Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:29][CH3:30])=[C:25]([OH:28])[CH:26]=2)[N:21]=[CH:20][N:19]=1.[N:31]1([CH2:37][CH2:38][CH2:39]O)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:29][CH3:30])=[C:25]([O:28][CH2:39][CH2:38][CH2:37][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:26]=2)[N:21]=[CH:20][N:19]=1
Reactant: COc1cc2ncnc(Cl)c2cc1O
Reactant: OCCCN1CCOCC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2ncnc(Cl)c2cc1OCCCN1CCOCC1
Reaction time: 2 h
Yield: 66.5 %

Procedure:
Di-tert-butyl azodicarboxylate (1.44 g, 6.26 mmol) was added portionwise at room temperature to a stirred suspension of 4-chloro-7-methoxyquinazolin-6-ol (1.20 g, 5.70 mmol), 3-morpholin-4-ylpropan-1-ol (0.91 g, 6.27 mmol) and triphenylphosphine (1.8 g, 6.87 mmol) in dichloromethane (25 ml). The reaction mixture was stirred for 2 hours and then the resulting orange solution was purified directly by silica gel chromatography eluting with a mixture of 5% methanol in dichloromethane to give 4-chloro-7-methoxy-6-(3-morpholin-4-ylpropoxy)quinazoline (1.28 g, 67% yield) as a pale yellow solid:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[S:6]1(=[O:23])=[O:22].[CH3:24][NH2:25].Cl>>[ClH:1].[F:21][C:18]1[CH:19]=[CH:20][C:15]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:5]([CH2:4][CH2:3][CH2:2][NH:25][CH3:24])[S:6]2(=[O:23])=[O:22])=[CH:16][CH:17]=1
Reactant: O=S1(=O)N(CCCCl)Cc2ccccc2N1c1ccc(F)cc1
Reactant: CN
Agent: Cl
Product: CNCCCN1Cc2ccccc2N(c2ccc(F)cc2)S1(=O)=O

Procedure:
In an analogous manner to Example 1, step 8, 3-(3-chloropropyl)-1-(4-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (50 mg) was reacted with methylamine and then treated with HCl to provide 3-[1-(4-fluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylpropan-1-amine hydrochloride (46 mg):
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[CH:28]=O>CO>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([N:1]=[CH:28][C:24]4[S:23][CH:27]=[CH:26][CH:25]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Reactant: O=Cc1cccs1
Solvent: CC(=O)O
Solvent: CO
Product: Clc1cccc(Nc2ncnc3[nH]nc(N=Cc4cccs4)c23)c1

Procedure:
Analogously to Example 32,261 mg (1.00 mmol) of 3-amino-4-(3-chlorophenylamino)-1H-pyrazolo[3,4-d]pyrimidine (see Step 1.6) and 180 mg of acetic acid are dissolved in 26 ml of methanol and reacted with 168 mg (1.5 mmol) of thiophene-2-carbaldehyde to form 4-(3-chloro-phenylamino)-3-[(thien-2-yl)-methyleneamino]-1H-pyrazolo[3,4-d]pyrimidine. Reduction of the above intermediate in 0.15 ml of DMEU with 8 ml (8 mmol) of DIBAL-H, analogous working-up and crystallization from ethyl acetate yield 4-(3-chloro-phenylamino)-3-[(thien-2-yl)-methylamino]-1H-pyrazolo[3,4-d]pyrimidine; m.p. 228-229° C., HPLC: tRet(grad20-100)=8-9; MS: (M)+=356.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.[OH:11]O>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:8]([OH:10])=[O:9])[N+:7]=1[O-:11]
Reactant: OO
Reactant: O=C(O)c1cccc(Cl)n1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cccc(Cl)[n+]1[O-]
Temperature: 25 °C
Yield: 67 %

