Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1.[NH2:27][CH2:28][CH:29]([OH:34])[C:30]([F:33])([F:32])[F:31].C(N(CC)CC)C>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15]([NH:27][CH2:28][CH:29]([OH:34])[C:30]([F:33])([F:32])[F:31])[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Reactant: NCC(O)C(F)(F)F
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(NCC(O)C(F)(F)F)c(Cl)c32)c(F)cc1F
Temperature: 60 °C
Reaction time: 6 h
Yield: 79.6 %

Procedure:
1-(5-Amino-2,4-difluorophenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (150 mg), 1-amino-3,3,3-trifluoro-2-propanol (120 mg) and triethylamine (120 mg) were added to pyridine (400 mg), and the mixture was stirred for 20 hours at room temperature and for 6 hours at 60° C. The reaction mixture was concentrated under reduced pressure. A process of adding ethanol (3 ml) to the residue and then concentrating the mixture under reduced pressure was conducted twice repeatedly. Concentrated hydrochloric acid (150 mg) was added to the residue, and the mixture was concentrated under reduced pressure. Ethanol (2 ml) was added to the resultant residue, and deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (153 mg) as a colorless powder.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:20](=[O:21])[C:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:35]#[N:36])=[CH:25][CH:24]=3)=[C:18]([CH2:37][CH2:38][CH3:39])[N:17]3[N:40]=[CH:41][N:42]=[C:16]23)[CH2:11][CH2:10]1)(=O)=O.[NH:43]1[CH:47]=[CH:46][N:45]=[CH:44]1.CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[N:43]1([CH2:6][CH2:7][O:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([N:15]3[C:20](=[O:21])[C:19]([CH2:22][C:23]4[CH:24]=[CH:25][C:26]([C:29]5[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=5)=[CH:27][CH:28]=4)=[C:18]([CH2:37][CH2:38][CH3:39])[N:17]4[N:40]=[CH:41][N:42]=[C:16]34)[CH2:11][CH2:10]2)[CH:47]=[CH:46][N:45]=[CH:44]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCCOS(C)(=O)=O)CC2)c2ncnn12
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCCn3ccnc3)CC2)c2ncnn12
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a mixture of 2-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]ethyl methanesulfonate (0.3 g), imidazole (0.042 g) and N,N-dimethylformamide (5 mL) was added sodium hydride (0.024 g), and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.24 g, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8]O.P(Br)(Br)[Br:11]>C(Cl)(Cl)Cl>[Br:11][CH2:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[Cl:1]
Reactant: BrP(Br)Br
Reactant: OCc1ccncc1Cl
Solvent: ClC(Cl)Cl
Product: Clc1cnccc1CBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3-chloropyridin-4-yl)methanol (700 mg, 4.9 mmol) in anhydrous chloroform (15 mL) was added dropwise a solution of phosphorus tribromide (460 μL, 4.9 mmol) in anhydrous chloroform (5 mL) at 0° C. The mixture was stirred for 8 hours at room temperature. The solid was filtered and washed with dichloromethane to afford crude 4-(bromomethyl)-3-chloropyridine, which was used for the next step without further purification; 1H NMR (400 MHz, MeOd4): δ 4.95 (s, 2H), 8.21 (d, J=6.0 Hz, 1H), 8.30 (d, J=6.0 Hz, 1H), 9.09 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:32])[C@@H:9]([CH3:31])[C:10]([NH:12][C@@H:13]([CH:28]([CH3:30])[CH3:29])[C:14]([N:16]1[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH2:18][C@H:17]1[C:25]([OH:27])=O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[F:57][C:58]1[CH:64]=[CH:63][C:62]([CH3:65])=[CH:61][C:59]=1[NH2:60].OS([O-])(=O)=O.[K+]>C(Cl)Cl>[F:57][C:58]1[CH:64]=[CH:63][C:62]([CH3:65])=[CH:61][C:59]=1[NH:60][C:25]([C@H:17]1[N:16]([C:14](=[O:15])[C@@H:13]([NH:12][C:10](=[O:11])[C@@H:9]([N:8]([CH3:32])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[CH3:31])[CH:28]([CH3:30])[CH3:29])[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH2:18]1)=[O:27]
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1c2ncccc2C[C@H]1C(=O)O
Reactant: Cc1ccc(F)c(N)c1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)c(NC(=O)[C@@H]2Cc3cccnc3N2C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)C)c1
Reaction time: 0.08 h
Yield: 79.4 %

