Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][O:5][C:6]1[C:7]2[CH:16]=[C:15]([CH2:17][CH3:18])[N:14]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:8]=2[N:9]=[C:10]([S:12][CH3:13])[N:11]=1.[C:27](Cl)(=[O:31])[C:28](Cl)=[O:29].[N:33]1C=CC=CC=1.[OH-].[NH4+]>C(Cl)(Cl)Cl.C(OC)(C)(C)C.O>[CH3:1][O:2][C:3](=[O:26])[CH2:4][O:5][C:6]1[C:7]2[C:16]([C:27](=[O:31])[C:28]([NH2:33])=[O:29])=[C:15]([CH2:17][CH3:18])[N:14]([CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:8]=2[N:9]=[C:10]([S:12][CH3:13])[N:11]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCc1cc2c(OCC(=O)OC)nc(SC)nc2n1Cc1ccccc1
Reactant: c1ccncc1
Agent: [NH4+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)OC)nc(SC)nc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 60 %

Procedure:
To a solution of 5.17 g (13.9 mmol) of [[2-(methylthio)-6-ethyl-7-(phenylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester in 100 mL of chloroform was added 3.64 mL of oxalyl chloride followed by 1.66 mL of pyridine. The reaction was stirred for 3 days at ambient temperature then poured into a solution prepared from 11 mL of concentrated ammonium hydroxide and 40 mL of water. The reaction was partitioned by the addition of 45 mL of water and 150 mL of methylene chloride. The organic phase was washed with 40 mL of water, dried with sodium sulfate, and concentrated to 5.90 g of yellow solid. The solid was first purified by flash chromatography (500 g of silica, ethyl acetate) and the product obtained was then slurried in 100 mL of methyl tert-butyl ether to provide 3.70 g (60%) of [[2-(methylthio)-5-(aminooxoacetyl)-6-ethyl-7-(phenylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester as a yellow solid. nmr (500 MHz, CDCl3) δ1.12 (t, J=7.5 Hz, 3H), 2.52 (s, 3H), 2.91 (q, J=7.5 Hz, 2H), 3.78 (s, 3H), 5.02 (s, 2H), 5.46 (s, 2H), 5.66 (s, 1H), 6.56 (s, 1H), 7.16.(d, J=6.9 Hz, 2H), 7.28 (m, 3H)
Reaction SMILES: [F:1][CH:2]1[C:7](=O)[CH2:6][CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1.[CH3:19][NH2:20].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C1COCC1>[F:1][CH:2]1[CH:7]([NH:20][CH3:19])[CH2:6][CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1F
Reactant: CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CNC1CCN(C(=O)OCc2ccccc2)CC1F
Reaction time: 2 h

Procedure:
To a solution of 9.4 g (37.5 mmol) of 2-2 in 150 mL of 1,2-dichloroethane was added 37.5 mL (74.9 mmol) of a 2M solution of methylamine in THF and 11.9 g (56.2 mmol) of Na(OAc)3BH. After stirring for 2 h, the reaction was quenched with saturated aqueous K2CO3, partitioned with EtOAc, separated, and the aqueous phase extracted 3×EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated by rotary evaporation. The residue was loaded onto a silica gel column and eluted with 80:10:10 CHCl3/EtOAc/MeOH to provide both the cis and trans isomers of 2-2a as colorless oils. Data for the trans isomer of 2-2a, first to elute (confirmed by NOE analysis): 1HNMR (600 MHz, CD2Cl2) δ 7.4-7.3 (m, 5H), 5.1 (m, 2H), 4.4-4.1 (m, 2H), 3.9 (m, 1H), 3.15-3.05 (m, 2H), 2.75 (m, 1H), 2.4 (s, 3H), 2.0 (in, 1H), 1.25 (m, 1H) ppm. Data for the cis isomer of 2-2a, second to elute (confirmed by NOE analysis): 1HNMR (600 MHz, CD2Cl2) δ 7.4-7.2 (m, 5H), 5.1 (m, 2H), 4.9-4.7 (m 1H), 4.4 (m, 1H), 4.15 (m, 1H), 3.1-2.9 (m, 2H), 2.6 (m, 1H), 2.4 (s, 3H), 1.8 (m, 1H), 1.6 (m, 1H) ppm. HRMS (ES) calc'd M+H for C14H19F1N2O2: 267.1504. Found: 267.1500.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]23[CH2:16][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)([CH2:15]2)[C:13](=[O:23])[N:12]([CH2:24][CH2:25][CH3:26])[C:11]3=[O:27])=[CH:6][CH:5]=1)([O-])=O.CCCCCC.CCOCC>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]23[CH2:15][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)([CH2:16]2)[C:13](=[O:23])[N:12]([CH2:24][CH2:25][CH3:26])[C:11]3=[O:27])=[CH:6][CH:5]=1
Reactant: CCCN1C(=O)C2(c3ccccc3)CC(c3ccc([N+](=O)[O-])cc3)(C2)C1=O
Agent: [Pd]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCN1C(=O)C2(c3ccccc3)CC(c3ccc(N)cc3)(C2)C1=O

