Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=1.ClC1C=CC=CC=1.[S:19](=[O:23])(=[O:22])([OH:21])N>CN1CCCC1=O>[NH2:1][C:2]1[C:7]([S:19]([OH:23])(=[O:22])=[O:21])=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=1
Reactant: NS(=O)(=O)O
Reactant: Cc1cc(N)ccc1[N+](=O)[O-]
Solvent: CN1CCCC1=O
Solvent: Clc1ccccc1
Product: Cc1cc(N)c(S(=O)(=O)O)cc1[N+](=O)[O-]

Procedure:
18.3 g of 1-amino-3-methyl-4-nitrobenzene, 120 ml of chlorobenzene, 24 g of sulphamic acid and 12 ml of 1-methylpyrrolid-2-one are warmed to 120°C whilst stirring. The reaction mixture is stirred for 8 hours at this temperature. After cooling, the reaction mixture is filtered and the residue is washed with trichloroethylene and recrystallised from 200 ml of water. The crystals which have precipitated are filtered off, suspended in 100 ml of trichloroethylene, stirred for one hour at 75°C, separated from the organic solvent by filtration and dried at 80°C. 25 g (84% of theory) of yellow crystals, which according to thin layer chromatography are a single substance, of 1-amino-3-methyl-4-nitro-benzene-6 -sulphonic acid in the form of its ammonium salt [melting point 290° C (decomposition)]are obtained.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH2:14])[C:5]2[CH:11]=[C:10]([CH:12]=O)[CH:9]=[N:8][C:6]=2[N:7]=1.[NH2:15][C:16]1[CH:37]=[CH:36][C:19]([C:20]([NH:22][C@H:23]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:21])=[CH:18][CH:17]=1>C(O)(=O)C.[Ni]>[NH2:1][C:2]1[N:3]=[C:4]([NH2:14])[C:5]2[CH:11]=[C:10]([CH2:12][NH:15][C:16]3[CH:17]=[CH:18][C:19]([C:20]([NH:22][C@H:23]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:21])=[CH:36][CH:37]=3)[CH:9]=[N:8][C:6]=2[N:7]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(N)cc1)C(=O)OCC
Reactant: Nc1nc(N)c2cc(C=O)cnc2n1
Agent: [Ni]
Solvent: CC(=O)O
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(NCc2cnc3nc(N)nc(N)c3c2)cc1)C(=O)OCC
Reaction time: 17 h

Procedure:
A solution of compound III (1.47 g, 5.90 mmol) in warm 70% acetic acid (59 ml) was cooled to 25° C., treated with diethyl p-aminobenzoyl-L-glutamate (2.28 g, 7.08 mmol) and hydrogenated in the presence of Raney nickel (6.3 g, weighed wet) at 25° C. and atmospheric pressure for 17 hours. The mixture was filtered and the catalyst was washed with 70% acetic acid (25 ml). The combined filtrate and wash was evaporated to dryness under high vacuum, and a solution of the residue in ethanol was filtered into 2 N Na2CO3 (60 ml). The mixture was stirred to give a homogeneous powder which was collected, washed with water and dried. A solution of the resultant powder in boiling ethanol (415 ml) was filtered hot and evaporated to dryness in vacuo. The residue was triturated with CHCl3 (85 ml), collected by filtration and the solid was washed with additional CHCl3 (40 ml). A suspension of the solid in boiling ethanol (140 ml) was stirred for 20 minutes and refrigerated. The product was collected by filtration and dried in vacuo (P2O5): yield 945 mg (32%), mp 262° C. (Kofler Heizbank). Mass spectrum, m/e 496 (M+1)+ ; λmax nm (ε×10-3); 0.1 N HCl --218 (42.4), 280 sh (19.3), 300 (22.0); pH 7--218 (36.4), 249 (20.2), 280 sh (22.3), 297 (23.6), 355 sh (6.10); 0.1 N NaOH --249 (22.0), 280 (23.8), 297 sh (22.5), 345 (7.23); 1H-NMR(DMSO-d6, 6% w/v), δ 1.18 m (CH3), 2.05 m (CH2CH2CO), 2.43 t (CH2CO), 4.08 m (CH2O), 4.32 m (CH2N, CHN), 6.31 s, 7.51 s (NH2), 6.67 d, 7.69 d (C6H4), 6.71 s (CH2NH), 8.25 d (CONH), 8.41 d (5 --CH, J=2.0 Hz), 8.66 d (7-CH, J=2.0 Hz).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]2[C:23]([N:24]3[CH2:28][CH2:27][N:26]([CH3:29])[C:25]3=[O:30])=[CH:22][C:21]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[CH:20][N:8]2[C:9](=[O:19])[C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.O.[NH3:38]>>[CH2:12]([O:11][C:10]1[C:9](=[O:19])[N:8]2[CH:20]=[C:21]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:22]=[C:23]([N:24]3[CH2:28][CH2:27][N:26]([CH3:29])[C:25]3=[O:30])[C:7]2=[N:6][C:5]=1[C:3]([NH2:38])=[O:2])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)c1nc2c(N3CCN(C)C3=O)cc(N3CCOCC3)cn2c(=O)c1OCc1ccccc1
Reactant: N
Solvent: O
Product: CN1CCN(c2cc(N3CCOCC3)cn3c(=O)c(OCc4ccccc4)c(C(N)=O)nc23)C1=O
Temperature: 40 °C
Yield: 62 %