Procedure:
To a solution of 6-chloro-2-pyridinecarboxylic acid (14.8 g, 0.093 mol, for preparation, see Delarge, II. Farmaco-Ed.Sc., 1967, 22, 1069) in trifluoroacetic acid (110 ml) was added 75 ml of 30% aqueous hydrogen peroxide solution. The mixture was heated to 60° for 2 hours, cooled to room temperature and poured onto ice water. The white precipitate was filtered and was washed well with water to yield 10.8 g (67%) of the title compound of this preparation. mp 168°-170° C. 1H NMR (CDCl3): δ 7.46 (1H, d, J=8), 7.77 (1H, dd, J=8, 8), 8.01 (1H, d, J=8).
Reaction SMILES: [CH2:1]1[CH2:8][NH:7][S:4](=[O:6])(=[O:5])[CH2:3][CH2:2]1.[H-].[Na+].[Br:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([CH2:18]Br)[CH:17]=1>CN(C=O)C.CCOC(C)=O>[Br:11][C:12]1[CH:17]=[C:16]([CH2:18][N:7]2[CH2:8][CH2:1][CH2:2][CH2:3][S:4]2(=[O:6])=[O:5])[CH:15]=[N:14][CH:13]=1
Reactant: BrCc1cncc(Br)c1
Reactant: O=S1(=O)CCCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=S1(=O)CCCCN1Cc1cncc(Br)c1
Reaction time: 0.25 h

Procedure:
To a vial is added 1,4-butanesultam (81 mg, 0.60 mmol) in 2 ml of DMF, followed by the addition of 60% NaH (24 mg, 0.6 mmol) at 0° C. The reaction mixture is stirred for 15 minutes, followed by the addition of To a vial is added 3-bromo-5-bromomethyl-pyridine, Intermediate E (100 mg, 0.40 mmol). The reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is diluted with EtOAc, washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. Purification by the flash column chromatography affords 86 mg of 2-(5-bromo-pyridin-3-ylmethyl)-[1,2]thiazinane 1,1-dioxide.
Reaction SMILES: FC(F)(F)S(O[C@H:7]1[CH2:12][C@@H:11]([CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17])[O:10][C@@:9]([O:33][CH3:34])([C@@H:18]2[CH2:22][S:21][C:20](=[O:23])[N:19]2[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[CH2:8]1)(=O)=O.[N-:37]=[N+:38]=[N-:39].[Na+]>CN(C=O)C.C(OCC)(=O)C>[N:37]([C@@H:7]1[CH2:12][C@@H:11]([CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17])[O:10][C@:9]([C@@H:18]2[CH2:22][S:21][C:20](=[O:23])[N:19]2[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)([O:33][CH3:34])[CH2:8]1)=[N+:38]=[N-:39]
Reactant: C=CCCC[C@@H]1C[C@H](OS(=O)(=O)C(F)(F)F)C[C@](OC)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCCC[C@@H]1C[C@@H](N=[N+]=[N-])C[C@](OC)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1
Temperature: 25 °C
Reaction time: 22 h
Yield: 82 %

Procedure:
A solution of the title compound from Example 22 (1.19 mmol, used directly from the previous reaction) in DMF (12 mL) was treated with sodium azide (400 mg, 6.15 mmol), and the mixture was stirred at room temperature for 22 h. The reaction mixture was diluted with ethyl acetate, washed with satd aq NaHCO3, ice cold 5% aq citric acid, and brine, and the organic phase was dried and concentrated. Chromatography of the residue on silica gel eluting with dichloromethane/ethyl acetate gave the title compound (432 mg, 82%) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.IC.[C:25](=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH3:25])[CH:17]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CCCCC(CC(=O)c1ccc(=O)[nH]c1)c1ccc(Br)cc1
Agent: [K+]
Solvent: CI
Product: CCCCC(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 161, step 1, 5-[3-(4-bromo-phenyl)-heptanoyl]-1H-pyridin-2-one was reacted with iodomethane in the presence of potassium carbonate to give the title compound as a colorless solid, MS (ESI+): m/z=376.2 [M+H]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]([C:17]1[O:18][C:19]([CH3:22])=[CH:20][CH:21]=1)([CH3:16])[CH2:13][CH2:14][OH:15].C(N(CC)CC)C>ClCCl.O>[CH3:16][C:12]([C:17]1[O:18][C:19]([CH3:22])=[CH:20][CH:21]=1)([CH3:11])[CH2:13][CH:14]=[O:15]
Reactant: Cc1ccc(C(C)(C)CCO)o1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(C)(C)CC=O)o1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 84.7 %