Procedure:
To a solution of (S)-1-((S)-2-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-3-methylbutanoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (Intermediate 8) (50 mg, 111 μmol, Eq: 1.00) and diisopropylethylamine (58.4 μL, 334 μmol, Eq: 3) in DCM (1.5 mL) was added diphenylphosphinic chloride (58.0 mg, 46.7 μL, 245 μmol, Eq: 2.2). After stirring for 5 min, 2-fluoro-5-methylaniline (21 mg, 167 μmol, Eq: 1.5) was added and the resulting solution was stirred at rt for 2 days. The reaction mixture was poured into 0.1 M aqueous KHSO4 (20 mL) and extracted with EtOAc. The crude material was purified by flash chromatography (silica gel, 12 g, 0% to 40% EtOAc in hexanes) to give tert-butyl (S)-1-((S)-1-((S)-2-(2-fluoro-5-methylphenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-3-methyl-1-oxobutan-2-ylamino)-1-oxopropan-2-yl(methyl)carbamate as a colorless oil (49 mg), m/z=556 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([S:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:9])=[O:8])[CH3:6])[CH3:2].ClC[C:21]1[CH:35]=[CH:34][C:24]([O:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:23][CH:22]=1>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([S:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:9])=[O:8])[CH2:6][C:21]1[CH:22]=[CH:23][C:24]([O:25][CH2:26][CH2:27][N:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)=[CH:34][CH:35]=1)[CH3:2]
Reactant: ClCc1ccc(OCCN2CCCCC2)cc1
Reactant: CCCCCCCCS(=O)(=O)C(C)C(=O)OCC
Product: CCCCCCCCS(=O)(=O)C(Cc1ccc(OCCN2CCCCC2)cc1)C(=O)OCC

Procedure:
2-(Octane-1-sulfonyl)-3-[4-(2-piperidin-yl-ethoxy)-phenyl]-propionic acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from 2-(octane-1-sulfonyl)-propionic acid ethyl ester (5.0 g, 18 mmol) and 1-[2-(4chloromethylphenoxy)-ethyl]-piperidine (5.6 g, 19.7 mmol); Yield 8.9g (96%); amber oil, MS 495.
Reaction SMILES: [ClH:1].CC1(C)[NH:7][CH:6]([P:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:10])[OH:9])[C:5]([CH3:18])([CH3:17])[S:4]1.Cl>O>[ClH:1].[NH2:7][CH:6]([P:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:9])[OH:10])[C:5]([SH:4])([CH3:18])[CH3:17]
Reactant: CC1(C)NC(P(=O)(O)c2ccccc2)C(C)(C)S1
Agent: Cl
Solvent: O
Product: CC(C)(S)C(N)P(=O)(O)c1ccccc1

Procedure:
0.3 g of DL-(2,2,5,5-tetramethyl-4-thiazolidinyl)phenylphosphinic acid hydrochloride (prepared as described in Example 7) was suspended in boiling water and concentrated hydrochloric acid was added until a solution had formed. The solution was filtered and the filtrate was evaporated to dryness under reduced pressure. The solid residue was recrystallized from 3N hydrochloric acid to give DL-(1-amino-2-mercapto-2-methylpropyl)phenylphosphinic acid hydrochloride of melting point 190°-192° C. (decomposition).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].C(N(CC)CC)C.[CH:21]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>ClCCl>[CH:21]1([NH:27][S:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NC1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.2 %

