Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH:15]=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=[O:5].[C:30](N1C=CN=C1)(N1C=CN=C1)=[O:31]>O1CCCC1>[N+:27]([C:25]1[CH:26]=[C:2]2[C:3]([C:4](=[O:5])[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][N:11]3[CH2:12][CH:13]=[C:14]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:15][CH2:16]3)[C:30](=[O:31])[NH:1]2)=[CH:23][CH:24]=1)([O-:29])=[O:28]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)NCCCCN1CC=C(c2ccccc2)CC1
Solvent: C1CCOC1
Product: O=c1[nH]c2cc([N+](=O)[O-])ccc2c(=O)n1CCCCN1CC=C(c2ccccc2)CC1
Yield: 57.7 %

Procedure:
A mixture of 2-amino-4-nitro-N-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]benzamide (0.52 g) and carbonyldiimidazole (0.43 g) in dry tetrahydrofuran (10 ml) was stirred under reflux for 2 hours. After evaporation of the solvent, the crude residue was crystallized and recrystallized from ethanol to give crystals of 7-nitro-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione (0.32 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[O:11])O[C:8](=[O:12])[N:7]([CH3:13])[C:6]=2[CH:14]=1.[H-].[Na+].CN(C=O)C.BrC1C=C[C:26]2[C:31](=[O:32])[O:30][C:29](=O)NC=2C=1.IC>O>[Br:1][C:2]1[CH:14]=[C:6]2[C:5]([C:10]([OH:11])=[C:26]([C:31]([O:30][CH3:29])=[O:32])[C:8](=[O:12])[N:7]2[CH3:13])=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2cc(Br)ccc2c(=O)o1
Reactant: Cn1c(=O)oc(=O)c2ccc(Br)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1c(O)c2ccc(Br)cc2n(C)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
7-Bromo-1-methyl-1H-benzo[d][1,3]oxazine-2,4-dione. Sodium hydride (0.47 g, 12 mmol) was added to a 3 neck 250 mL round bottom flask under nitrogen and then washed with hexanes. Once the hexanes were decanted, DMF (20.0 mL, 11 mmol) was added. The resulting mixture was cooled to 0° C. using an ice-water bath, and then 7-bromo-1H-benzo[d][1,3]oxazine-2,4-dione (2.7 g, 11 mmol) was added in one batch. After stirring at room temperature for 1 hour, iodomethane (0.70 mL, 11 mmol) was added dropwise to the yellow solution, and the reaction mixture was stirred for 16 hours. Water (50 mL) was added, and the resulting precipitate that formed was collected via filtration. The solid was washed with additional water (100 mL), followed by ether (100 mL). Drying in a vacuum oven overnight at 50° C. provided the title compound as an off-white solid (2.1 g, 74% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[C:7]=1[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:5])[CH3:2].[F:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:34]3[CH:35]=[CH:36][C:31]([C:30]([F:41])([F:40])[F:29])=[CH:32][CH:33]=3)[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[C:7]=1[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1cccc(Cl)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(C(F)(F)F)cc3)ccc2n1-c1cccc(Cl)c1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 1-(3-chlorophenyl)-2-ethoxycarbonylmethyl-5-hydroxyindole-3-carboxylic acid ethyl ester (141 mg, 0.35 mmol, see step (b) Example 8) and 4-trifluoromethylphenylboronic acid (100 mg, 0.53 mmol). Yield 120 mg (63%).
Reaction SMILES: [CH3:1][C:2]([CH2:8][CH2:9][CH3:10])=[C:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[CH3:11][Li]>C1COCC1.CCOCC.O>[CH3:1][C:2]([C:3]1[CH2:7][CH:6]=[CH:5][CH:4]=1)([CH3:11])[CH2:8][CH2:9][CH3:10]
Reactant: CCCC(C)=C1C=CC=C1
Reactant: [Li]C
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CCCC(C)(C)C1=CC=CC1
Temperature: 25 °C
Yield: 82 %