Procedure:
Step E To a solution of oxalyl chloride (0.91 g, 7.1 mmol) (Aldrich) in dichloromethane (20 mL) at −78° C. was added the solution of dimethyl sulfoxide (1 mL, 14.3 mmol) in dichloromethane (5 mL) dropwise. After 5 mins, the solution of 3-methyl-3-(5-methyl-furan-2-yl)-butan-1-ol (1.2 g, 7.1 mmol) in dichloromethane (5 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 15 min. Triethylamine (3.6 mL, 26 mmol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min. Then water was added. The organic layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 10% of HCl, saturated NaHCO3, brine, dried over MgSO4, and concentrated to give 3-methyl-3-(5-methyl-furan-2-yl)-butyraldehyde as a yellow oil (Yield: 1 g, 83%).
Reaction SMILES: C(=O)(O)[O-].[Na+].C(O[CH2:10][C:11]1[CH2:12][S:13][C@@H:14]2[CH:21]([NH2:22])[C:20](=[O:23])[N:15]2[C:16]=1[C:17]([OH:19])=[O:18])(=O)C.[CH3:24][C:25]1[CH:30]=[C:29]([CH3:31])[N:28]=[C:27]([SH:32])[N:26]=1>O.CC(C)=O>[NH2:22][CH:21]1[C:20](=[O:23])[N:15]2[C:16]([C:17]([OH:19])=[O:18])=[C:11]([CH2:10][S:32][C:27]3[N:28]=[C:29]([CH3:31])[CH:30]=[C:25]([CH3:24])[N:26]=3)[CH2:12][S:13][C@H:14]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: Cc1cc(C)nc(S)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1cc(C)nc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)n1
Reaction time: 23 h

Procedure:
A solution of sodium bicarbonate (9.45 g.) in water (100 ml.) was added in portions to a stirred suspension of 3-acetoxymethyl-7-aminoceph-3-em-4-carboxylic acid (13.5 g.) in water (100 ml.) and acetone (50 ml.). The solid dissolved with effervescence. To this solution under nitrogen at 55° was added rapidly, drop by drop, a solution of 4,6-dimethyl-2-mercaptopyrimidine (10.5 g.) in water (100 ml.) and acetone (100 ml.), the pH being maintained between 7.4 and 7.8 by addition of 6 NHCl or 5% w/v aqueous NaHCO3. After 23 hours at 55°, the reaction mixture was cooled to 0° and acidified to pH 4.0. The resulting precipitate was filtered, washed with water and acetone, and dried over P2O5 to give 7-amino-3-(4,6-dimethylpyrimid-2-yl)thiomethylceph-3-em-4-carboxylic acid. A mixture of this acid (3.52 g.) and O-t-butyl-1,3-diisopropylisourea (6.0 g.) in dry CH2Cl2 (60 ml.) was stirred under nitrogen for 20 hours. The reaction mixture was filtered, the filtrate evaporated and the residue purified by chromatography on silica gel (200 g.) at -40° using CH2Cl2 /ether 6:4 v/v as eluant to give the t-butyl ester.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[NH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[NH2:7]>C(O)C>[NH2:4][C:3]1[N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:7]=[C:1]([CH2:2][C:3]#[N:4])[C:2]=1[C:1]#[N:5]
Reactant: N#CCC#N
Reactant: NNc1ccccn1
Solvent: CCO
Product: N#CCc1nn(-c2ccccn2)c(N)c1C#N
Temperature: 25 °C
Yield: 37.2 %

Procedure:
A solution of malononitrile (19.8 g, 300 mmol) and 2-hydrazinopyridine (16.4 g, 150 mmol) in ethanol (300 mL) was heated under reflux for 12 hours. The solution was cooled to room temperature, and the resulting crystals were collected by filtration. The crystals were purified by silica gel column chromatography (chloroform to 2% methanol/chloroform) to give the title compound (12.5 g, 37% yield).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N+:7]([C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]2[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=2)=[CH:12][CH:11]=1)([O-])=O>C1COCC1>[NH2:7][C:10]1[CH:11]=[CH:12][C:13](/[CH:16]=[CH:17]/[C:18]2[CH:19]=[C:20]([O:28][CH3:29])[C:21]([O:26][CH3:27])=[C:22]([O:24][CH3:25])[CH:23]=2)=[CH:14][CH:15]=1
Reactant: COc1cc(/C=C/c2ccc([N+](=O)[O-])cc2)cc(OC)c1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(/C=C/c2ccc(N)cc2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.6 %

