Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH3:12].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[O:36]1[CH2:39][CH:38]([NH2:40])[CH2:37]1>C(Cl)Cl>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:40][CH:38]2[CH2:39][O:36][CH2:37]2)=[O:8])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: NC1COC1
Reactant: COc1cc(C(=O)O)ccc1N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1cc(C(=O)NC2COC2)ccc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
To a solution of 4-amino-3-methoxybenzoic acid (1 equiv) in DCM (0.11 M) was added HOBT (1.2 equiv), EDC (1.2 equiv) and DIEA (4 equiv). Oxetan-3-amine (1.2 equiv) was added then the reaction mixture was stirred at room temperature overnight. The mixture was extracted with ethyl acetate then the organic layer was dried over sodium sulfate The solids were filtered off, the filtrate was concentrated and the product was purified by silica gel chromatography (5% DCM in MeOH) to afford the title compound (53% yield) as a yellow solid. MS (ESI) m/z 223.1 [M+1]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:15][C:16]2[N:20]([CH3:21])[C:19]3[C:22]([N:26]([CH2:30][CH2:31][CH3:32])[CH2:27][CH2:28][CH3:29])=[CH:23][CH:24]=[CH:25][C:18]=3[N:17]=2)=[C:6]([CH:14]=1)[O:7][CH2:8][CH2:9][CH2:10][C:11](O)=[O:12].F[P-](F)(F)(F)(F)F.[N:40]1(OC(N(C)C)=[N+](C)C)[C:44]2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.CN>O1CCCC1.O>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:15][C:16]2[N:20]([CH3:21])[C:19]3[C:22]([N:26]([CH2:27][CH2:28][CH3:29])[CH2:30][CH2:31][CH3:32])=[CH:23][CH:24]=[CH:25][C:18]=3[N:17]=2)=[C:6]([CH:14]=1)[O:7][CH2:8][CH2:9][CH2:10][C:11]([NH:40][CH3:44])=[O:12]
Reactant: CCCN(CCC)c1cccc2nc(Nc3ccc(Cl)cc3OCCCC(=O)O)n(C)c12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCCN(CCC)c1cccc2nc(Nc3ccc(Cl)cc3OCCCC(=O)NC)n(C)c12
Product: Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.5 %

Procedure:
To a slurry of 20 mg (0.044 mmol) of 4-[5-chloro-2-[[7-(dipropylamino)-1-methyl-1H-benzimidazol-2-yl]amino]phenoxy]butyric acid in 2 mL of tetrahydrofuran was added 25 mg (0.065 mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU), 19 μL (0.11 mmol) of diisopropylethylamine, and 54 μL (0.11 mmol) of methylamine (2M solution in tetrahydrofuran). The reaction was stirred at room temperature for 3 h, diluted with water and extracted with dichloromethane. The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. The thus obtained residue was purified via preparative TLC eluting with a 75% ethyl acetate/hexanes solution. The isolated product was washed off the silica with 100% ethyl acetate and concentrated in vacuo. The thus obtained residue was dissolved in methanol and hydrochloric acid (1N solution in diethyl ether) was added. The resulting slurry was concentrated in vacuo to give 9.0 mg (44%) of the title compound as the hydrochloric salt.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[C@@H:9]([O:10][CH3:11])[CH2:8][CH2:7][N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=O.[NH3:19]>CO>[C:15]([O:14][C:12]([N:6]1[CH2:7][CH2:8][C@H:9]([O:10][CH3:11])[C@H:5]1[C:3](=[O:2])[NH2:19])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: N
Reactant: COC(=O)[C@@H]1[C@@H](OC)CCN1C(=O)OC(C)(C)C
Solvent: CO
Product: CO[C@H]1CCN(C(=O)OC(C)(C)C)[C@@H]1C(N)=O
Yield: 31 %