Procedure:
To a solution of 7.00 g (52.2 mmol) of 6-methyl-6-propylfulvene in 40 ml of THF, 50.3 ml (57.3 mmol) of an ether solution of methyllithium was dropwise added in a nitrogen atmosphere with ice cooling, followed by stirring at room temperature for one night. After the reaction solution was diluted with 100 ml of ether, 30 ml of water was added. The separated organic phase was washed with water and a saturated saline solution, then dried over magnesium sulfate and filtered. From the filtrate, the solvent was removed under reduced pressure to obtain a liquid. The liquid was subjected to vacuum distillation (75° C./5-7 mmHg) to obtain 6.40 g (42.6 mmol) of a light yellow liquid (yield: 82%). The analyzed values are given below.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH:35]1([C:38](O)=[O:39])[CH2:37][CH2:36]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH:35]1([C:38]([NH:2][C@@H:3]2[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]3[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=3[O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=3)[CH2:5][CH2:4]2)=[O:39])[CH2:37][CH2:36]1
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](N)CC2)c1
Reactant: O=C(O)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](NC(=O)C3CC3)CC2)c1
Temperature: 25 °C
Reaction time: 64 h
Yield: 98.3 %

Procedure:
N-(cis-4-Amino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide hydrochloride (100 mg, 0.243 mmol) was dissolved in dimethylformamide (1 ml) and triethylamine (100 μl, 0.729 mmol) was added followed by cyclopropanecarboxylic acid (23 μl, 0.291 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (56 mg, 0.291 mmol) and 1-hydroxybenzotriazole (39 mg, 0.291 mmol). The reaction was stirred under nitrogen at room temperature for 64 h and the solvent was removed under reduced pressure. The residue was partitioned between sat. sodium bicarbonate solution (5 ml) and ethyl acetate (10 ml) and the aqueous phase was extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with water (2×5 ml), brine (5 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was triturated with diethylether (5 ml) to give N-[cis-4-(Cyclopropanecarbonyl-amino)-cyclohexyl]-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide (106 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH2:9]1[O:13][C:10]1([CH3:12])[CH3:11]>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:9][C:10]([OH:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1
Reactant: CC1(C)CO1
Reactant: Nc1ccc(F)cc1
Product: CC(C)(O)CNc1ccc(F)cc1
Temperature: 120 °C
Yield: 65.5 %

Procedure:
A mixture of 4-fluoroaniline (1.12 g, 10 mmol) and isobutene oxide (0.70 g, 10 mmol) was heated in a sealed tube at 120° C. overnight. The resultant oil was purified by flash chromatography to give the title compound as an oil (1.20 g, 65%).
Reaction SMILES: [O-:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([O-:15])(=[O:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.[Na+].[Na+].Cl[CH2:19][CH2:20][CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[N:22]1([CH2:21][CH2:20][CH2:19][O:1][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][C:8]([S:12]([OH:15])(=[O:13])=[O:14])=[CH:9]3)=[CH:4][CH:3]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=S(=O)([O-])c1ccc2ccc([O-])cc2c1
Reactant: ClCCCN1CCCC1
Agent: [Na+]
Product: O=S(=O)(O)c1ccc2ccc(OCCCN3CCCC3)cc2c1
Yield: 54.9 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 26B, sodium 7-oxidonaphthalene-2-sulfonate (Pfaltz and Bauer, 200 mg, 0.75 mmol) and 1-(3-chloropropyl)pyrrolidine (110 mg, 0.75 mmol) were converted to the title compound (138 mg, 55%). MS(ESI+) m/z 336.1 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH:11]1([NH2:14])[CH2:13][CH2:12]1>>[CH:11]1([NH:14][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:13][CH2:12]1
Reactant: NC1CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: O=[N+]([O-])c1ccc(NC2CC2)cc1
Temperature: 0 °C

Procedure:
1-Fluoro-4-nitrobenzene (3.5 g, 24.8 mmoles) is refluxed for 5 hours with 8.1 g (0.14 moles) of cyclopropylamine. After that, the reaction product is poured onto 250 g of ice/water and the precipitate is filtered off. After recrystallization from ethanol, a yellow solid with a melting point of 126°-128° C. is obtained.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[C:4]([C:12]2[N:24]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:15]3=[N:16][CH:17]=[C:18]4[CH:22]=[N:21][N:20]([CH3:23])[C:19]4=[C:14]3[CH:13]=2)=[CH:3]1.Cl[CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:36][CH2:37][N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[CH:8][CH:9]=2)[C:4]([C:12]2[N:24]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:15]3=[N:16][CH:17]=[C:18]4[CH:22]=[N:21][N:20]([CH3:23])[C:19]4=[C:14]3[CH:13]=2)=[CH:3]1
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3cn(C)c4ccc(O)cc34)cc3c4c(cnc32)cnn4C)cc1
Reactant: ClCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2c(-c3cn(C)c4ccc(OCCN5CCOCC5)cc34)cc3c4c(cnc32)cnn4C)cc1
Temperature: 50 °C
Yield: 21.6 %