Procedure:
To a solution of 2-nitrobenzene-1-sulfonyl chloride (22.1 g, 100 mol) in dichloromethane (500 mL) at 0° C. was added triethylamine (14 g, 138.6 mol) and cyclohexanamine (11.9 g, 120.2 mmol) in several portions over 10-15 minutes. The reaction mixture was stirred at room temperature for 4 hours, concentrated and purified by silica gel chromatography to afford the product N-cyclohexyl-2-nitrobenzenesulfonamide (25.7 g, yield 90.5%). 1H NMR (400 MHz, CDCl3) δ ppm 8.16-8.19 (m, 1H), 7.85-7.87 (m, 1H), 7.72-7.78 (m, 2H), 5.24-5.26 (d, 1H, J=7.6 Hz), 3.34-3.36 (m, 1H), 1.77-1.81 (m, 2H), 1.63-1.69 (m, 2H), 1.52-1.56 (m, 1H), 1.17-1.30 (m, 5H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:13][O:12][C:11](=[O:14])[C:10]2[CH:15]=[C:16]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH:17]=[C:18]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[C:9]=2[CH2:8][S:7][CH2:6][C@@H:5]([C:35]([O:37][CH3:38])=[O:36])[NH:4][C:3]1=[O:39].C(N(CC)CC)C.[Cl:47][CH2:48][C:49](Cl)=[O:50]>C(Cl)Cl>[Si:28]([O:27][C:16]1[CH:17]=[C:18]([O:19][Si:20]([C:23]([CH3:24])([CH3:25])[CH3:26])([CH3:21])[CH3:22])[C:9]2[CH2:8][S:7][CH2:6][C@@H:5]([C:35]([O:37][CH3:38])=[O:36])[NH:4][C:3](=[O:39])[C@@H:2]([NH:1][C:49](=[O:50])[CH2:48][Cl:47])[CH2:13][O:12][C:11](=[O:14])[C:10]=2[CH:15]=1)([C:31]([CH3:32])([CH3:33])[CH3:34])([CH3:30])[CH3:29]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)[C@@H]1CSCc2c(O[Si](C)(C)C(C)(C)C)cc(O[Si](C)(C)C(C)(C)C)cc2C(=O)OC[C@H](N)C(=O)N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1CSCc2c(O[Si](C)(C)C(C)(C)C)cc(O[Si](C)(C)C(C)(C)C)cc2C(=O)OC[C@H](NC(=O)CCl)C(=O)N1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
To a solution of 1.30 g of methyl (4R, 7S)-7-amino-12,14-bis(tert-butyldimethylsilyloxy)-1,3,4,5,6,7,8,10-octahydro-6,10-dioxo-9,2,5-benzoxathiaazacyclododecine-4 -carboxylate and 0.23 g of triethylamine in 50 ml of methylene chloride, was added at 0° C. within 2 minutes a solution of 0.25 g of chloro-acetyl chloride in 3 ml of methylene chloride. The mixture was stirred at 0° C. for 30 minutes, then diluted with methylene chloride and washed successively with 0.03N hydrochloric acid and water. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel using ethyl acetate/hexane (1:1, v/v) as eluent to yield 1.20 g of methyl (4R, 7S)-12,14-bis (tert-butyldimethylsilyloxy)-7-(2-chloroacetamido)-1,3,4,5,6,7,8,10-octahydro-6,10-dioxo-9,2,5-benzoxathiaazacyclododecine-4-carboxylate as a white solid. A sample of 287 mg of this material was treated with ammonium fluoride in methanol in an analogous manner to the procedure described in Example 13 to yield, after crystallization from ethyl acetate, 115 mg of methyl (4R, 7S)-7-(2chloroacetamido)-1,3,4,5,6,7,8,10-octahydro-12,14-dihydroxy6,10-dioxo-9,2,5-benzoxathiaazacyclododecine-4 -carboxylate as a white solid, m.p. 182° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:6]=O.[N+:13]([CH3:16])([O-:15])=[O:14].[OH-].[Na+].Cl>O.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:6]=[CH:16][N+:13]([O-:15])=[O:14]
Reactant: C[N+](=O)[O-]
Reactant: COc1cc(C=O)cc(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(C=C[N+](=O)[O-])cc(OC)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 34.5 g. (0.208 mole) 3,5-dimethoxybenzaldehyde and 12.68 g. (0.208 mole) nitromethane in 40 ml. methanol was cooled to 0° C. under a nitrogen atmosphere. To this was added dropwise a cold solution of 8.43 g. (0.211 mole) sodium hydroxide in 30 ml. water and stirring continued at 0° C. for 15 minutes after the addition was completed. The mixture was diluted with ice-water and added slowly to a solution of 40 ml. concentrated hydrochloric acid in 60 ml. water. The precipitated product (44 g.) was collected by filtration and recrystallized from methanol to give 28.6 g., M.P. 132° C. J. Org. Chem., 27, 376 (1976) reported M.P. 133.5°-134.5° C.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([OH:19])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:23]2)=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:38](Cl)(=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40]>>[Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])[CH2:23]2)=[CH:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reactant: CC(C)(C)C(=O)Cl
Product: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](OC(=O)C(C)(C)C)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Yield: 46.8 %