Procedure:
In a manner analogous to that described in Example 12a, 1.8 g of 1-(4-nitrophenyl)-5-phenyl-3-n-propyl-3-azabicyclo[3.1.1]heptane-2,4-dione are dissolved in 40 ml of ethyl acetate, hydrogenated in the presence of 0.2 g of 5% palladium-on-carbon and worked up. Melting point 144°-145° (from n-hexane/ether).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([OH:13])[C:5]=1[CH2:14][CH:15]=C.[O:18]=[O+][O-].CSC>ClCCl.CO>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]2[O:13][CH:15]([OH:18])[CH2:14][C:5]=12)=[O:17]
Reactant: O=[O+][O-]
Reactant: C=CCc1c(C(=O)OC)ccc([N+](=O)[O-])c1O
Solvent: CO
Solvent: ClCCl
Solvent: CSC
Product: COC(=O)c1ccc([N+](=O)[O-])c2c1CC(O)O2
Temperature: -70 °C
Reaction time: 0.33 h

Procedure:
Into a solution of 2-allyl-3-hydroxy-4-nitro-benzoic acid methyl ester (6.11 g 25.6 mmol) in dichloromethane (100 mL) and methanol (10 mL) at −78° C. was bubbled with ozone for 40 minutes. After stirring for another 20 min at −70° C., a stream of nitrogen gas was passed through the reaction mixture. Dimethyl sulfide (5 mL, 68.1 mmol) was added at −78° C. The reaction solution was allowed to warm up gradually to room temperature overnight. The reaction mixture was partitioned between dichloromethane and water. The aqueous layer was further extracted twice with dichloromethane. The organic extract was washed with brine, dried (anhydrous sodium sulfate), and concentrated under reduced pressure to give 2-hydroxy-7-nitro-2,3-dihydro-benzofuran-4-carboxylic acid methyl ester as a yellow solid (6.0 g). 1H NMR (CDCl3) &: 3.51-3.74 (m, 2H), 3.96 (s, 3H), 6.43 (dd, 1H, J=6.4 Hz, 2.6 Hz), 7.63 (d, 0.1H, J=8.8), 8.01 (d, 1H, J=8.9 Hz).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[C:8](=[O:13])[N:7]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=1)[CH2:6]2.CN[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[CH:35]([N:38](C(C)C)CC)(C)C>C(#N)C>[CH2:28]([CH2:35][NH:38][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[C:8](=[O:13])[N:7]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=1)[CH2:6]2)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1cc(CBr)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Reactant: CNCc1ccccc1
Solvent: CC#N
Product: Cc1cc(CNCCc2ccccc2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Yield: 82.5 %

Procedure:
A solution of 5-bromomethyl-7-methyl-2-(4-trifluoromethoxybenzyl)-2,3-dihydroisoindol-1-one (50 mg, 0.12 mmol) in acetonitrile (3 mL) was added drop wise to N-methylbenzylamine (24 mg, 0.2 mmol) and diisopropylethylamine (0.17 mL, 1 mmol) in acetonitrile (5 mL). After 4 hours the reaction was evaporated. The residue was chromatographed on silica gel, eluting with 0 to 25% ethyl acetate in methylene chloride, to give 45 mg (83% yield) of 5-[(benzylmethylamino)methyl]-7-methyl-2-(4-trifluoromethoxybenzyl)-2,3-dihydroisoindol-1-one as a colorless oil. 1H NMR (300.132 MHz, CDCl3) δ 7.37-7.28 (m, 6H), 7.25-7.14 (m, 5H), 4.75 (s, 2H), 4.21 (s, 2H), 3.53 (s, 2H), 3.52 (s, 2H), 2.74 (s, 3H), 2.18 (s, 3H).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:18])[C@@H:12]2[C@@H:15]([OH:17])[CH3:16])[C:9]=1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])(=[O:3])[CH3:2].[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(N(CC)CC)C>ClCCl>[C:1]([NH:4][CH2:5][CH2:6][S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:18])[C@@H:12]2[C@@H:15]([O:17][S:33]([CH3:32])(=[O:35])=[O:34])[CH3:16])[C:9]=1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)NCCSC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@H](C)O)[C@H]2C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCSC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@H](C)OS(C)(=O)=O)[C@H]2C1

