[C:16]2[C:12]([C:13]([C:22]#[N:23])=[CH:14][NH:15]2)=[C:11]([CH:4]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:3][CH2:2][NH:25][CH3:24])[CH:19]=1
Reactant: CNCCC(c1ccccc1)c1ccc2[nH]cc(C#N)c2c1
Reactant: COc1cc(C(CCO)c2ccccc2)c2c(C#N)c[nH]c2c1
Product: CNCCC(c1ccccc1)c1cc(OC)cc2[nH]cc(C#N)c12

Procedure:
6-Methoxy-4-(3-methylamino-1-phenyl-propyl)-1H-indole-3-carbonitrile CXXXII (90 mg) was prepared from 4-(3-hydroxy-1-phenyl-propyl)-6-methoxy-1H-indole-3-carbonitrile using the procedure described above for preparation of 5-(3-Methylamino-1-phenyl-propyl)-1H-indole-3-carbonitrile LXVI. MS (M+H)=320.
Reaction SMILES: [Cl-].[In+3:2].[Cl-].[Cl-].[Sn:5](Cl)Cl.N.[OH2:9]>>[OH-:9].[Sn+4:5].[In+3:2].[OH-:9].[OH-:9].[OH-:9].[OH-:9].[OH-:9].[OH-:9]
Reactant: Cl[Sn]Cl
Reactant: O
Agent: N
Agent: [Cl-]
Agent: [In+3]
Product: [OH-]
Product: [Sn+4]

Procedure:
An aqueous indium chloride (InCl3) solution (containing 18 g of In metal) (50 mL) was mixed with 3.6 g of tin dichloride (SnCl2·2H2O) and the obtained mixed aqueous solution and an aqueous ammonia (NH3) solution were simultaneously added dropwise in 500 ml of water. After adjusting to pH 7, the mixture was reacted at a liquid temperature of 30° C. for 30 minutes. The thus obtained precipitate was repeatedly subjected to inclination washing with ion-exchange water. After resistivity of the supernatant liquid reaches 50,000 Ω·cm or more, a precipitate (In/Sn co-precipitated hydroxide) was separated by filtration to obtain a co-precipitated indium tin hydroxide whose dry powder has a persimmon tone.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]([F:16])([F:15])[F:14])=[C:11]([C:17]([OH:19])=O)[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][CH:21]([CH3:39])[CH2:22][CH2:23][NH:24][C:25]([C:27]1[N:28]=[N:29][C:30]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:31][CH:32]=1)=[O:26]>>[CH3:20][CH:21]([CH3:39])[CH2:22][CH2:23][NH:24][C:25]([C:27]1[N:28]=[N:29][C:30]([N:33]2[CH2:38][CH2:37][N:36]([C:17]([C:11]3[N:10]=[N:9][N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:12]=3[C:13]([F:14])([F:15])[F:16])=[O:19])[CH2:35][CH2:34]2)=[CH:31][CH:32]=1)=[O:26]
Reactant: O=C(O)c1nnn(Cc2ccccc2)c1C(F)(F)F
Reactant: CC(C)CCNC(=O)c1ccc(N2CCNCC2)nn1
Product: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)c3nnn(Cc4ccccc4)c3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 9, making variations only as required to use 1-benzyl-5-trifluoromethyl-1H-[1,2,3]triazole-4-carboxylic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl)amide, the title compound was obtained as a white powder (32% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.03, 7.81, 7.33-7.27, 6.86, 5.92, 5.39, 3.71, 3.47, 3.05, 2.63, 2.43, 1.65, 1.48, 0.92. MS (ES+) m/z 531.2 (M+1).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:7]=[CH:6][NH:5][N:4]=1.[Cl:10][C:11]1[CH:18]=[C:17](F)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:10][C:11]1[CH:18]=[C:17]([C:7]2[C:3]([C:2]([F:9])([F:8])[F:1])=[N:4][NH:5][CH:6]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: FC(F)(F)c1cc[nH]n1
Reactant: N#Cc1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2c[nH]nc2C(F)(F)F)cc1Cl
Temperature: 25 °C
Yield: 92 %