Procedure:
A mixture of 1-methyl-3-(1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-7-yl)-1H-indol-5-ol (0.21 g, 0.42 mmol), 4-(2-chloroethyl)morpholine (0.12 g, 0.78 mmol, Beta Pharm) and Cs2CO3 (0.42 g, 1.27 mmol) in DMF (4 mL) was heated at about 50° C. for about 20 h. After cooling to rt the mixture was filtered. The filtrate was purified by preparative reverse phase HPLC (Table 2, Method j) to give 4-(2-(1-methyl-3-(1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-7-yl)-1H-indol-5-yloxy)ethyl)morpholine (0.053 g, 21%): LC/MS (Table 2, Method a) Rt=2.07 min; MS m/z 585 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9]C(=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=O.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>C1COCC1>[NH2:11][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:13][C:6]=1[C:7]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:9]
Reactant: C1COCCN1
Reactant: O=c1[nH]c2ccc(Br)cc2c(=O)o1
Solvent: C1CCOC1
Product: Nc1ccc(Br)cc1C(=O)N1CCOCC1
Reaction time: 1.5 h
Yield: 47.1 %

Procedure:
Into an 8 mL screw cap vial were added 5-bromoisatoic anhydride (0.200 g, 0.826 mmol), anhydrous THF (5 mL), and morpholine (101 mg, 1.16 mmol). The vial was sealed and placed in a heat block at 60° C. for 1.5 h after which it was concentrated under vacuum. The crude product was triturated with Et2O/hexanes to afford 111 mg (94%) of (2-Amino-5-bromo-phenyl)-morpholin-4-yl-methanone as a tan solid. m/z 285/287 [MH+].
Reaction SMILES: C(O[C:4]([NH:6][C:7]1[N:17]=[CH:16][CH:15]=[CH:14][C:8]=1[C:9]([O:11]CC)=O)=[O:5])C.NC1N=CC=CC=1C(OCC)=O.ClC(OCC)=O.C(N(CC)C(C)C)(C)C.[NH2:45][CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][CH:51]([C:54](=[O:62])[C:55]2[CH:60]=[CH:59][C:58]([F:61])=[CH:57][CH:56]=2)[CH2:50][CH2:49]1>C1(C)C=CC=CC=1.CO>[F:61][C:58]1[CH:57]=[CH:56][C:55]([C:54]([CH:51]2[CH2:50][CH2:49][N:48]([CH2:47][CH2:46][N:45]3[C:9](=[O:11])[C:8]4[CH:14]=[CH:15][CH:16]=[N:17][C:7]=4[NH:6][C:4]3=[O:5])[CH2:53][CH2:52]2)=[O:62])=[CH:60][CH:59]=1
Reactant: CCOC(=O)Nc1ncccc1C(=O)OCC
Reactant: NCCN1CCC(C(=O)c2ccc(F)cc2)CC1
Agent: CCOC(=O)Cl
Agent: CCOC(=O)c1cccnc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C(c1ccc(F)cc1)C1CCN(CCn2c(=O)[nH]c3ncccc3c2=O)CC1

Procedure:
A mixture of 2.06 g of ethyl 2-ethoxycarbonylaminonicotinate (m.p. 60°, obtainable by boiling ethyl 2-aminonicotinate with ethyl chloroformate for 5 h in the presence of N,N-diisopropylethylamine in toluene) and 2.54 g of 1-(2-aminoethyl)-4-p-fluorobenzoylpiperidine (Rf 0.43 on silica gel with butanol/ethanol/water/ethyl acetate/acetic acid 50:50:50:25:25) is heated at 190° for 1 h. The mixture is cooled and taken up in methanol and, on cooling, 3-[2-(4-p-fluorobenzoylpiperidino)ethyl]-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine is obtained, m.p. 237°. Hydrochloride m.p. 297°-298°. Fumarate m.p. 253°-255°.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:17])=O.CN(C=O)C>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([Cl:17])=[O:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Br
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc([N+](=O)[O-])ccc1Br
Reaction time: 1.5 h