Procedure:
p-Nitrobenzyl (5R,6S)-3-(2-acetamidoethylthio)-6-[(S)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (e7) (100 mg) was treated with methanesulphonyl chloride and triethylamine in dichloromethane as described in Example 1. After work-up, evaporation of the dichloromethane solution afforded p-nitrobenzyl (5R,6S)-3-(2-acetamidoethylthio)-6-[(S)-1-methylsulphonyloxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (e8) (112 mg) as a foam; νmax (CH2Cl2) 1785, 1700 sh, 1680, 1525, 1350, 1335 and 1175 cm-1.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:20]N(CCN(C)C)C.[Li]CCCC.CI>C1COCC1>[Cl:1][C:2]1[C:3]2[CH:10]=[C:9]([CH3:20])[N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Cl)ncnc21
Reactant: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc2c(Cl)ncnc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
To the solution of 4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (3 g, 12.6 mmol, 1.0 eq) and TMEDA (3.0 mL, 18.9 mmol, 1.5 eq) in THF (120 mL), n-BuLi (7.5 mL, 18.9 mmol, 1.5 eq) was added at −78° C. After 3 min, CH3I (3.7 mL, 59.2 mmol, 4.7 eq) was added. After 3 h, the reaction mixture was warmed to RT over 1 h. The reaction was quenched by addition of sat NH4Cl (10 mL) at −78° C. EtOAc (200 mL) and water (100 mL) was added. The organic layer was separated, dried and concentrated to afford 4-chloro-6-methyl-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine as a brown solid (6.7 g, 90% in yield).
Reaction SMILES: Br[C:2]1[C:3]2[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[CH3:16][CH:17]([SH:19])[CH3:18].N12CCCN=C1CCCCC2>CN(C)C=O>[Cl:15][C:14]1[C:3]2[C:2]([S:19][CH:17]([CH3:18])[CH3:16])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[S:5][C:4]=2[CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)S
Reactant: COC(=O)c1sc2cccc(Cl)c2c1Br
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1sc2cccc(Cl)c2c1SC(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of methyl 3-bromo-4-chlorobenzo[b]thiophene-2-carboxylate (0.62 g, 2.0 mmol) , 2-propanethiol (0.30 mL, 0.25 g, 3.2 mmol) , and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.33 mL, 0.34 g, 2.2 mmol) in 5.0 mL of N,N-dimethylformamide is stirred at room temperature for 24 hours. The reaction mixture is partitioned between 150 mL of cold 1.0N HCl and 75 mL of dichloromethane, and the aqueous layer is extracted several times with fresh dichloromethane. The combined organic layers are washed with 1.0N HCl and brine, then dried (anhydrous sodium sulfate) and evaporated to yield methyl 4-chloro-3-[(1-methylethyl)thio]benzo[b]thiophene-2-carboxylate as an oil.
Reaction SMILES: O=S(Cl)Cl.[Br:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[C:13]([F:16])[C:12]([CH2:17][C:18](O)=[O:19])=[C:11]([F:21])[CH:10]=2.COC(=O)CC1C(F)=C2C(=CC=1F)N=CC(Br)=C2.[NH2:40][NH2:41]>CO>[Br:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[C:13]([F:16])[C:12]([CH2:17][C:18]([NH:40][NH2:41])=[O:19])=[C:11]([F:21])[CH:10]=2
Reactant: NN
Reactant: O=C(O)Cc1c(F)cc2ncc(Br)cc2c1F
Agent: COC(=O)Cc1c(F)cc2ncc(Br)cc2c1F
Solvent: O=S(Cl)Cl
Solvent: CO
Product: NNC(=O)Cc1c(F)cc2ncc(Br)cc2c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 402.6 %