Procedure:
(2S,3S)-3-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (518 mg, 2.0 mmol) was stirred in 7M ammonia in methanol (5 mL) for 4 days. The reaction mixture was concentrated in vacuo and the residue was subjected to flash chromatography (SiO2, gradient 0 to 6% methanol in DCM) to give (2S,3S)-2-Carbamoyl-3-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester (153 mg, 31%). 1H NMR 400 MHz (DMSO-d6) δ: 7.54 (1H, br, s), 7.09 (1H, br, s), 4.09-4.00 (1H, m), 3.78 (1H, m), 3.47 (1H, m), 3.26 (3H, s), 1.93 (3H, m), 1.37 (9H, s)
Reaction SMILES: [Br:1][C:2]1[C:7]2[O:8][CH2:9][C@@H:10]3[C@@H:15]([CH2:16][OH:17])[CH2:14][N:13]([CH3:18])[CH2:12][C@H:11]3[C:6]=2[CH:5]=[C:4]([O:19][CH3:20])[CH:3]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl.CO>[Br:1][C:2]1[C:7]2[O:8][CH2:9][C@@H:10]3[C@@H:15]([CH2:16][O:17][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:14][N:13]([CH3:18])[CH2:12][C@H:11]3[C:6]=2[CH:5]=[C:4]([O:19][CH3:20])[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(Br)c2c(c1)[C@@H]1CN(C)C[C@H](CO)[C@H]1CO2
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(Br)c2c(c1)[C@@H]1CN(C)C[C@H](COS(C)(=O)=O)[C@H]1CO2
Reaction time: 0.25 h

Procedure:
To a solution of 1.69 g of (±)-[4R*,4aS*,10bR*]-7-bromo-4-(hydroxymethyl)-1,3,4,4a,5,10b-hexahydro-9-methoxy-2-methyl-2 H-[1]benzopyrano[4,3-c]pyridine and 0.82 ml triethylamine in 60 ml CH2Cl2 is added 0.42 ml of methanesulfonyl chloride. After 15 min. 1 drop methanol is added and the reaction mixture is washed with saturated NaHCO3 and dried over Na2SO4. Filtration and removal of solvents under reduced pressure yields (±)-[4R*,4aS*,10bR*]-7-bromo-4-(methylsulfonyloxymethyl)-1,3,4,4a,5,10b-hexahydro-9-methoxy-2-methyl-2H-[1]benzopyrano[4,3-c]pyridine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C:9]([O:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])=[C:8]3[NH:21][C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][C:27]=4[C:7]3=[CH:6][C:5]2=1.[CH3:29][I:30]>ClCCl>[I-:30].[F:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:8]1[C:9]([O:15][CH2:16][CH2:17][N+:18]([CH3:29])([CH3:19])[CH3:20])=[C:10]3[NH:11][C:12]4[CH:13]=[CH:14][C:2]([F:1])=[CH:3][C:4]=4[C:5]3=[CH:6][C:7]2=1
Reactant: CN(C)CCOc1c2[nH]c3ccc(F)cc3c2cc2c1[nH]c1ccc(F)cc12
Reactant: CI
Solvent: ClCCl
Product: C[N+](C)(C)CCOc1c2[nH]c3ccc(F)cc3c2cc2c1[nH]c1ccc(F)cc12
Product: [I-]
Yield: 62 %

Procedure:
To a solution of 2-(2,10-difluoro-5,7-dihydroindolo[2,3-b]carbazol-6-yloxy)-N,N-dimethylethanamine (14 mg) in dichloromethane (8 mL) was added MeI (1.0 mL) at RT under Ar. The resultant solution was stirred overnight and the solid formed. The solid was collected by filtration and washed once with dichloromethane and dried under vacuum to give the title compound (12 mg, 62%). 1H NMR (400 MHz, CD3OD) δ ppm 8.51 (s, 1H), 7.84 (dd, J=9.2, 2.8 Hz, 2H), 7.44 (dd, J=8.8, 4.0 Hz, 2H), 7.12 (ddd, J=9.2, 9.6, 2.4 Hz, 2H), 4.75-4.68 (m, 2H), 4.12-4.07 (m, 2H), 3.46 (s, 9H); MS (ESI) e/z 394 (M−I)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)[OH:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.O>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(C(O)c2c[nH]c3ncc(-c4cccnc4)cc23)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1cccc([N+](=O)[O-])c1)c1c[nH]c2ncc(-c3cccnc3)cc12
Reaction time: 1 h

Procedure:
To (3-nitro-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol (P-1399, R═H, 500 mg, 1.44 mmol) in dimethylformamide (26 mL) was added Dess-Martin periodane (674 mg, 1.59 mmol). The reaction was stirred for one hour and the reaction was poured into water. All solids were filtered and purified by silica gel column chromatography eluting with 3% methanol in dichloromethane to give the compound (536, 295 mg, 59%). MS (ESI)[M+H+]+=345.2.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([O:7][C:8]([NH:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:9])([CH3:6])[CH3:5].[CH3:16]I>CCCCCC.C1COCC1>[C:4]([O:7][C:8]([N:10]([CH3:16])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:9])([CH3:3])([CH3:5])[CH3:6]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN(CCC(=O)O)C(=O)OC(C)(C)C
Yield: 101.8 %