Procedure:
3-Benzyloxy-9-(3-methyl-2-oxo-imidazolidin-1-yl)-7-morpholin-4-yl-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylic acid methyl ester (example 221, 1 g, 2.03 mmol) was mixed with ammonia water (28%, 50 ml) and the mixture was heated at 40° C. overnight. The precipitates were collected by filtration and dried in vacuo to give the titled compound (600 mg, 62%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:37]=[CH:38][CH:39]=1)[CH2:7][N:8]([CH2:16][CH2:17][N:18]1[CH:27]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23](F)[CH:24]=2)[CH2:19]1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])([O-])=O.[BH4-].[Na+].O>CO.[Ni](Cl)Cl>[NH2:1][C:4]1[CH:5]=[C:6]([CH:37]=[CH:38][CH:39]=1)[CH2:7][N:8]([CH2:16][CH2:17][N:18]1[CH:27]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1)[C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:14])[CH3:12]
Reactant: CC(C)(C)OC(=O)N(CCN1Cc2ccc(F)cc2CC1Cc1ccc(F)cc1)Cc1cccc([N+](=O)[O-])c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCN1Cc2ccccc2CC1Cc1ccc(F)cc1)Cc1cccc(N)c1
Temperature: 25 °C
Yield: 89.6 %

Procedure:
Under an argon atmosphere, 190 mg of tert-butyl 3-nitrobenzyl[2-[6-fluoro-3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]ethyl]carbamate was dissolved in 8 mL of methanol, followed by stirring under ice-cooling. 343 mg of nickel chloride.hexahydrate was added thereto, and then 73 mg of sodium borohydride was slowly added thereto. After completion of addition of a reagent, the reaction liquid was warmed to room temperature, followed by stirring for 10 minutes. After completion of the reaction, water was added to the reaction liquid, followed by extraction with chloroform. The organic layer was then washed with an aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 155 mg (yield 87%) of a title compound as a yellow oily substance.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([C:17]([OH:19])=O)=[CH:14][C:13]=3[CH:20]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:22][O:23][C:24](=[O:35])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][NH2:34])=[CH:27][CH:26]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[CH3:22][O:23][C:24](=[O:35])[C:25]1[CH:26]=[CH:27][C:28]([O:31][CH2:32][CH2:33][NH:34][C:17]([C:15]2[O:16][C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)=[CH:20][C:13]=3[CH:14]=2)=[O:19])=[CH:29][CH:30]=1
Reactant: O=C(O)c1cc2cc(OCCN3CCCC3)ccc2o1
Reactant: COC(=O)c1ccc(OCCN)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(OCCNC(=O)c2cc3cc(OCCN4CCCC4)ccc3o2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.9 %