Procedure:
SOCl2 (394 mg, 3.31 mmol) was added dropwise to a stirred solution of (3-bromo-5,7-difluoro-quinolin-6-yl)-acetic acid (500 mg, 1.65 mmol) in 12 ml of methanol at 0° C. under N2. After stirring for 2 hours at room temperature the solvent was evaporated and the crude (3-bromo-5,7-difluoro-quinolin-6-yl)-acetic acid methyl ester was used directly in the next step. To a mixture of (3-bromo-5,7-difluoro-quinolin-6-yl)-acetic acid methyl ester (2.29 g, 7.22 mmol) in methanol (100 mL) was added anhydrous hydrazine (2.31 g, 72.2 mmol). The mixture was heated at 55° C. for 4 hours. Additional anhydrous hydrazine (1.16 g, 36.1) was added and the mixture was heated at 55° C. for 2 hours. The reaction mixture was cooled to room temperature to give a white solid. The white solid was filtered and washed with cold methanol to obtain 2.1 g of the title compound (92% yield). MS: m/z 318 [M+H+]. 1H NMR (500 MHz. DMSO-d6): δ 1.99 (2H, s), 4.25 (2H, bs), 7.72 (1H, d), 8.74 (1H, s), 9.03 (1H, s), 9.35 (1H, s).
Reaction SMILES: [C:1]([C@@:4]1([OH:23])[C@@H:8]([CH:9]([C:11](=[O:13])[CH3:12])[OH:10])[O:7][C@@H:6]([N:14]2[CH:21]=[C:20]([Br:22])[C:18](=O)[NH:17][C:15]2=[O:16])[CH2:5]1)(=[O:3])[CH3:2].C(N(CC)CC)C.C1(C)C=C(C)C=C(C)C=1S(Cl)(=O)=[O:40].C1CCN2C(=NCCC2)CC1.[NH2:55][C:56]1[CH:61]=[C:60]([N+:62]([O-:64])=[O:63])[CH:59]=[CH:58][C:57]=1O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:22][C:20]1[C:18]([NH:55][C:56]2[CH:57]=[CH:58][CH:59]=[C:60]([N+:62]([O-:64])=[O:63])[C:61]=2[OH:40])=[N:17][C:15](=[O:16])[N:14]([CH:21]=1)[C@@H:6]1[O:7][C@H:8]([CH:9]([C:11](=[O:13])[CH3:12])[OH:10])[C@@:4]([C:1](=[O:3])[CH3:2])([OH:23])[CH2:5]1
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: CC(=O)C(O)[C@H]1O[C@@H](n2cc(Br)c(=O)[nH]c2=O)C[C@@]1(O)C(C)=O
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)C(O)[C@H]1O[C@@H](n2cc(Br)c(Nc3cccc([N+](=O)[O-])c3O)nc2=O)C[C@@]1(O)C(C)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3′, 5′-diacetyl-5-bromo-2′-deoxyuridine (4.8 g; 12 mmol), methylene chloride (50 ml), triethylamine (5.0 g; 50 mmol) and DMAP (0.10 g) was added 2-mesitylsulfonyl chloride (5.2 g; 24 mmol). After stirring at room temperature for 4 h., DBU (3.6 g; 24 mmol) and 2-amino4-nitrophenol (7.4 g; 48 mmol) were added and the solution was stirred for 3 h. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate saturated sodium bicarbonate. The organic layer was purified by flash column chromatography on silica gel. The isolated product had some impurity and was triturated with ethyl acetate. The yellowish precipitate was filtered off and washed with methylene chloride to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2.[N:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH:19][C:20]([C:22]2[S:30][C:29]3[C:24](=[N:25][CH:26]=[CH:27][C:28]=3Cl)[CH:23]=2)=[O:21])=[CH:14][CH:13]=1>>[N:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH:19][C:20]([C:22]2[S:30][C:29]3[C:24](=[N:25][CH:26]=[CH:27][C:28]=3[NH:11][C:7]3[CH:8]=[C:9]4[C:4](=[CH:5][CH:6]=3)[NH:3][C:2]([CH3:1])=[CH:10]4)[CH:23]=2)=[O:21])=[CH:14][CH:13]=1
Reactant: O=C(NCc1ccncc1)c1cc2nccc(Cl)c2s1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)NCc5ccncc5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 2-methyl-1H-indol-5-ylamine and 7-chloro-thieno[3,2-b]pyridine-2-carboxylic acid (pyridin-4-ylmethyl)-amide by a procedure analogous to Example 1C. MS: 414 (MH+), HPLC Rf: 3.97 min.; HPLC purity 94%.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][S:18][C:17]([CH3:22])([CH3:21])[CH:16]2[C:23]([O-:25])=[O:24])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][S:18][C:17]([CH3:21])([CH3:22])[CH:16]2[C:23]([OH:25])=[O:24])(=[O:13])=[O:14])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)N2CCSC(C)(C)C2C(=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC#CCOc1ccc(S(=O)(=O)N2CCSC(C)(C)C2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
To a solution of tert-butyl 4-({[4-(2-butynyloxy)phenyl]sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylate (0.31 g, 0.71 mmol) in dichloromethane (7 mL) was added trifluoroacetic acid (3 mL) and the resulting mixture was stirred at room temperature for 1 hour, after which the solvents were evaporated and toluene was added. The toluene and excess trifloroacetic acid were removed to give 0.25 g of (3S)-4-({[4-(2-butynyloxy)phenyl]sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid, which was used for the next step without further purification. Yield: 92.6%. mp 129-131° C. %. Electrospray Mass Spec 381.8(M−H)−.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[NH:11][C:12](=[O:14])[CH3:13].[OH2:15].CN(C)[CH:18]=[O:19]>C(N(CC)CC)C>[C:12]([NH:11][C:3]1[CH:4]=[CH:5][C:6]([CH:8]([CH3:10])[CH3:9])=[CH:7][C:2]=1[C:18]([OH:19])=[O:15])(=[O:14])[CH3:13]
Reactant: CC(=O)Nc1ccc(C(C)C)cc1Br
Reactant: CN(C)C=O
Reactant: O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(C(C)C)cc1C(=O)O
Reaction time: 18 h