Procedure:
To a solution of 2-bromo-5-nitrobenzoic acid (1.00 g, 4.06 mmol) in methylene chloride (15 mL) is added oxalyl chloride (1.42 mL, 16.24 mmol) followed by 1 drop DMF. Addition of DMF results in vigorous gas evolution. After 1.5 h, the reaction mixture is concentrated under reduced pressure to give an oil which is used as is without purification.
Reaction SMILES: [CH3:1][N:2]1[C:6](SC)=[C:5]([N+:9]([O-:11])=[O:10])[S:4][C:3]1=[O:12].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][NH:21][CH3:22])=[CH:16][N:15]=1>C(O)C>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]([C:6]2[N:2]([CH3:1])[C:3](=[O:12])[S:4][C:5]=2[N+:9]([O-:11])=[O:10])[CH3:22])=[CH:16][N:15]=1
Reactant: CSc1c([N+](=O)[O-])sc(=O)n1C
Reactant: CNCc1ccc(Cl)nc1
Solvent: CCO
Product: CN(Cc1ccc(Cl)nc1)c1c([N+](=O)[O-])sc(=O)n1C
Temperature: 25 °C
Yield: 91.7 %

Procedure:
A mixture consisting of 3-methyl-4-methylthio-5-nitro-2-thiazolone (1.0 g), N-(2-chloro-5-pyridylmethyl)-N-methylamine (0.9 g) and ethanol (30 ml) was heat-refluxed for five hours and then cooled to room temperature to obtain the desired 4-[N-(2-chloro-5-pyridylmethyl)-N-methylamino]-3-methyl-5-nitro-2-thiazolone (1.4 g) having a melting point in the range from 147° to 148° C. in a crystal form.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:33][C:13]3[N:14]([CH2:24][C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[F:32])[CH:15]=[C:16]([S:19]([CH:21]([CH3:23])[CH3:22])=[O:20])[C:17](=[O:18])[C:12]=3[C:11]=2[CH2:34][N:35]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH3:36])=[CH:6][CH:5]=1)([O-])=O.CO.Cl.C(=O)(O)[O-].[Na+]>[Fe].C(Cl)(Cl)Cl>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[S:33][C:13]3[N:14]([CH2:24][C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[F:32])[CH:15]=[C:16]([S:19]([CH:21]([CH3:22])[CH3:23])=[O:20])[C:17](=[O:18])[C:12]=3[C:11]=2[CH2:34][N:35]([CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH3:36])=[CH:8][CH:9]=1
Reactant: CC(C)S(=O)c1cn(Cc2c(F)cccc2F)c2sc(-c3ccc([N+](=O)[O-])cc3)c(CN(C)Cc3ccccc3)c2c1=O
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)S(=O)c1cn(Cc2c(F)cccc2F)c2sc(-c3ccc(N)cc3)c(CN(C)Cc3ccccc3)c2c1=O
Reaction time: 5 h

Procedure:
The compound (0.54 g, 0.87 mmol) obtained in Example 19 and iron powder (0.26 g, 4.3 mmol) were added to methanol (10 ml) and to the mixture conc.hydrogen chloride (5 ml) was added dropwise for one hour. The mixture was stirred for 5 hours under ice-cooling. To the reaction mixture saturated sodium bicarbonate (30 ml) was added carefully. After adding chloroform (50 ml) and Celite, the mixture was subjected to filtration.
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([C:6]1[C:15]([CH3:16])=[C:14]([OH:17])[CH:13]=[CH:12][C:7]=1[C:8](OC)=[O:9])[CH3:5]>C(O)CCC>[CH2:4]([C:6]1[C:15]([CH3:16])=[C:14]([OH:17])[CH:13]=[CH:12][C:7]=1[C:8]([NH:2][NH2:3])=[O:9])[CH3:5]
Reactant: NN
Reactant: CCc1c(C(=O)OC)ccc(O)c1C
Solvent: O
Solvent: CCCCO
Product: CCc1c(C(=O)NN)ccc(O)c1C
Yield: 68 %