Procedure:
To a solution of 5-(2-pyrrolidin-1-ylethoxy)benzofuran-2-carboxylic acid (156 mg, 0.50 mmol) and 4-(2-aminoethoxy)benzoic acid methyl ester hydrochloride (129 mg, 0.56 mmol) in DMF (4.5 ml) in a 20 ml vial was added diisopropylethylamine (0.88 ml, 5.1 mmol). A solution of O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (740 μL, 0.82 M, 0.61 mmol) in DMF was added to give a bright yellow solution. The vial was purged with nitrogen and stirred at room temperature for 18 h. The solution was removed and the residue was dissolved in EtOAc (25 ml) and washed with H2O, 1.0M aqueous K2CO3, and brine. The organic layer was dried over anhydrous MgSO4 and solvent was removed on a rotary evaporator. Purification of the residue by column chromatography on a silica gel column using 93:5:2 CH2Cl2:MeOH:TEA eluent provided 4-{2-[5-(2-pyrrolidin-1-ylethoxy)benzofuran-2-carbonylamino]-ethoxy}-benzoic acid methyl ester as a beige solid (174 mg).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:14][S:15](Cl)(=[O:17])=[O:16].O>C(Cl)Cl>[CH3:14][S:15]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(S(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89.2 %

Procedure:
To 1,1-dimethylethyl 1-piperazinecarboxylate (568 g, 3.05 mol) in DCM (4 L) was added TEA (617 g, 6.10 mol). After stirring for 10 min at 0° C., methanesulfonyl chloride (384 g, 3.35 mol) was added via addition funnel. The mixture was stirred at rt overnight. The mixture was poured into H2O (1 L) and extracted with DCM (1 L). The organic layer was separated, washed with H2O (1 L), dried (Na2SO4), and rotovapped down to provide the title compound of step A (720 g, 2.72 mol, 90%) which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 1.44 (s, 9H), 2.76 (s, 3H), 3.11-3.17 (m, 4H), 3.50-3.53 (m, 4H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[OH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18](=[O:27])[N:19]([CH3:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:13][CH:12]=1.Cl.O[N:30]1[CH:34]=[CH:33][N:32]=[CH:31]1>>[N:30]1([O:8][CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18](=[O:27])[N:19]([CH3:26])[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:15][CH:16]=2)[CH:34]=[CH:33][N:32]=[CH:31]1
Reactant: CN(C(=O)Oc1ccc(CCO)cc1)c1ccccc1
Reactant: On1ccnc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)Oc1ccc(CCOn2ccnc2)cc1)c1ccccc1
Yield: 79 %

Procedure:
The title compound was prepared as its TFA salt in 79% yield as an oil using methyl-phenyl-carbamic acid 4-(2-hydroxy-ethyl)-phenyl ester and 1-hydroxyimidazole hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([Cl:16])=[CH:14][NH:13][C:12](=[O:17])[CH:11]=2)[CH:3]=1.Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>>[Cl:16][C:15]1[C:10]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:9]=[CH:8][C:5]=2[C:6]#[N:7])=[CH:11][C:12](=[O:17])[N:13]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:14]=1
Reactant: N#Cc1ccc(Cl)cc1-c1cc(=O)[nH]cc1Cl
Reactant: CC(C)(C)OC(=O)CBr
Product: CC(C)(C)OC(=O)Cn1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
400 mg (purity 91%, 1.37 mmol) of 4-chloro-2-(5-chloro-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile and 1.2 eq. of tert-butyl bromoacetate were reacted according to General Method 4B at 100° C. Yield: 421 mg (80% of theory)
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH:16][C:17](=[O:33])[CH2:18][C:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH:21]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:15][C:11]1[C:12]([F:14])=[CH:13][C:8]2[N:7]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[CH:21]=3)[CH2:18][C:17](=[O:33])[NH:16][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(Cl)cc1NC(=O)CC(=O)c1cccc(-c2ccccn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-c3ccccn3)c2)=Nc2cc(F)c(Cl)cc2N1

Procedure:
The title compound was prepared from {4-chloro-5-fluoro-2-[3-oxo-3-(3-pyridin-2-yl-phenyl)-propionylamino]-phenyl}-carbamic acid tert-butyl ester (Example M48) (270 mg, 0.54 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (174 mg).
Reaction SMILES: [N:1]1([C:7]2[C:18]3=[C:19]4[N:14]([CH2:15][CH2:16][CH2:17]3)[CH:13]=[C:12]([C:20]([OH:22])=[O:21])[C:11](=[O:23])[C:10]4=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[OH-].[K+].[CH3:26][S:27](Cl)(=[O:29])=[O:28]>O>[CH3:26][S:27]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[C:18]3=[C:19]4[N:14]([CH2:15][CH2:16][CH2:17]3)[CH:13]=[C:12]([C:20]([OH:22])=[O:21])[C:11](=[O:23])[C:10]4=[CH:9][CH:8]=2)[CH2:2][CH2:3]1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(O)c1cn2c3c(c(N4CCNCC4)ccc3c1=O)CCC2
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CS(=O)(=O)N1CCN(c2ccc3c(=O)c(C(=O)O)cn4c3c2CCC4)CC1
Reaction time: 8 h
Yield: 40 %