Procedure:
A mixture of Example 2A (3.33 g, 13.0 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1.00 g, 1.2 mmol) in triethylamine (5.5 mL), dimethylformamide (25 mL), and water (5 mL) was shaken at 120° C. in a reactor pressurized with 850 psi of CO for 18 hours. The mixture was filtered, the filter cake was washed with ethyl acetate, and the combined filtrates were partitioned between diethyl ether and 1M NaOH. The aqueous phase was acidified with 12M HCl and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated to provide the desired product (2.38 g). MS (ESI(+)) m/e 222 (M+H)+, 244 (M+Na)+; (ESI(−)) m/e 220 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]([O:18]C)=[O:17])[N:13]=2)=[N:6][CH:7]=1.O.[OH-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[N:13]=2)=[N:6][CH:7]=1
Reactant: COC(=O)CCc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1
Reaction time: 8 h
Yield: 51.7 %

Procedure:
To a mixture of methyl 3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)propanoate (0.100 g, 0.230 mmol) in 10 mL THF, and 5 mL water was added sodium hydroxide (0.0368 g, 0.921 mmol) and the reaction was stirred overnight. The mixture was concentrated to dryness. Water was added and washed with Et20 and EtOAc. The aqueous was acidified with a saturated NH4Cl solution, extracted with 3:1 CH2Cl2-THF. The organics were dried over Na2SO4 and concentrated to a residue. The crude solids were recrystallized from EtOAc/Hexanes to give the title compound (0.050 g, 51.7% yield). 1H NMR (d6 DMSO) δ 2.58 (t, J=7.5 Hz, 2H), 2.81 (t, J=7.5 Hz, 2H), 6.66 (s, 1H), 7.10 (d, J=7.8 Hz, 2H), 7.21 (t, J=7.4 Hz, 1H), 7.39 (d, J=2.0 Hz, 1H), 7.44 (t, J=8.0 Hz, 2H), 8.21 (d, J=2.0 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]([N+:17]([O-:19])=[O:18])([CH2:15][CH3:16])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[NH:6][CH:5]=1.[H-].[Na+].[CH3:22]I>CN(C)P(=O)(N(C)C)N(C)C>[CH3:22][N:6]1[C:7]2[C:12](=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[C:4]([CH2:3][C:2]([CH3:1])([N+:17]([O-:19])=[O:18])[CH2:15][CH3:16])=[CH:5]1
Reactant: CI
Reactant: CCC(C)(Cc1c[nH]c2ccc(OC)cc12)[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCC(C)(Cc1cn(C)c2ccc(OC)cc12)[N+](=O)[O-]