Procedure:
1 ml of butanol and 4.5 ml of hydrazine hydrate are added to 1.88 g of methyl 2-ethyl-4-hydroxy-3-methylbenzoate in a screw-lid vial, and the mixture is stirred at 100° C. until the hydrazide formation is complete. The cooled reaction mixture is poured onto water, the precipitate is filtered off with suction and dried. Purification by recrystallisation from water/1 -propanol gives 1.28 g of 2-ethyl-4-hydroxy-3-methylbenzohydrazide as colourless crystals (68%); MS-FAB (M+H+)=1.95.1; Rf (polar method): 0.99 min.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:12][CH2:13][C:14]1[CH:15]=[C:16]([CH2:22][CH:23]([O:29][CH:30]([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21].C(N(CC)CC)C.O>O1CCCC1.C(OCC)C>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:12][CH2:13][C:14]1[CH:15]=[C:16]([CH2:22][CH:23]([O:29][CH:30]([CH3:31])[CH3:32])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21])=[O:5]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CN)c1)OC(C)C
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C(Cc1ccc(OC)c(CNC(=O)c2ccc(Cl)cc2Cl)c1)OC(C)C
Temperature: 25 °C
Yield: 95.3 %

Procedure:
A solution of 15.9 g 2,4-dichlorobenzoyl chloride in tetrahydrofuran (15 ml) was added dropwise to a solution of 18.67 g ethyl 3-[3-(aminomethyl)-4-methoxyphenyl]-2-isopropoxypropanoate and 7.7 g triethylamine in diethyl ether (300 ml) under ice-cooling. After stirring under ice-cooling for 30 minutes and further at room temperature for 30 minutes, the reaction solution was poured into 500 ml water and extracted with 300 ml ethyl acetate. The organic layer was successively washed with 200 ml saturated aqueous sodium bisulfate, 200 ml saturated sodium hydrogencarbonate and 200 ml brine, dried over anhydrous magnesium sulfate and the solvent was evapoarated. The residue was purified by silica gel column chromatography (eluting solvent: hexane-ethyl acetate), to give 28.2 g of ethyl 3-(3-{[(2,4-dichlorobenzoyl)amino]methyl}-4-methoxyphenyl)-2-isopropoxypropanoate identical in TLC and 1H-NMR to the compound obtained in Example 31g) as a colorless solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:12]([CH2:13][CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][C@H:16]3[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:11][CH2:10][S:9][C:8]=2[CH:27]=1)([O-])=O.CCO.I.[S:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[C:37](SC)=[NH:38].N>[Pd].CO.C(Cl)Cl>[C:23]([O:22][C:20]([C@@H:16]1[CH2:17][CH2:18][CH2:19][N:15]1[CH2:14][CH2:13][N:12]1[CH2:11][CH2:10][S:9][C:8]2[CH:27]=[C:4]([NH:1][C:37]([C:33]3[S:32][CH:36]=[CH:35][CH:34]=3)=[NH:38])[CH:5]=[CH:6][C:7]1=2)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1CCN1CCSc2cc([N+](=O)[O-])ccc21
Reactant: CSC(=N)c1cccs1
Agent: [Pd]
Agent: I
Agent: N
Solvent: CO
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1CCN1CCSc2cc(NC(=N)c3cccs3)ccc21
Yield: 63.1 %