Procedure:
Lithium aluminum hydride (76 mg, 2 mmol) was added to a solution of nitro stilbene 6l (270 mg, 0.87 mmol) in THF (25 mL), and the mixture was stirred at room temperature for 12 h. Solvent was evaporated at reduced pressure, and the residue was decomposed by careful addition of ice water (20 mL) containing 2 mL of glacial acetic acid. The red solid formed was filtered and crystallized from CH2Cl2 -ether to give 6z (200 mg, 82%); mp 251°-3° C.; IR (KBr) 3440, 3400, 3000, 2920, 2820, 1600, 1580, 1510, 1340, 1240, 1130, 990, 950, 830 cm-1 ; 1H NMR (DMSO-d6, 300 MHz) δ7.87 (d, J=8.3 Hz, 2H), 7.59 (d, J=8.3 Hz, 2H), 7.08 (d, J-16.0 Hz, 1H), 7.01 (d, J= 16.0 Hz, 1H), 6.71 (s, 2H), 3.87 (s, 6H), 3 82 (s, 3H); CIMS (isobutane) m/e 286 (MH+, 100). Anal. (C17H19NO3) C, H.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[N:14]=[C:13](/[CH:15]=[C:16]3/[C:17](=[O:22])[NH:18][C:19](=[O:21])[S:20]/3)[CH:12]=[C:11]([O:23][CH3:24])[N:10]=2)[CH2:5][CH2:4]1.[S:25]1[CH:29]=[CH:28][C:27]([C:30]2[N:35]=[C:34]([CH:36]=O)[CH:33]=[CH:32][CH:31]=2)=[CH:26]1>>[CH3:24][O:23][C:11]1[N:10]=[C:9]([N:6]2[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][CH2:36][C:34]3[CH:33]=[CH:32][CH:31]=[C:30]([C:27]4[CH:28]=[CH:29][S:25][CH:26]=4)[N:35]=3)[CH2:4][CH2:5]2)[N:14]=[C:13](/[CH:15]=[C:16]2/[C:17](=[O:22])[NH:18][C:19](=[O:21])[S:20]/2)[CH:12]=1
Reactant: O=Cc1cccc(-c2ccsc2)n1
Reactant: COc1cc(/C=C2\SC(=O)NC2=O)nc(N2CCC(CN)CC2)n1
Product: COc1cc(/C=C2\SC(=O)NC2=O)nc(N2CCC(CNCc3cccc(-c4ccsc4)n3)CC2)n1

Procedure:
(Z)-5-((6-methoxy-2-(4-((((6-(thiophen-3-yl)pyridin-2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using (Z)-5-((2-(4-(aminomethyl)piperidin-1-yl)-6-methoxypyrimidin-4-yl)methylene)thiazolidine-2,4-dione (Example 153), the general reductive amination procedure and 6-(thiophen-3-yl)picolinaldehyde (34.3 mg, 65 mg theoretical, 52.8%). LC-MS m/z 523 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH2:5][C:6]1([C:9]([OH:11])=[O:10])[CH2:8][CH2:7]1.[CH3:15][C:16]1[C:20]([CH:21]([OH:31])[CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:19]([C:32]2[CH:37]=[CH:36][C:35](B3OC(C)(C)C(C)(C)O3)=[CH:34][CH:33]=2)[O:18][N:17]=1>>[OH:31][CH:21]([C:20]1[C:16]([CH3:15])=[N:17][O:18][C:19]=1[C:32]1[CH:33]=[CH:34][C:35]([C:2]2[CH:14]=[CH:13][CH:12]=[C:4]([CH2:5][C:6]3([C:9]([OH:11])=[O:10])[CH2:8][CH2:7]3)[CH:3]=2)=[CH:36][CH:37]=1)[CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1noc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1C(O)CCCc1ccccc1
Reactant: O=C(O)C1(Cc2cccc(Br)c2)CC1
Product: Cc1noc(-c2ccc(-c3cccc(CC4(C(=O)O)CC4)c3)cc2)c1C(O)CCCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using 1-(3-bromo-benzyl)-cyclopropanecarboxylic acid and 1-{3-methyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]isoxazol-4-yl}-4-phenyl-butan-1-ol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[C:10]([C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=[S:20])=[CH:14][CH:13]=1)#[N:11]>C(#N)C>[C:10]([C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]([NH:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:9])=[S:20])=[CH:16][CH:17]=1)#[N:11]
Reactant: N#Cc1ccc(N=C=S)cc1
Reactant: CC(C)(C)OC(=O)CN
Solvent: CC#N
Product: CC(C)(C)OC(=O)CNC(=S)Nc1ccc(C#N)cc1
Reaction time: 12 h
Yield: 78.3 %