Procedure:
60% NaH in mineral oil (0.528 g, 13.21 mmol) was washed with hexane (2×10 mL). It was suspended in dry THF (6 mL) and cooled to 0° C. before BOC-BETA-ALA-OH (1 g, 5.29 mmol) in dry THF (6 mL) was added. MeI (0.823 mL, 13.21 mmol) in dry THF (6 mL) was dropwise added after 5 min. and the resulting suspension was stirred at 0° C. to room temperature over the weekend. The reaction mixture was quenched with ice cold H2O (50 mL) and washed with Et2O (25 mL). The aqueous layer was acidified with concentrated aqueous HCl (3 mL) and extracted with EtOAc (3×20 mL). The combined EtOAc extracts were dried (Na2SO4) and concentrated to afford the desired product (1.095 g, quantitative) as a yellow oil.
Reaction SMILES: N1(O[C:11](=[O:23])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:14][CH:13]=2)C2C=CC=CC=2N=N1.[NH2:24][NH:25][C:26]([NH2:28])=[S:27].C(OC(C)C)(C)C>CN(C)C=O>[CH2:19]([O:18][C:15]1[CH:14]=[CH:13][C:12]([C:11]([NH:24][NH:25][C:26]([NH2:28])=[S:27])=[O:23])=[CH:17][CH:16]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCOc1ccc(C(=O)On2nnc3ccccc32)cc1
Reactant: NNC(N)=S
Solvent: CC(C)OC(C)C
Solvent: CN(C)C=O
Product: CCCCOc1ccc(C(=O)NNC(N)=S)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.4 %

Procedure:
To a solution of 4-n-butyloxybenzoic acid benzotriazol-1-yl ester (15 g) in N,N-dimethylformamide (100 ml) was added thiosemicarbazide (5.27 g) and the mixture was stirred for 12 hours at ambient temperature. The reaction mixture was pulverized with diisopropyl ether. The precipitate was collected by filtration to give 1-(4-n-butyloxybenzoyl)thiosemicarbazide (11.51 g).
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][O:10][CH:9]([CH:13]([CH3:15])[CH3:14])[CH2:8]2)=[CH:4][CH:3]=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].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.C(O)C>[CH:13]([CH:9]1[O:10][CH2:11][CH2:12][N:7]([CH2:6][C:5]2[CH:16]=[CH:17][C:2]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[C:19]([F:30])([F:29])[F:18])=[CH:3][CH:4]=2)[CH2:8]1)([CH3:15])[CH3:14]
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: CC(C)C1CN(Cc2ccc(Br)cc2)CCO1
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: Cc1ccccc1
Solvent: CCO
Product: CC(C)C1CN(Cc2ccc(-c3ccccc3C(F)(F)F)cc2)CCO1
Temperature: 120 °C

Procedure:
The above compound could be made in the following manner: 1 eq. of 4-(4-Bromo-benzyl)-2-isopropyl-morpholine could be combined with 1.5 eq. of 2-(Trifluoromethyl)phenyl boronic acid, 10 mol % of tetrakis(triphenylphosphine)palladium(0), 6.7 eq. of 2M sodium carbonate solution, toluene and ethanol. The reaction mixture could be heated in a sealed tube at 120° C. overnight in an oil bath. The reaction mixture is filtered through Celite and concentrated in vacuo. The residue could be diluted with water and extracted with ethyl acetate. The combined organic phases could be washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material could be purified by flash chromatography to afford product.
Reaction SMILES: [CH:1]1([NH:7][CH2:8][C:9]([OH:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>C(#N)C>[CH2:17]([N:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[CH2:8][C:9]([OH:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C(C)(O)CNC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)C(C)(O)CN(Cc1ccccc1)C1CCCCC1
Temperature: 80 °C
Yield: 75 %