Procedure:
A round bottom flask containing (S)-tert-butyl 1-(2-(7-nitro-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethyl)pyrrolidine-2-carboxylate (525 mg, 1.334 mmol) was purged with argon. This flask was charged with palladium on activated carbon (10% wt; 142 mg, 0.133 mmol) followed by EtOH (25 mL). The resulting suspension was evacuated using a pump, and hydrogen was let into the system via a balloon. The mixture was stirred under a balloon filled with hydrogen for 2 hours. At this time, the hydrogen balloon was removed, and methyl thiophene-2-carbimidothioate hydroiodide (761 mg, 2.67 mmol) was added to the mixture. The suspension was stirred at room temperature for 17 hours (overnight). At this time, the mixture was filtered through a pad of Celite, and the pad was rinsed with MeOH (20 mL). The filtrate was concentrated, and the residue partitioned between saturated sodium bicarbonate solution (50 mL) and CH2Cl2 (100 mL). The mixture was transferred to a separatory funnel and extracted. After extraction, the organic layer was separated, dried (Na2SO4), filtered, and concentrated to give a dark residue. This residue was subjected to flash chromatography on silica gel using 2:98 MeOH:CH2Cl2 followed by 3.5:96.5 (2M NH3 in MeOH):CH2Cl2 to give a yellow-green residue (398 mg, 63.1%). 1H-NMR (CDCl3) δ 7.39 (dd, J=1.2, 5.1 Hz, 1H), 7.37 (dd, J=1.2, 3.9 Hz, 1H), 7.05 (dd, J=3.6, 4.8 Hz, 1H), 6.73 (brd, J=5.1 Hz, 1H), 6.71 (brs, 1H), 6.65 (dd, J=2.1, 8.7 Hz, 1H), 4.86 (brs, 2H), 3.63-3.60 (m, 2H), 3.44 (t, J=7.5 Hz, 2H), 3.25-3.19 (m, 1H), 3.11 (brdd, J=5.4, 8.4 Hz, 1H), 3.04-2.94 (m, 3H), 2.71-2.59 (m, 1H), 2.45 (brdd, J=7.8, 16.2 Hz, 1H), 2.13-1.99 (m, 1H), 1.97-1.74 (m, 3H), 1.45 (s, 9H); ESI-MS (m/z, %): 473 (MH+, 90), 417 (85), 276 (100); HPLC Purity: 99.6% a/a.
Reaction SMILES: FC(F)(F)S([O:6][C@@H:7]1[C@@H:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:11]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@H:10]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:9][CH2:8]1)(=O)=O.N([O-])=O.[Na+].O>CN(C=O)C>[CH2:14]([O:13][C@H:12]1[C@H:11]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@H:10]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[O:9][CH2:8][C@@H:7]1[OH:6])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S(=O)(O[C@H]1CO[C@@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1)C(F)(F)F
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O[C@H]1CO[C@@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 10 °C
Reaction time: 14 h

Procedure:
The triflate (12) was dissolved in DMF (36.2 kg, 3.02 kg/kg starting material) and cooled to 10° C. Sodium nitrite (5.9 kg, 3.0 equivalents) was added, the solution exothermed to approximately 30° C., then the reaction mixture was cooled to 15° C. to 25° C. and stirred for 12-16 h. The mixture was cooled to 5° C., and water (152 kg, 4.2 kg/kg DMF) was added at a rate that kept the temperature <15° C. The resulting mixture was agitated at 10° C. for 2 hours. The solids were filtered and washed with water (2×12 kg). The filtered solids were dissolved in ethyl acetate (21.6 kg, 1.8 kg/kg starting material). The solution was washed with brine (15.5 kg), dried with MgSO4 (2.5 kg), filtered, and the filtrate was concentrated to dryness under vacuum at 35° C. Isopropanol (9.5 kg) was added and heated to 75° C. to dissolve the crude product. Heptane (24.6 kg) was added to the solution and the mixture cooled to 15° C. to 25° C. The mixture was further cooled to 0° C. and stirred overnight. The solids were filtered and washed with heptane (2×8.2 kg). The material was dried in a vacuum oven. (3S,4R,5S,6R)-4,5,6-Tris(benzyloxy)tetrahydro-2H-pyran-3-ol (13) was obtained as a yellow solid, 5.3 kg (44%). 1H NMR (300 MHz, CDCl3): δ 7.37 (m, 15H), 4.96 (d, J=11 Hz, 1H), 4.80 (m, 2H), 4.68 (d, J=12 Hz, 1H), 4.61 (m, 2H), 4.53 (d, J=12 Hz, 1H), 3.78 (m, 1H), 3.67 (m, 3H), 3.50 (dd, J=9, 3 Hz, 1H), 2.42 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4]Br.[CH3:7][C:8]1[NH:9][CH:10]=[CH:11][N:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:6])[CH2:4][N:9]1[CH:10]=[CH:11][N:12]=[C:8]1[CH3:7]
Reactant: COC(=O)CBr
Reactant: Cc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1ccnc1C
Temperature: 25 °C
Yield: 47 %

Procedure:
4 ml of bromo acetic acid methyl ester is dissolved in 30 ml DMF and 5.2 g of 2-methylimidazole and 11.2 g potassium carbonate are added. The reaction mixture is stirred at room temperature for several hours and then subjected to aqueous work up. After removal of the solvent the pure product is obtained by flash chromatography in 47 to 78% yield.