Procedure:
10.7 g (82 mmol) of glycine t-butyl ester are added to a solution of 13 g (82 mmol) of 4-cyanophenyl isothiocyanate dissolved in 100 cm3 of acetonitrile. After 12 hours of stirring, the precipitate formed is filtered off and is then washed with ethyl ether, to give 18.7 g (yield 78%) of the desired thiourea.
Reaction SMILES: [O:1]=[C:2]1[C:11]2([CH2:16][CH2:15][N:14]([CH2:17][C:18]([O:20]CC)=[O:19])[CH2:13][CH2:12]2)[CH2:10][CH2:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[OH-].[Na+]>CCO>[O:1]=[C:2]1[C:11]2([CH2:12][CH2:13][N:14]([CH2:17][C:18]([OH:20])=[O:19])[CH2:15][CH2:16]2)[CH2:10][CH2:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: CCOC(=O)CN1CCC2(CCc3ccccc3C2=O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CN1CCC2(CCc3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.2 %

Procedure:
To a stirred solution of ethyl 2-(1-oxo-3,4-dihydro-1H-spiro[naphthalene-2,4′-piperidine]-1′-yl)acetate (71 mg, 0.236 mmol) in EtOH (2 mL) at 25° C. was added NaOH (2 N, 1.39 mL, 2.78 mmol). After being stirred at 25° C. for 16 h, the reaction mixture was extracted with 5 mL of CH2Cl2. The aqueous layer was basified with 2 M HCl to pH 5, and extracted three times with 10 mL of ethyl acetate, dried over Na2SO4 and concentrated. The crude product was purified by flash chromatography (gradient of 100% CH2Cl2 to 90:10 CH2Cl2/ethyl acetate over 20 min) to give the title compound (37 mg, 0.135 mmol). MS calculated for C16H20NO3 274.3. found (ESI) m/z 271.4 (M+H)+, retention time 0.93 min.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)=[O:5].C(=O)([O-])[O-].[K+].[K+].[Br:26][CH2:27][CH2:28][CH2:29][CH2:30]Br>CC(C)=O>[Br:26][CH2:27][CH2:28][CH2:29][CH2:30][O:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)=[O:5]
Reactant: O=C(Nc1cccc2[nH]ccc12)c1ccccc1O
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(Nc1cccc2[nH]ccc12)c1ccccc1OCCCCBr

Procedure:
A suspension of 7.5 g of 2-hydroxy-N-(1H-indol-4-yl)benzamide and 8.28 g of potassium carbonate in 150 ml of acetone was refluxed for 75 minutes with 18 ml of 1,4-dibromobutane and the mixture was cooled. The precipitate was filtered off and rinsed with acetone and the filtrate was evaporated to dryness. The residue was purified by chromatography over silica (eluant: methylene chloride/ethyl acetate 9:1), followed by crystallization from ethyl acetate to obtain 2-(4-bromobutoxy)-N-(1H-indol-4-yl)benzamide melting at 135° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[CH2:9]([O:11][CH2:12][C:13](O)=O)[CH3:10].[OH-].[Na+]>>[CH2:9]([O:11][CH2:12][C:13]1[S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1)[CH3:10]
Reactant: CCOCC(=O)O
Reactant: Nc1ccccc1S
Agent: [Na+]
Agent: [OH-]
Product: CCOCc1nc2ccccc2s1
Yield: 63 %