Procedure:
To ethyl 3-(cyclohexylamino)-2-hydroxy-2-methylpropanoate (6.7 g, 29.2 mmol) in 50 ml of acetonitrile at room temperature, was added benzyl bromide (5.2 ml, 43.8 mmol) dropwise, followed by K2CO3 (12 g, 87.6 mmol). The reaction mixture was heated at 80° C. for 18 h. It was then diluted to EtOAc, washed by brine and water. Organic extract dried and concentrated to a residue, which was purified on silica gel column chromatographically (Hex/EtOAc=100:1 to 10:1) to give 7 g product (75%). [M+H] calc'd for C19H29NO3, 320. found 320.
Reaction SMILES: Cl[C:2]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.O>O1CCOCC1>[N+:13]([C:12]1[C:2]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[C:3]([CH:9]=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])([O-:15])=[O:14]
Reactant: C1CCNCC1
Reactant: CCOC(=O)c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(C(F)(F)F)cc([N+](=O)[O-])c1N1CCCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of ethyl 2-chloro-3-nitro-5-trifluoromethylbenzoate (4.2 g; 1 eq.) in dioxane (40 ml) is added piperidine (3.9 ml; 2.1 eq.). After stirring for 18 hours at room temperature, the medium is poured into water (50 ml) and the product is extracted with ethyl ether. The organic phase is washed with water, dried and concentrated. 4.9 g of ethyl 3-nitro-2-piperid-1-yl-5-trifluoromethylbenzoate are obtained in the form of a colourless oil.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.C(O)=O.[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[C@H:19]([F:40])[CH:20]1[CH2:25][CH2:24][N:23]([C:26]2[N:27]=[C:28]3[CH2:39][CH2:38][NH:37][CH2:36][C:29]3=[N:30][C:31]=2[NH:32][CH:33]([CH3:35])[CH3:34])[CH2:22][CH2:21]1.CO>C1COCC1>[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[C@H:19]([F:40])[CH:20]1[CH2:25][CH2:24][N:23]([C:26]2[N:27]=[C:28]3[CH2:39][CH2:38][N:37]([C:5](=[O:7])[CH3:6])[CH2:36][C:29]3=[N:30][C:31]=2[NH:32][CH:33]([CH3:35])[CH3:34])[CH2:22][CH2:21]1
Reactant: CC(C)Nc1nc2c(nc1N1CCC([C@@H](F)c3ccc(F)cc3F)CC1)CCNC2
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CO
Solvent: O=CO
Product: CC(=O)N1CCc2nc(N3CCC([C@@H](F)c4ccc(F)cc4F)CC3)c(NC(C)C)nc2C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Acetic anhydride (14.1 μL, 0.149 mmol) and formic acid (38.1 μL, 0.994 mmol) were combined in THF (99 μL) and stirred at room temperature for 10 min. This solution was cooled to 0° C. and was added to a stirring solution of (R)-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine (41.7 mg, 0.099 mmol) in THF (895 μL) at 0° C. After 10 min, UPLC-MS showed conversion not to the formylated product, but to the acetylated product. The reaction mixture was treated with MeOH, concentrated under reduced pressure, taken up in MeOH, filtered, and purified by HPLC Method B to give the title compound, as a TFA salt, as a pale yellow solid (17.5 mg, 30.6%). 1H NMR (500 MHz, methanol-d4, mixture of rotamers) δ ppm 1.28 (m, 6H), 1.45 (d, J=12.7 Hz, 1H), 1.65 (m, 2H), 2.01 (m, 1H), 2.09 (m, 1H), 2.18 (s, 1.1H), 2.20 (s, 1.9H), 2.76 (m, 4H), 3.49 (m, 2H), 3.81 (t, J=6.1 Hz, 1.3H), 3.85 (t, J=5.9 Hz, 0.7H), 4.13 (m, 1H), 4.57 (s, 0.7H), 4.61 (s, 1.3H), 5.52 (m, 1H), 7.02 (m, 2H), 7.50 (m, 1H); ESI-MS m/z [M+H]+ 462.4.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@@H:3]([CH2:6][OH:7])[CH2:2]1.ClC1N=C2C(N=CN2CC2CCOCC2)=C(Cl)N=1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl>[CH3:33][S:34]([O:7][CH2:6][CH:3]1[CH2:4][CH2:5][O:1][CH2:2]1)(=[O:36])=[O:35]
Reactant: OC[C@@H]1CCOC1
Reactant: CS(=O)(=O)Cl
Agent: Clc1nc(Cl)c2ncn(CC3CCOCC3)c2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CCOC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (3S)-tetrahydro-3-furanylmethanol, Isomer 2 (1.4 g) in dry dichloromethane (40 ml) at 0° C. and under nitrogen, was added triethylamine (3.83 ml) followed by methanesulfonyl chloride (1.39 ml). The reaction was stirred at room temperature overnight. The orange solution was diluted with dichloromethane (50 ml) and washed with saturated aqueous sodium bicarbonate (20 ml). The organic layer was separated, dried through a hydrophobic frit and concentrated in vacuo to yield the title compound as an orange oil (2.6 g).
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]3[CH:14]=[CH:13][NH:12][C:11](=[O:15])[C:10]=3[N:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:17]Br.O>C(O)(=O)C>[Br:17][C:14]1[C:9]2[S:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:16][C:10]=2[C:11](=[O:15])[NH:12][CH:13]=1
Reactant: BrBr
Reactant: O=c1[nH]ccc2sc(-c3ccccc3)nc12
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]cc(Br)c2sc(-c3ccccc3)nc12
Temperature: 25 °C
Yield: 98 %