Procedure:
A procedure similar to that described in Example 4, above, was followed, but using 1.10 g (2.0 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above] and 486 mg (4.0 mmol) of pivaloyl chloride, to provide 594 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([OH:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.CC(C)=[O:14]>>[OH:14][N:3]1[C:4]([CH3:10])([CH3:9])[CH2:5][CH:6]([OH:8])[CH2:7][C:2]1([CH3:11])[CH3:1]
Reactant: CC(C)=O
Reactant: CC1(C)CC(O)CC(C)(C)N1
Product: CC1(C)CC(O)CC(C)(C)N1O
Reaction time: 2 h

Procedure:
In a 100 ml flask, a solution of 0.047 M DMD in acetone (21.2 ml, 1 mmol) was added to a cold stirred solution of 2,2,6,6-tetramethyl-4-piperidinol (0.1572 g, 1 mmol) in acetone (10 ml). The reaction mixture was stirred for two hours in an ice bath. Solvent was removed on a rotary evaporator to give a white crystalline solid (0.1727 g, 99% yield, mp 161-163). Sublimation on the Kugelrohr (110-120°, 1×10-4 mmHg) gave white needles (0.170 g). Measured mp was 162-163; reported mp is 155-159 (Lee et al 1975 and Rozantsey et al 1966).
Reaction SMILES: [CH3:1][OH:2].Cl[CH2:4][N:5]([CH3:10])[S:6]([Cl:9])(=[O:8])=[O:7].C1CCCCC1>C(N(CC)CC)C>[CH3:1][O:2][CH2:4][N:5]([CH3:10])[S:6]([Cl:9])(=[O:8])=[O:7]
Reactant: CO
Reactant: CN(CCl)S(=O)(=O)Cl
Solvent: C1CCCCC1
Solvent: CCN(CC)CC
Product: COCN(C)S(=O)(=O)Cl
Temperature: 40 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
500 parts of methanol are added in the course of 2 minutes at 25° C. to a mixture of 400 parts of N-chloromethyl-N-methylsulfamic acid chloride and 1,000 parts of cyclohexane. 227 parts of triethylamine are then added in the course of 30 minutes at from 0° to 7° C. The reaction mixture is then stirred for one hour at 40° C., after which it is concentrated under reduced pressure. The hydrochloride which has precipitated is filtered off and the filtrate is distilled, giving 282 parts (72% of theory) of N-methoxymethyl-N-methylsulfamic acid chloride of boiling point 84°-87° C./12 mbar and nD25 =1.4536.
Reaction SMILES: CS(O[C@@H:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:9]=1)[CH3:7])(=O)=O.[N-:21]=[N+:22]=[N-:23].[Na+].O>CN(C)C=O>[C:17]([O:16][C:14]([C:10]1[CH:9]=[C:8]([C@@H:6]([N:21]=[N+:22]=[N-:23])[CH3:7])[CH:13]=[CH:12][CH:11]=1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: C[C@@H](OS(C)(=O)=O)c1cccc(C(=O)OC(C)(C)C)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](N=[N+]=[N-])c1cccc(C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
(R)-1-(3-tert-butyloxycarbonylphenyl)-ethyl methanesulfonyl ether (3.28 mmol) was dissolved in N,N-dimethylformamide (20 mL) and sodium azide (8.57 mmol) was added. The resultant mixture was heated to 60° C. for 45 min then stirred at room temperature overnight. Worked up by pouring into water and extracting 3× with diethyl ether. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated under reduced pressure to yield 769 mg of an oil which was used without further purification. 1H NMR (500 MHz, CDCl3): δ 7.96 (m, 2H); 7.52 (m, 1H); 7.45 (m, 1H); 4.69 (q, J=6.9 Hz, 1H): 1.63 (s, 9H); 1.57 (d, J=6.8 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[C:19](=[O:20])[O:18][CH:17]3[OH:22])[N:4]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:32])[CH3:31].Cl>O1CCCC1>[C:30]([O:22][CH:17]1[C:16]2[C:21](=[C:12]([O:11][C:5]3[N:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[N:6]=3)[CH:13]=[CH:14][CH:15]=2)[C:19](=[O:20])[O:18]1)(=[O:32])[CH3:31]