Procedure:
2.5 g (18.4 mmol) of 3-trifluoromethylpyrazole, 2.9 g (18.4 mmol) of 2-chloro-4-fluorobenzonitrile and 2.8 g (20.2 mmol) of potassium carbonate in 20 ml of N,N-dimethylformamide were stirred at 60° C. for 2 hours. After cooling to room temperature, the reaction mixture was poured into 100 ml of water, and the organic matters were extracted with 50 ml of ethyl acetate twice. The ethyl acetate layers were combined, washed with 50 ml of water twice and dried over anhydrous magnesium sulfate, and the ethyl acetate was distilled off under reduced pressure. After washed with n-hexane, the residue afforded 4.6 g of 2-chloro-4-(3-trifluoromethylpyrazolyl)benzonitrile (yield 92.0%) as a white powder, which was used in Reference Example 3 as the starting material.
Reaction SMILES: C[O:2][C:3](=[O:35])[C@@H:4]([NH:9][C:10](=[O:34])[C@@H:11]([NH:23][S:24]([C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)(=[O:26])=[O:25])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]=[CH2:22])=[CH:15][CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[OH-].[Na+].CO>C1COCC1.O>[CH2:20]([O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][C@H:11]([NH:23][S:24]([C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)(=[O:25])=[O:26])[C:10]([NH:9][C@@H:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]([OH:35])=[O:2])=[O:34])=[CH:14][CH:15]=1)[CH:21]=[CH2:22]
Reactant: C=CCOc1ccc(C[C@H](NS(=O)(=O)c2ccc(F)cc2)C(=O)N[C@@H](CC(C)C)C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C=CCOc1ccc(C[C@H](NS(=O)(=O)c2ccc(F)cc2)C(=O)N[C@@H](CC(C)C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl ester 11 (2.70 g, 5.33 mmol) was dissolved in THF (30 mL). Sodium hydroxide (0.853 g, 21.3 mmol) pre-dissolved in water (10 mL) was added. Methanol (15 mL) was added to obtain a homogenous solution and this was stirred at rt for 18 h before being concentrated in vacuo. The residue was partitioned between EtOAc and 1M hydrochloric acid. The aqueous phase was extracted twice more with EtOAc and the combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo to yield a white foam, 2.50 g, 95%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C[OH:11]>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:1]=[O:11])=[CH:3][CH:4]=1
Reactant: CO
Reactant: COc1ccc(C)cc1
Product: COc1ccc(C=O)cc1
Yield: 97.3 %

Procedure:
In the same manner as in Example 1, p-methyl anisole is oxidized with use of an 80% by weight aqueous solution of methanol in place of methanol, affording anisaldehyde in a yield of 97.3%. With use of cerium salt regenerated in the same manner as in Example 1 (and using an 80% by weight methanol aqueous solution in place of methanol) for the second oxidation, anisaldehyde is obtained in a yield of 94.3%.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([N:11]([CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][C:51]([O:53][CH3:54])=[O:52])[CH3:12])[CH:6]=[C:7]([CH2:9][OH:10])[CH:8]=1.C(N(CC)CC)C.[CH3:62][S:63](Cl)(=[O:65])=[O:64]>ClCCl>[CH3:62][S:63]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([N:11]([CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][C:51]([O:53][CH3:54])=[O:52])[CH3:12])[CH:6]=[C:7]([CH2:9][O:10][S:63]([CH3:62])(=[O:65])=[O:64])[CH:8]=1)(=[O:65])=[O:64]
Reactant: COC(=O)CCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCN(C)c1cc(CO)cc(CO)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCN(C)c1cc(COS(C)(=O)=O)cc(COS(C)(=O)=O)c1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
To a stirred solution of methyl 2-(3,5-bis(hydroxymethyl)phenyl)-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxa-2-azahentetracontan-41-oate (265d) (71 mg, 0.091 mmol) in anhydrous dichloromethane (1.4 mL) was added triethylamine (0.038 mL, 0.272 mmol). The mixture was cooled to −5° C. and methanesulfonyl chloride (0.018 mL, 0.227 mmol) was added slowly. After stirring for one hour at −5° C. the reaction was quenched with cold water and extracted with cold ethyl acetate. The organic extracts were washed with cold water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give methyl 2-(3,5-bis((methylsulfonyloxy)methyl)phenyl)-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxa-2-azahentetracontan-41-oate. MS (m/z), found 960.2 (M+Na)+. To a mixture of methyl 2-(3,5-bis((methylsulfonyloxy)methyl)phenyl)-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxa-2-azahentetracontan-41-oate (69 mg, 0.074 mmol) and compound 8 (54.1 mg, 0.184 mmol) in anhydrous DMF (0.8 mL) was added potassium carbonate (50.8 mg, 0.368 mmol). The reaction was allowed to stir for 18 hours at room temperature. The reaction was quenched with water and extracted twice with dichloromethane. The remaining aqueous layer was extracted twice with 50% MeOH/CH2Cl2. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by flash silica gel chromatography (5% MeOH/CH2Cl2) followed by preparative reverse phase HPLC (C18 column, eluted with CH3CN/H2O) gave compound 265e (23 mg, 23%). MS (m/z), found 1375.4 (M+Na+H2O)+, 1393.4 (M+Na+2H2O)+.
Reaction SMILES: [Li].[Br-:2].[C:3]([N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=O)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH2:17]1COCC1>>[Br:2][CH:17]=[C:13]1[CH2:14][CH2:15][N:10]([C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH2:11][CH2:12]1
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Reactant: [Br-]
Agent: [Li]
Product: CC(C)(C)OC(=O)N1CCC(=CBr)CC1
Temperature: 25 °C