Procedure:
If the 3-(2'-methyl-2'-nitrobutyl)-5-methoxy-indole obtained as intermediate product in Example 2 is methylated by the procedure described in Example 4 (or by means of sodium hydride and methyl iodide in hexamethyl phosphoric acid triamide), 1-methyl-3-(2'-methyl-2'-nitrobutyl)-5-methoxy-indole is obtained and melts at 95°-96°C. after crystallisation from acetone/water and distillation. Catalytic reduction thereof yields 1-methyl-3-(2'-methyl-2'-aminobutyl)-5-methoxy-indole. Melting point of the benzoic acid salt 179.5°-184°C. (insoluble in ether).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4](I)[C:3]=1[F:13].C(O)CCC.C(=O)([O-])[O-].[Cs+].[Cs+].[O:25]1[C:29]2[CH:30]=[CH:31][C:32](B(O)O)=[CH:33][C:28]=2[O:27][CH2:26]1>C1(C)C=CC=CC=1.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.O>[O:25]1[C:29]2[CH:30]=[CH:31][C:32]([C:4]3[C:3]([F:13])=[C:2]([Cl:1])[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[N:5]=3)=[CH:33][C:28]=2[O:27][CH2:26]1
Reactant: Fc1c(I)nc2ccccc2c1Cl
Reactant: OB(O)c1ccc2c(c1)OCO2
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: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCCCO
Solvent: O
Product: Fc1c(-c2ccc3c(c2)OCO3)nc2ccccc2c1Cl
Temperature: 50 °C
Reaction time: 24 h
Yield: 58 %

Procedure:
To a solution of 4-chloro-3-fluoro-2-iodo-quinoline (from Example 1, step D, 0.127 g, 0.41 mmol) in toluene (5 mL) was added n-butanol (2 mL), water (3 mL) and cesium carbonate (0.404 g, 1.2 mmol). The resulting mixture was degassed for 5 min., after which tetrakis(triphenylphosphine)palladium(0) (0.002 g, 5 mol %) and benzo[1,3]dioxole-5-boronic acid (0.086 g, 0.4 mmol) were added. The reaction mixture was stirred at 50° C. for 24 h. and then extracted with ethyl acetate. The organic layer was dried and concentrated in a rotary evaporator. The residue was purified by silica gel column chromatography using ethyl acetate/hexane gradient to yield the title compound (0.070 g, 57%). MS (ES) 302 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].Cl[C:19]1[CH:24]=[N:23][CH:22]=[CH:21][N:20]=1.C(=O)([O-])[O-].[K+].[K+].N1C=CC=CC=1>C(Cl)Cl.[Cu](I)I.CCOC(C)=O>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[CH:11]=1)[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: Clc1cnccn1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1cccc(O)c1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@H](NC(=O)OC(C)(C)C)c1cccc(Oc2cnccn2)c1
Temperature: 115 °C
Yield: 113.2 %

Procedure:
A mixture of (S)-[1-(3-hydroxy-phenyl)-ethyl]-carbamic acid tert-butyl ester (1 g, 4.2 mmol), 2-chloro-pyrazine (0.58 g, 5.1 mmol), potassium carbonate (powder, 1.4 g, 10.1 mmol), copper iodide (325 mesh powder, 0.6 g, 3.2 mmol) and pyridine (5 mL) was heated at 115° C. for 24 h. CH2Cl2 (100 mL) was added, and the reaction mixture was diluted with CH2Cl2 (100 mL), filtered through celite, and rinse with CH2Cl2 (2×50 mL). The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel eluting with 1:1/Hexane:EtOAc to give the title product (1.5 g, quantitative yield).
Reaction SMILES: [OH2:1].[NH2:2][NH2:3].[OH-].[Na+].[Cl:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9](Cl)=[O:10]>O>[Cl:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([NH:2][NH:3][C:9](=[O:1])[C:8]1[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=1[Cl:6])=[O:10]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: O
Reactant: NN
Agent: [Na+]
Agent: [OH-]
Product: O=C(NNC(=O)c1ccccc1Cl)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of hydrazine hydrate (25 g) in water (500 ml) was treated dropwise and simultaneously with sodium hydroxide (43.6 g) in water (150 ml) and 2-chlorobenzoyl chloride (180.25 g). The addition over the mixture was stirred at room temperature for 2 hours. The solid was filtered off, washed with acetone/water 1:1 and recrystallised from acetic acid. Yield 97.5 g, m.p. 217°-219°.