Reactant: CC(=O)Cl
Reactant: COc1cc(OC)nc(Oc2cccc3c2C(=O)OC3O)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(OC)nc(Oc2cccc3c2C(=O)OC3OC(C)=O)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.3 g of 7-[(4,6-dimethoxy-pyrimidin-2-yl)oxy]-3-hydroxy-phthalide (see Example 84) are dissolved in 30 ml of tetrahydrofuran, and 0.6 ml of triethylamine is added to the solution which is then treated dropwise at 25° C. (internal temperature) with 0.5 ml of acetyl chloride. After subsequently stirring for 2 hours at room temperature, the reaction mixture is treated with ice-water and dilute hydrochloric acid and extracted with ethyl acetate, and the organic phase is washed with sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. Column chromatography on silica gel [eluant: ethyl acetate/n-hexane (2:3)] yields 3-acetoxy-7-[(4,6-dimethoxy-pyrimidin-2-yl)oxy]-phthalide in the form of white crystals, m.p. 119°-120° C.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][S:7][C:8]1[N:9]=[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]2[C:16]=1[CH2:17][C:18]1[C:19]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:20]=2[S:21][CH:22]=1.O.[OH-].[Li+]>C1COCC1.O>[Cl:27][C:25]1[CH:24]=[CH:23][C:20]2[S:21][CH:22]=[C:18]([CH2:17][C:16]3[N:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]4=[N:9][C:8]=3[S:7][CH2:6][CH2:5][CH2:4][C:3]([OH:28])=[O:2])[C:19]=2[CH:26]=1
Reactant: COC(=O)CCCSc1nc2ccccn2c1Cc1csc2ccc(Cl)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCCSc1nc2ccccn2c1Cc1csc2ccc(Cl)cc12
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A solution of 15 mg (0.04 mmol) of 4-[3-(5-chloro-benzo[b]thiophen-3-ylmethyl)-imidazo[1,2-a]pyridin-2-ylsulfanyl]-butyric acid methyl ester in 2 mL of THF is treated with a solution of 10 mg (0.24 mmol) of lithium hydroxide monohydrate in 1 mL of water at room temperature. The resulting mixture is heated to 50° C., and stirred at this temperature for 2 h. The reaction mixture is then cooled to room temperature and concentrated in vacuo. The residue is purified by preparative TLC on silica gel to give the title compound. LCMS (ESMS): m/z 417 (M+H+).
Reaction SMILES: [OH:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]1([CH2:34][OH:35])[CH2:33][O:32][CH2:31]1>C(#N)C>[OH:35][CH2:34][C:30]1([CH2:29][O:1][C:2]2[C:3]([O:20][CH3:21])=[C:4]([C:10]3[CH:11]=[C:12]4[C:16](=[CH:17][CH:18]=3)[C:15](=[O:19])[O:14][CH2:13]4)[CH:5]=[CH:6][C:7]=2[O:8][CH3:9])[CH2:33][O:32][CH2:31]1
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(OC)c1O
Reactant: OCC1(CBr)COC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2ccc3c(c2)COC3=O)c(OC)c1OCC1(CO)COC1
Temperature: 80 °C
Yield: 23.2 %