Procedure:
2.0 g of 8-(1-piperazinyl)-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid was dissolved in 20 ml of water having dissolved therein 0.8 g of potassium hydroxide and 0.8 g of methanesulfonyl chloride was added dropwise to the solution. The resulting mixture was allowed to stand overnight at the same temperature as above while stirring. The crystals precipitated were separated by filtration and washed with water. The crystals thus-treated were dissolved in 1 N aqueous sodium hydroxide solution and the solution was treated with activated carbon and rendered neutral with a 10% aqueous hydrochloric acid solution to precipitate crystals, which were separated by filtration and washed with water. Recrystallization of the crystals thus-obtained from dimethylformamide gave 1.0 g of 8-(4-methanesulfonyl-1-piperazinyl)-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid as white needles having a melting point of not lower than 300° C.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([C:6](=O)[CH2:7][CH:8]2[C:13](=O)[CH2:12][CH2:11][S:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:18][N:19]([CH3:24])[CH2:20][CH2:21][CH2:22][NH2:23].C(O)C.[ClH:28]>CCOCC>[ClH:28].[CH3:18][N:19]([CH3:24])[CH2:20][CH2:21][CH2:22][N:23]1[C:6]([C:5]2[CH:16]=[CH:17][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:7][C:8]2[CH2:9][S:10][CH2:11][CH2:12][C:13]1=2
Reactant: CN(C)CCCN
Reactant: O=C(CC1CSCCC1=O)c1ccc(F)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CN(C)CCCn1c(-c2ccc(F)cc2)cc2c1CCSC2

Procedure:
A solution of 4.0 g (0.016 mole) of 3-(4-fluorophenacyl)-2,3,5,6-tetrahydrothiopyran-4-one [Example 5 (a)], 1.62 g of 3-dimethylaminopropylamine and 40 ml. of ethanol is heated under reflux for 2.5 hours, cooled, treated with 4 ml. of saturated ethereal hydrogen chloride, warmed to boiling, and diluted to the cloud point with ether. Upon cooling a solid separates. Recrystallization from ethanol gives off-white crystals of 1-(3-dimethylaminopropyl)-2-(4-fluorophenyl)-1,4,6,7-tetrahydrothiopyrano[4,3-b]pyrrole hydrochloride, m.p. 199° to 201°C. dec.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:19][C:3]2[CH:4]=[CH:5][C:6]([N:8]3[CH2:12][CH2:11][CH:10]([N:13]4[CH2:17][CH2:16][CH2:15][CH:14]4[CH3:18])[CH2:9]3)=[CH:7][C:2]=2[CH3:1])=[O:26])=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1ccc(F)cc1

Procedure:
The title compound was prepared in a manner substantially the same as Example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 4-fluorobenzoyl chloride. LCMS: RT=1.54 minutes, MS: 382 (M+H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13])=[O:2].[Cl:17][C:18]1[CH:19]=[C:20]([Mg]Br)[CH:21]=[CH:22][C:23]=1[Cl:24]>C1COCC1>[Cl:17][C:18]1[CH:19]=[C:20]([CH:1]([OH:2])[C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:8]=2[C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[CH:21]=[CH:22][C:23]=1[Cl:24]
Reactant: N#Cc1cccc(-c2ccncc2C=O)c1
Reactant: Clc1ccc([Mg]Br)cc1Cl
Solvent: C1CCOC1
Product: N#Cc1cccc(-c2ccncc2C(O)c2ccc(Cl)c(Cl)c2)c1