Procedure:
A solution of 2-phenyl-5H-thiazolo[4,5-c]pyridin-4-one 44 (400 mg, 1.75 mmol) in acetic acid (5 mL) at rt was treated with bromine (320 mg, 1.93 mmol) and the resulting mixture was heated at reflux for 30 min. After cooling to rt, water (20 mL) was added to the mixture. The yellow solid which formed was filtered, washed with water and dried in the air to afford 45 (527 mg). 1H NMR (400 MHz, d6-DMSO) δ: 7.57 (m, 3H), 7.70 (s, 1H), 8.05 (m, 2H). MS (EI) m/z (M+H+) 308.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].C1(CN)CCCCC1.[O:12]=[C:13]1[C:21]2([CH2:25][O:24][C:23]3[CH:26]=[C:27]4[C:31](=[CH:32][C:22]2=3)[CH2:30][CH2:29][O:28]4)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]1[CH2:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=1.O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[CH2:1]([NH:3][C:38](=[O:39])[C:37]1[CH:41]=[CH:42][C:34]([CH2:33][N:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]3([CH2:25][O:24][C:23]4[CH:26]=[C:27]5[C:31](=[CH:32][C:22]3=4)[CH2:30][CH2:29][O:28]5)[C:13]2=[O:12])=[CH:35][CH:36]=1)[CH3:2]
Reactant: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1
Reactant: CCN
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: CCNC(=O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using ethylamine (2 M solution in tetrahydrofuran) to replace cyclohexanemethylamine, and 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, N-ethyl-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide was obtained (57%) as a colorless solid: mp 190-191° C.; 1H NMR (300 MHz, CDCl3) δ7.79-7.71 (m, 2H), 7.44-7.36 (m, 2H), 7.24-7.15 (m, 2H), 7.08-6.99 (m, 1H), 6.77-6.70 (m, 1H), 6.47 (s, 1H), 6.43 (s, 1H), 6.14-6.04 (m, 1H), 4.99 (ABq, 2H), 4.85 (ABq, 2H), 4.59-4.50 (m, 2H), 3.54-3.43 (m, 2H), 3.09-2.90 (m, 2H), 1.28-1.21 (m, 3H); 13C NMR (75 MHz, CDCl3) δ178.0, 166.8, 161.9, 161.3, 141.8, 139.1, 134.4, 132.6, 128.7, 127.5 (2C), 124.0, 123.6, 120.0, 118.8, 109.1, 93.3, 80.6, 72.4, 57.7, 43.8, 34.9, 29.0, 14.8; MS (ES+) m/z 441.2 (M+1).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>C1(C)C=CC=CC=1>[C:1]([CH:5]1[CH2:10][CH2:9][C:8]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNC1
Reactant: CC(C)(C)C1CCC(=O)CC1
Solvent: Cc1ccccc1
Product: CC(C)(C)C1CC=C(N2CCCC2)CC1