Procedure:
Lithium bis-trimethylsylylamide (1 M in THF, 7.38 mL, 7.38 mmol) was dropped into a suspension of bromomethyltriphenylphsphonium bromide (3.22 g, 7.38 mmol) at −15° C. under nitrogen atmosphere. After 15 min. under stirring at the same temperature, N-Boc piperidone (1.4 g, 7.03 mmol) dissolved in THF (10 ml) was added. Stirring was maintained and after 2 h at r.t., the reaction mixture was quenched with water and with EtOAc. The combined extracts were washed, dried over Na2SO4 and evaporated to dryness. The crude residue was purified by flash chromatography (EtOAc—Petroleum Ether 98:2) affording the title product (1.27 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:20]1(/[CH:25]=[C:26](\B2OC(C)(C)C(C)(C)O2)/[CH2:27][OH:28])[CH2:24][CH2:23][CH2:22][CH2:21]1.[F-].[Cs+].C1COCC1>O1CCOCC1.C1(P([Pd-4](P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:20]1(/[CH:25]=[C:26](\[C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)(=[O:10])=[O:9])=[CH:4][CH:3]=2)/[CH2:27][OH:28])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC1(C)OB(/C(=C\C2CCCC2)CO)OC1(C)C
Reactant: O=S(=O)(NCCc1ccccn1)c1ccc(Br)cc1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: O=S(=O)(NCCc1ccccn1)c1ccc(/C(=C\C2CCCC2)CO)cc1
Temperature: 25 °C
Yield: 49.2 %

Procedure:
Heat a suspension of 4-bromo-N-(2-pyridin-2-yl-ethyl)-benzenesulfonamide (1.67 g, 4.89 mmol), (E)-3-cyclopentyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-prop-2-en-1-ol (1.60 g, 6.36 mmol), caesium fluoride (2.23 g, 14.7 mmol) and tetrakis(triphenylphosphino)palladium(0) (565 mg, 489 μmol) in 50 mL dioxane to reflux for 2 d and cool to r.t. thereafter. After addition of 50 mL THF filtrate the resulting suspension, wash with dichloromethane and concentrate under reduced pressure. Further purify the resulting brown oil by column chromatography, eluting with a gradient from 100:0 to 0:100 hexanes:ethyl acetate to afford (E)-4-(2-cyclopentyl-1-hydroxymethyl-vinyl)-N-(2-pyridin-2-yl-ethyl)-benzenesulfonamide (929 mg) as a pale yellow oil. MS (m/e): 387 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)(=O)[CH3:14].CC[OH:24].CC(O)=O>[OH-].[K+]>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]=[C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH:14]=[C:5]2[C:6]([OH:11])=[O:24]
Reactant: CCO
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Reactant: CC(=O)c1ccccn1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=C(O)c1cc(-c2ccccn2)nc2ccc(Br)cc12

Procedure:
To a suspension of 5-bromo isatin (5 g, 20.5 mmol) and 2-acetylpyridine (2.5 g, 20.5 mmol) in aqueous KOH (1.2 g, 33%) was added EtOH until a solution formed. The mixture was refluxed over night. The reaction mixture was neutralized with HOAc (50%) and filtered. The solid was resuspended in EtOH and filtered to give the title compound (5.5 g). LC: 1.66 and MH+: 329.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=1[CH3:24].C(N(CC)C(C)C)(C)C>CS(C)=O>[CH3:24][C:16]1[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:15]=1[N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1cc([N+](=O)[O-])ccc1N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
In the same manner as in Production Example 5-1, but using tert-butyl piperazine-1-carboxylate in place of N-ethylpiperazine used in Production Example 5-1, using 2-fluoro-5-nitrotoluene in place of 2-fluoro-5-nitrobenzyl alcohol, using N,N-diisopropylethylamine in place of potassium carbonate, and using dimethylsulfoxide in place of N-methylpyrrolidone, 4.91 g of crude tert-butyl 4-[2-methyl-4-nitrophenyl]piperazine-1-carboxylate was obtained as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:16][NH:17][C:18]([N:20]1[CH2:34][CH2:33][CH2:32][C@H:21]1[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])=[O:19])([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5])[CH3:2].[H-].[Na+].[CH3:37]I>O1CCCC1>[CH3:37][N:17]([CH2:16][P:4]([O:3][CH2:1][CH3:2])([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5])[C:18]([N:20]1[CH2:34][CH2:33][CH2:32][C@H:21]1[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])=[O:19]
Reactant: CI
Reactant: CCOP(=O)(CCCCc1ccccc1)CNC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOP(=O)(CCCCc1ccccc1)CN(C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-[[[[ethoxy(4-phenylbutyl)-phosphinyl]methyl]amino]carbonyl]-L-proline, phenylmethyl ester (2.43 g., 5 mmole) in dry tetrahydrofuran (15 ml.) is treated with 50% sodium hydride oil dispersion (0.24 g., 5 mmole) and stirred at room temperature for one hour. The mixture is then treated with methyl iodide (0.34 ml., 5.5 mmole) and stirred at room temperature for an additional 3 hours. The mixture is then partitioned between ethyl acetate-5% potassium bisulfate. The organic phase is washed successively with saturated sodium bicarbonate and saturated sodium chloride, dried (Na2SO4) and evaporated. The residue is purified by flash chromatography on silica eluting with acetone/dichloromethane (2:3) to give 1-[[methyl[[ethoxy(4-phenylbutyl)phosphinyl]methyl]amino]carbonyl]-L-proline, phenylmethyl ester.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=3[F:30])[C:16]=2[NH:31][S:32]([CH:35]2[CH2:37][CH2:36]2)(=[O:34])=[O:33])[CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[NH2:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[O:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=2[F:30])[C:16]=1[NH:31][S:32]([CH:35]1[CH2:36][CH2:37]1)(=[O:33])=[O:34]
Reactant: CC(C)(C)OC(=O)Nc1cccc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2NS(=O)(=O)C2CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cccc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2NS(=O)(=O)C2CC2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 77.3 %