Procedure:
To a solution of 3-(3-formyl-pyridin-4-yl)-benzonitrile (30 mg, 0.15 mmol) in THF (1.5 mL) at −78° C. was added 0.5 M 3,4-dichlorophenylmagnesium bromide in THF (0.6 mL). The reaction mixture was quenched with ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash chromatography eluted with 5% methanol in dichlordmethane to yield 3-{3-[(3,4-dichloro-phenyl)-hydroxy-methyl]-pyridin-4-yl}-benzonitrile as white crystals.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:9]=[C:10]([CH3:12])[CH:11]=1)[NH2:8])(=[O:3])[CH3:2].Br[CH:14]([CH3:18])[C:15](=O)[CH3:16]>CN(C)C=O>[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:9]([C:14]([CH3:18])=[C:15]([CH3:16])[NH:8]2)=[C:10]([CH3:12])[CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(C)cc(N)c1
Reactant: CC(=O)C(C)Br
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(C)c2c(C)c(C)[nH]c2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
9 g of 3-acetamido-5-methylaniline are dissolved in 20 ml of dimethylformamide and 3.2 ml of 3-bromobutan-2-one are then added. The mixture is left at ambient temperature for 1 hour and the temperature is then raised to 100°-110° C. for one hour. The mixture is cooled and poured into 100 ml of ice-water. The precipitate is drained and washed successively with 50 ml of distilled water, 20 ml of ethanol and 20 ml of isopropyl ether. 4.2 g of white precipitate are obtained.
Reaction SMILES: [CH:1]([C@@H:3]1[CH2:20][CH:19]2[C@:14]([CH3:22])([CH2:15][CH2:16][C:17](=[O:21])[CH2:18]2)[C@@H:13]2[C@@H:4]1[C@H:5]1[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:23])[CH2:7][CH2:6]1)=[O:2].[O-:24][Mn](=O)(=O)=O.[K+]>>[C:1]([C@@H:3]1[CH2:20][CH:19]2[C@:14]([CH3:22])([CH2:15][CH2:16][C:17](=[O:21])[CH2:18]2)[C@@H:13]2[C@@H:4]1[C@H:5]1[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:23])[CH2:7][CH2:6]1)([OH:24])=[O:2]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: C[C@]12CCC(=O)CC1C[C@@H](C=O)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [K+]
Product: C[C@]12CCC(=O)CC1C[C@@H](C(=O)O)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 0.08 h
Yield: 96 %

Procedure:
To a stirred suspension of 7α-formylandrostane-3,17-dione (1.77 g) in t-ButOH (35 mL) and 5% aqueous Na2HPO4 solution (21.5 mL), 1N aqueous KMnO4 (35 mL) was added. After 5 minutes at room temperature, the mixture was quenched by addition of 40% aqueous NaHSO3 solution. The suspension was filtered, washed with H2O and the filtrate was freeze-dried. The residue was taken up with H2O (50 mL) and extracted with EtOAc (4×70 mL). The combined organic extracts were dried over Na2SO4 and evaporated to dryness to give 7α-carboxyandrostane-3,17-dione (1.80 g, 96%). 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 12.00 (1H, bb), 2.65 (1H, m), 2.45-0.70 (20H, m), 1.00 (3H, s), 0.79 (3H, s).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]([C:13]1[S:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[CH:14]=1)([CH3:12])[CH3:11].C([Li])CCC.[C:27](=[O:29])=[O:28].Cl>O1CCCC1>[S:17]1[C:13]([C:10]([C:3]2[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=2[C:27]([OH:29])=[O:28])([CH3:12])[CH3:11])=[CH:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]1=2
Reactant: O=C=O
Reactant: COc1ccc(Br)c(C(C)(C)c2cc3ccccc3s2)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)O)c(C(C)(C)c2cc3ccccc3s2)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 55 %

Procedure:
2-[1-(2-Bromo-5-methoxy-phenyl)-1-methylethyl]-benzo[b]thiophene (Compound Z3, 40 mg, 0.11 mmol) was dissolved in tetrahydrofuran (0.5 mL), cooled to −78° C., added with n-butyl lithium (1.57 M, hexane solution, 0.07 mL), and the mixture was stirred for 10 min. The reaction mixture was added with dry ice and then maintained for 1 hr. After that, the mixture was added with 0.5 N hydrochloric acid, extracted with ethyl acetate and washed with water. The organic layer was dried over magnesium sulfate. The residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (22 mg, 55%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[NH2:10][C:11]1[N:20]=[C:19]([NH2:21])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2F)[N:12]=1>CS(C)=O>[NH2:10][C:11]1[N:20]=[C:19]([NH2:21])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:12]=1
Reactant: Nc1ccccc1
Reactant: Nc1nc(N)c2c(F)cccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Nc1nc(N)c2c(Nc3ccccc3)cccc2n1
Yield: 4.8 %