Procedure:
2-Aminothiophenol was reacted with an equimolar amount of ethoxyacetic acid at 110° C. for 15 hours in a sealed tube. After cooling the reaction mixture, it was neutralized with a 20% aqueous solution of sodium hydroxide, followed by an extraction with ether. Ether was driven off and the residue was then subjected to distillation under reduced pressures, thereby obtaining 2-ethoxymethylbenzothiazole (boiling point: 126°-128° C./4 mmHg; yield: 63%).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[CH2:6]([O:13][C:14]([NH:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([C:23]([OH:25])=O)[CH2:19][CH2:18]1)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH2:6]([O:13][C:14](=[O:15])[NH:16][C@H:17]1[CH2:18][CH2:19][C@H:20]([C:23](=[O:25])[N:3]([O:4][CH3:5])[CH3:2])[CH2:21][CH2:22]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CNOC
Reactant: O=C(N[C@H]1CC[C@H](C(=O)O)CC1)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CON(C)C(=O)[C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
N,O-dimethyl-hydroxylamine hydrochloride (10 mg, 0.10 mmol, 1.2 equivalent) is added at room temperature to a stirred solution of trans-4-benzyloxycarbonylamino-cyclohexanecarboxylic acid (23 mg, 0.08 mmol, 1.0 eq) in N,N-dimethylformamide (5 mL), followed by O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (63 mg, 0.16 mmol, 2.0 eq) and sodium hydrogen carbonate (15 mg, 0.18 mmol, 2.2 eq). After 12 hours stirring at room temperature, solvent is evaporated and the residue is extracted with ethyl acetate (3×10 mL) and a saturated ammonium chloride aqueous solution (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 2:1, v/v) to afford [trans-4-(methoxy-methyl-carbamoyl)-cyclohexyl]-carbamic acid benzyl ester as a colorless solid (8 mg, 30% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([F:32])[CH:31]=1)[CH2:5][C@H:6]1[C@@H:10]([C@H:11]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][N:12]2C(OC(C)(C)C)=O)[O:9][C:8](=[O:28])[NH:7]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([F:32])[CH:31]=1)[CH2:5][C@H:6]1[C@@H:10]([C@H:11]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][NH:12]2)[O:9][C:8](=[O:28])[NH:7]1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@@H]1[C@H]1OC(=O)N[C@H]1Cc1cc(F)cc(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1N[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2Cc3ccccc3CN2)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 103.3 %

Procedure:
A solution of (R)-tert-butyl 3-((4S,5S)-4-(3,5-difluorobenzyl)-2-oxooxazolidin-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (Step A (6), 400 mg) in CH2Cl2 (20 mL) was treated with TFA (10 mL). This reaction mixture was stirred at rt for 3 h. The mixture was then concentrated in vacuo with addition of toluene. The residue was partitioned between ethyl acetate (200 mL) and aqueous sodium carbonate solution. The organic phase was washed again with aqueous sodium carbonate solution, H2O, and dried (Na2SO4), and concentrated in vacuo to give 320 mg (100% yield) of the title compound: 1H NMR (CDCl3, 500 MHz) δ 2.62 (1H, dd, J=10, 15 Hz), 2.66 (1H, dd, J=10, 15 Hz), 3.10 (1H, dd, J=5, 15 Hz), 3.24 (1H, dt, J=5, 10 Hz), 3.33 (1H, dd, J=5, Hz), 3.98 (2H, s), 4.05 (1H, m), 4.39 (1H, m), 5.64 (1H, s), 6.70 (1H, m), 6.76 (2H, d, J=10 Hz), 7.02 (1H, t, J=5 Hz), 7.12-7.17 (3H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([NH2:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][C:3]=1[NH2:4].C(=O)([O-])[O-].[Ca+2].Br.[Br:19][CH2:20][CH2:21][NH:22]C1C=CC=CC=1>O>[OH2:11].[BrH:19].[CH3:1][C:2]1[CH:8]=[C:7]([NH2:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][C:3]=1[NH:4][CH2:20][CH2:21][NH2:22]
Reactant: BrCCNc1ccccc1
Reactant: Cc1cc(N)c([N+](=O)[O-])cc1N
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: Cc1cc(N)c([N+](=O)[O-])cc1NCCN
Temperature: 0 °C

Procedure:
A suspension of 0.05 mol (8.35 g) of 2-methyl-4-amino-5-nitroaniline and 0.035 mol (3.5 g) of calcium carbonate in 100 ml of water is heated beforehand on a boiling water-bath, whilst stirring. A solution of 0.07 mol (14.35 g) of β-bromoethylaniline hydrobromide in 20 ml of water is added gradually, whilst stirring. After heating for two hours on the boiling water-bath, the hot reaction medium is filtered. After cooling the filtrate for 24 hours at 0° C., the expected product, which has crystallised in the form of the hydrobromide, is filtered off. The crude product is washed with acetone and then recrystallised from boiling water. After filtration, washing with acetone and drying in vacuo, 2-methyl-4-amino-5-nitro-N-(β-aminoethyl)-aniline hydrobromide monohydrate is obtained.