Procedure:
1.19 g of tert-butyl(3-{2-[(cyclopropylsulfonyl)amino]-5-fluoro-3-[(2-fluoro-4-iodophenyl)amino]phenoxy}phenyl)carbamate (1.8 mmol, 1 eq.) were dissolved in 15 mL DCM, treated with 2 mL TFA and stirred at rt for 6 h. The reaction mixture was cooled to 0° C. and adjusted with 1N Sodium hydroxide to pH 10. The layers were separated, the aqueous layer was reextracted with DCM. The combined organic layers were dried, filtered and concentrated in vacuo to yield 776 mg of the crude product (77% yield), which was used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][OH:11])[C:5]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][N:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([CH3:32])(=[N:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:25])=[CH:20][CH:19]=1>>[CH2:30]([O:29][C:27]([N:26]=[S:24]([C:21]1[CH:20]=[CH:19][C:18]([NH:17][C:2]2[N:7]=[C:6]([NH:8][CH2:9][CH2:10][OH:11])[C:5]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)=[CH:4][N:3]=2)=[CH:23][CH:22]=1)([CH3:32])=[O:25])=[O:28])[CH3:31]
Reactant: CCOC(=O)N=S(C)(=O)c1ccc(N)cc1
Reactant: OCCNc1nc(Cl)ncc1-c1cccs1
Product: CCOC(=O)N=S(C)(=O)c1ccc(Nc2ncc(-c3cccs3)c(NCCO)n2)cc1
Yield: 37 %

Procedure:
In the reaction of 2-(2-chloro-5-(2-thienyl)pyrimidine-4-ylamino)ethanol (200 mg, 0.8 mmol) with (RS)—S-(4-aminophenyl)-N-(ethoxycarbonyl)-S-methyl-sulfoximide (173 mg, 0.7 mmol) according to procedure 5a, the desired product is obtained in 37% yield (120 mg) after chromatographic purification (silica gel, dichloromethane/methanol (0%-20% methanol)).
Reaction SMILES: C(NC(=O)[O-])C.C[O:8][C:9]1[C:10]([Cl:22])=[CH:11][C:12]2[CH:13]([CH3:21])[CH:14]3[CH2:18][NH:17][CH2:16][CH:15]3[C:19]=2[CH:20]=1>Cl>[OH:8][C:9]1[C:10]([Cl:22])=[CH:11][C:12]2[CH:13]([CH3:21])[CH:14]3[CH2:18][NH:17][CH2:16][CH:15]3[C:19]=2[CH:20]=1
Reactant: COc1cc2c(cc1Cl)C(C)C1CNCC21
Agent: CCNC(=O)[O-]
Agent: Cl
Product: CC1c2cc(Cl)c(O)cc2C2CNCC12
Temperature: 25 °C

Procedure:
A solution of N-ethylcarbamate-5-methoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 3, Step A) (61 mg, 0.2 mmol) in concentrated HCl was stirred overnight at 120° C. The reaction solution was cooled to room temperature and concentrated on a speed vac. The crude product was purified by reverse-phase liquid chromatography to afford the title compound. 1H NMR (d6-DMSO 300 MHz) * 7.04 (s, 1H), 6.73 (s, 1H), 3.52 (m, 1H), 3.22 (m, 2H), 2.83 (m, 3H), 2.41 (m, 1H), 1.18 (d, 3H) ppm. MS calculated for C12H14ClNO+H: 224, observed: 224.