Procedure:
Aniline (Aldrich) (5 g, 50 mmol), sodium hydride (80% disp in mineral oil) (1.5 g, 50 mmol) and 2,4-diamino-5-fluoroquinazoline (4.4 g, 25 mmol) were reacted in 80 ml of dimethyl sulphoxide according to procedure A to give 2,4-diamino-5-anilinoquinazoline (0.3 g, 4.8%, m.p. 279-283° C. (dec)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:25]=[CH:24][N:23]=[C:22]([C:26](O)=[O:27])[CH:21]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:29]=1.[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[C:31]1([NH:30][C:26]([C:22]2[CH:21]=[C:20]([N:17]3[CH2:16][CH2:15][CH:14]([N:10]4[CH2:9][CH2:8][C:7]5[CH:29]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=5[NH:12][C:11]4=[O:13])[CH2:19][CH2:18]3)[N:25]=[CH:24][N:23]=2)=[O:27])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Nc1ccccc1
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)O)ncn3)CC1)C(=O)N2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)Nc4ccccc4)ncn3)CC1)C(=O)N2

Procedure:
120.0 mg (0.30 mmol) 6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid, 30 μL (0.33 mmol) aniline, 120.0 mg (0.37 mmol) TBTU and 100 μL (0.71 mmol) triethylamine in 2 mL DMF were stirred overnight at RT. The mixture was filtered through a syringe filter and purified by preparative HPLC. The product fractions were combined and lyophilised.
Reaction SMILES: CN(C=[N:5][S:6]([CH2:9][C:10]([CH2:15][CH3:16])([CH2:13][CH3:14])[CH2:11][OH:12])(=[O:8])=[O:7])C.Cl[C:18]1[CH:19]=[C:20]([CH3:28])[C:21]2[N:22]([N:24]=[C:25]([CH3:27])[N:26]=2)[N:23]=1>>[CH2:15]([C:10]([CH2:13][CH3:14])([CH2:9][S:6](=[O:7])(=[O:8])[NH2:5])[CH2:11][O:12][C:18]1[CH:19]=[C:20]([CH3:28])[C:21]2[N:22]([N:24]=[C:25]([CH3:27])[N:26]=2)[N:23]=1)[CH3:16]
Reactant: CCC(CC)(CO)CS(=O)(=O)N=CN(C)C
Reactant: Cc1nc2c(C)cc(Cl)nn2n1
Product: CCC(CC)(COc1cc(C)c2nc(C)nn2n1)CS(N)(=O)=O

Procedure:
Using 3-(N,N-dimethylaminomethylene)aminosulfonyl-2,2-diethyl-1-propanol and 6-chloro-2,8-dimethyl[1,2,4]triazolo[1,5-b]pyridazine, the same reaction as in Example 6 was conducted to produce the title compound. m.p. 159°-160° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[C:6]([CH3:12])[CH:7]=[CH:8][C:9]=2[CH3:11])[NH:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14].N1C=CC=CC=1.Cl[C:24]([O:26][CH3:27])=[O:25]>C1COCC1>[CH3:27][O:26][C:24]([NH:1][C:2]1[C:10]2[C:5](=[C:6]([CH3:12])[CH:7]=[CH:8][C:9]=2[CH3:11])[NH:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14])=[O:25]
Reactant: COC(=O)c1[nH]c2c(C)ccc(C)c2c1N
Reactant: COC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)Nc1c(C(=O)OC)[nH]c2c(C)ccc(C)c12
Temperature: 0 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
A mixture of 0.6 g (2.75 mmol) of methyl 3-amino-4,7-dimethylindole-2-carboxylate, 0.22 ml (3.3 mmol) of pyridine and 15 ml of anhydrous THF was prepared. 10 ml of a solution of 0.26 ml (3.3 mmol) of methyl chloroformate in anhydrous THF was added dropwise at 0° C. over a period of 15 minutes and the reaction mixture was stirred for 1 hour. The reaction mixture was poured into 150 ml of ice water and extracted with 30 ml of ethyl acetate three times. The ethyl acetate layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The solids thus obtained were recrystallized from ethyl acetate to provide 600 mg of red crystals. Yield: 79% m.p.: 184°-185° C.; 1H-NMR (300 MHz, DMSO-d6 /TMS; δppm): 8.64 (brs, 1H), 6.98 (d, 1H), 6.80 (d, 1H), 6.63 (brs, 1H), 3.92 (s, 3H), 3.79 (brs, 3H), 2.59 (s, 3H), 2.42 (s, 3H)