Procedure:
A 50 mL round-bottomed flask containing 4-tert-butylcyclohexanone (6.01 gm) in anhydrous toluene (20 mL) was fitted with a Dean-Stark trap containing 3A molecular sieves, reflux condenser and a heating mantle. Pyrrolidine (6.00 mL) was added, and the solution heated to reflux for 18 hr. The solvent was evaporated and the crude product was used directly for the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][C:12](Cl)=[O:13].[CH2:15]([NH:17][CH2:18][CH3:19])[CH3:16]>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][C:12]([N:17]([CH2:18][CH3:19])[CH2:15][CH3:16])=[O:13]
Reactant: CCNCC
Reactant: O=C(Cl)Cc1ccc([N+](=O)[O-])cc1Cl
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)Cc1ccc([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At 0° C. a solution of 3.20 g (13.673 mmol) (2-chloro-4-nitro-phenyl)-acetyl-chloride in 50 mL EtOAc was slowly added dropwise to a solution of 5.67 mL (54.000 mmol) diethylamine in 50 mL EtOAc, then the cooling bath was removed and the mixture was stirred for 2 h at RT . The reaction mixture was diluted with EtOAc, the org. phase was washed with water and saturated aqueous NaCl solution, dried over sodium sulphate and evaporated down i. vac.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:18])[NH:5][C:6](=[O:17])[N:7]([CH:16]=1)[C@@H:8]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:10]([F:15])[CH2:9]1)#[CH:2].[C:19](OC(=O)C)(=[O:21])[CH3:20]>N1C=CC=CC=1>[C:19]([O:13][CH2:12][C@H:11]1[O:14][C@@H:8]([N:7]2[CH:16]=[C:3]([C:1]#[CH:2])[C:4](=[O:18])[NH:5][C:6]2=[O:17])[CH2:9][C@@H:10]1[F:15])(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: C#Cc1cn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]c1=O
Solvent: c1ccncc1
Product: C#Cc1cn([C@H]2C[C@H](F)[C@@H](COC(C)=O)O2)c(=O)[nH]c1=O
Temperature: 0 °C

Procedure:
To a stirred solution of 2',3'-dideoxy-5-ethynyl-3'-fluorouridine (1.106 g 0.4 mmol) in dry pyridine (5 ml) at 0° C. was added acetic anhydride (0.05 ml, 0.48 mmol) and stirring maintained at 0° C. for 1.5 hours. After stirring at room temperature for 24 hours, a further aliquot of acetic anhydride (0.02 ml, 0.2 mmol) was added and the mixture stirred at room temperature for 3 hours. After quenching with methanol (1 ml) the solvent was removed by evaporation under reduced pressure and co-evaporated with portions of ethanol (2×30 ml). The residue was recrystallised from ethanol to give a white crystalline solid.
Reaction SMILES: ClC1C(C)=CC(O)=CC=1.[S:10]([C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([CH3:21])=[CH:16][C:15]=1[OH:22])([OH:13])(=[O:12])=[O:11].S([C:27]1[CH:32]=[C:31]([Cl:33])[C:30]([CH3:34])=[C:29]([Cl:35])[C:28]=1[OH:36])(O)(=O)=O.[N+:37]([O-])([OH:39])=[O:38].S(=O)(=O)(O)O>>[N+:37]([C:27]1[CH:32]=[C:31]([Cl:33])[C:30]([CH3:34])=[C:29]([Cl:35])[C:28]=1[OH:36])([O-:39])=[O:38].[S:10]([C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([CH3:21])=[CH:16][C:15]=1[OH:22])([OH:13])(=[O:11])=[O:12]
Reactant: O=[N+]([O-])O
Reactant: Cc1c(Cl)cc(S(=O)(=O)O)c(O)c1Cl
Agent: Cc1cc(O)c(S(=O)(=O)O)cc1Cl
Agent: Cc1cc(O)ccc1Cl
Agent: O=S(=O)(O)O
Product: Cc1c(Cl)cc([N+](=O)[O-])c(O)c1Cl

Procedure:
2-NITRO-4,6-DICHLORO-5-METHYLPHENOL IS PREPARED BY THE SULFONATION OF 4-CHLORO-5-METHYLPHENOL TO FORM 2-SULFO-4-CHLORO-5-METHYLPHENOL WHICH IS CHLORINATED TO 2-SULFO-4,6-DICHLORO-5-METHYLPHENOL WHICH IS IN TURN REACTED WITH NITRIC ACID TO FORM THE DESIRED PRODUCT. The sulfonation is carried out with concentrated sulfuric acid at elevated temperatures to form 2-sulfo-4-chloro-5-methylphenol. Thereafter the reaction mixture is diluted with water to a sulfuric acid content of 20-30%. The resulting 2-sulfo-4-chloro-5-methylphenol is chlorinated with chlorine at elevated temperature and normal or elevated pressures to form 2-sulfo-4,6-dichloro-5-methylphenol which is then reacted with nitric acid.