Procedure:
To a stirring solution of 5-(3-Hydroxy-2,4-dimethoxy-phenyl)-3H-isobenzofuran-1-one (80 mg, 0.279 mmol) in acetonitrile (10 mL) was added potassium carbonate (115 mg, 0.837 mmol) and (3-(bromomethyl)oxetan-3-yl)methanol (151 mg, 0.837 mmol) and the resultant reaction mixture was heated to 80° C. for 4 h. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-50% ethyl acetate in pet ether) to afford the title compound as a solid (25 mg, 23.2%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>CC(O)=O.CCCCCC>[C:13]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1)(=[O:15])[CH3:14]
Reactant: O=C(O)c1ccc2[nH]ncc2c1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: CCCCCC
Product: CC(=O)n1ncc2cc(C(=O)O)ccc21
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 78.5 %

Procedure:
To a solution of 1H-indazole-5-carboxylic acid (8.6 g, 53.04 mmol) in AcOH (200 ml) was added acetic anhydride (16.2 g), and the reaction was stirred for 2.5 h at 80° C. The resulting solution was diluted with n-hexane (400 ml). The solids were collected by filtration and washed with hexane (5×100 ml) to afford 1-acetyl-1H-indazole-5-carboxylic acid as an orange solid (8.5 g, 78%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][NH:8][C:9]2=O)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([CH3:1])[CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: Cc1ccc2cc[nH]c(=O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1ccc2ccnc(Cl)c2c1
Temperature: 25 °C

Procedure:
7-Methyl-2H-isoquinolin-1-one (2.1 g, 13.2 mmol) in phosphorus oxychloride (30 mL) is heated to reflux for 13 hours. The mixture is cooled to room temperature, then concentrated to a smaller volume. The residue is diluted with ice water and the pH is adjusted to ca. 8 by slow addition of 10 N NaOH. The aqueous solution is extracted with methylene chloride (4×20 mL) and the combined organic layers are washed with brine, dried over MgSO4, filtered and concentrated. The resulting dark oil is purified by column chromatography eluting with 25% EtOAc/hexanes to give the product (1.6 g, 9 mmol) as a light yellow solid.
Reaction SMILES: [OH-].[Na+].CC1(C)C(C)(C)OB([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[CH:14][NH:15]3)O1.Br[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1>[Pd].C1COCC1>[N:24]1[CH:25]=[CH:26][CH:27]=[C:22]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[CH:14][NH:15]3)[CH:23]=1
Reactant: Brc1cccnc1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: c1cncc(-c2cccc3[nH]ccc23)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 62.8 %

Procedure:
Palladium catalyst Pd(PPh3)4 (284 mg, 0.25 mmol) and freshly prepared aqueous sodium hydroxide (984 mg in 9 mL of water) were added to a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (2 g, 8.2 mmol) and 3-bromopyridine (0.8 mL, 8.3 mmol) in THF (28 mL). The system was degassed and then purged three times with nitrogen. The mixture was stirred under nitrogen at 70° C. in an oil bath for 6 hours. It was then cooled to room temperature and 400 ml ethyl acetate was added. The organic layer was isolated, washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was column chromatographed to give 1 g (62%) of 4-pyridin-3-yl-1H-indole as a white solid.