Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:23]=[CH:22][C:8]([C:9]([NH:11][C:12]2[N:17]=[CH:16][C:15]3[CH:18]=[CH:19][N:20]([CH3:21])[C:14]=3[CH:13]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[Cl:24]N1C(=O)CCC1=O.O>CN(C=O)C>[Cl:24][C:18]1[C:15]2[CH:16]=[N:17][C:12]([NH:11][C:9](=[O:10])[C:8]3[CH:22]=[CH:23][C:5]([C:2]([OH:1])([CH3:3])[CH3:4])=[CH:6][CH:7]=3)=[CH:13][C:14]=2[N:20]([CH3:21])[CH:19]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1ccc2cnc(NC(=O)c3ccc(C(C)(C)O)cc3)cc21
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(Cl)c2cnc(NC(=O)c3ccc(C(C)(C)O)cc3)cc21
Temperature: 50 °C
Reaction time: 3 h
Yield: 27 %

Procedure:
In a 125 ml round bottom flask, 4-(2-hydroxypropan-2-yl)-N-(1-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl)benzamide (2.8 g, 9.05 mmol) was dissolved in DMF (25 ml). To this was added N-chlorosuccinimide (1.5 g, 11 mmol) and the mixture was stirred at 50° C. for 3 hours. The mixture was then poured into 50 ml water and then extracted with ethyl acetate (3×100 ml). Combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by preparatory HPLC (RFA-mode: eluting with 25-55% ACN in water). Fractions containing the desired mono chlorinated product were combined and concentrated. To the residue was added saturated NaHCO3 and the aqueous mixture was extracted with ethyl acetate (2×100 ml). Combined organic layers were dried over sodium sulfate, filtered and concentrated to obtain the title compound (840 mg, 27% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.25-1.26 (m, 1 H) 1.46 (s, 139 H) 3.66-3.86 (m, 3 H) 5.17 (s, 1 H) 7.40-7.69 (m, 3 H) 8.01 (d, J=8.59 Hz, 2 H) 8.34 (s, 1 H) 8.59 (s, 1 H) 10.68 (s, 1 H)
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([O:13][CH3:14])[CH:4]=1)=[O:2].S(=O)(=O)([OH:17])N.Cl([O-])=O.[Na+]>CC(C)=O>[CH3:14][O:13][C:5]1[CH:4]=[C:3]([CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])[C:1]([OH:17])=[O:2]
Reactant: COC(=O)c1ccc(C=O)cc1OC
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(C(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 123.1 %

Procedure:
To a cold solution of methyl 4-formyl-2-methoxybenzoate (6.0 g, 7.73 mmol) in acetone (50 mL) was added aqueous sulphamic acid solution (4.5 g, 11.59 mmol) and aqueous sodium chlorite solution (4.04 g, 11.59 mmol) at 0-5° C. The reaction mixture was stirred at RT for 3-4 h. Excess of solvent was removed under vacuum. The obtained residue was diluted with water and basified with saturated sodium bicarbonate solution. The aqueous layer was washed with diethyl ether to remove organic impurities and the obtained aqueous layer was again acidified with conc.HCl. The solid obtained was filtered and suck dried to afford 2.00 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.80 (s, 3H), 3.87 (s, 3H), 7.55-7.59 (m, 2H), 7.70 (d, J=7.8 Hz, 1H), 13.37 (s, 1H); MS (m/z): 210.97 (M+H)+.
Reaction SMILES: B.[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([N+:13]([O-:15])=[O:14])=[C:8]([CH2:10][C:11]#[N:12])[CH:9]=1.CO.Cl>C1COCC1>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([N+:13]([O-:15])=[O:14])=[C:8]([CH2:10][CH2:11][NH2:12])[CH:9]=1
Reactant: COc1ccc([N+](=O)[O-])c(CC#N)c1
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc([N+](=O)[O-])c(CCN)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere 200 mL (200 mmol) of a 1M borane in THF solution were slowly added dropwise at RT to 12.6 g (65.7 mmol) (5-methoxy-2-nitrophenyl)-acetonitrile in 380 mL THF. The reaction mixture was refluxed for 2 h. After cooling 30 mL methanol were added dropwise within 20 min. During this time the temperature was maintained at 10° C. to 20° C. with an ice bath. The reaction mixture was stirred for 30 min at RT and then 45 mL of a 2M aqueous hydrochloric acid solution was added dropwise thereto within 30 min. The reaction mixture was concentrated by rotary evaporation i. vac. with gentle heating. The residue was diluted with water to approx. 200 mL and extracted with 200 mL EtOAc. The aqueous phase was made alkaline with a 15% (w/v) aqueous potassium carbonate solution and continuously extracted overnight with a rotary perforator according to Ludwig (Messrs. Normag) with diethyl ether. The organic extract was evaporated to dryness by rotary evaporation.
Reaction SMILES: [Li+].[OH-].[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@H:20]([CH2:41][C:42]3[CH:47]=[C:46]([CH3:48])[C:45]([NH2:49])=[C:44]([CH3:50])[CH:43]=3)[C:21]([N:23]3[CH2:28][CH2:27][CH:26]([CH:29]4[CH2:34][CH2:33][N:32]([CH2:35][C:36]([O:38]CC)=[O:37])[CH2:31][CH2:30]4)[CH2:25][CH2:24]3)=[O:22])=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:51]=[CH:52][CH:53]=[CH:54][C:6]=2[NH:5]1>O.C1COCC1>[O:3]=[C:4]1[N:10]([CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C@H:20]([CH2:41][C:42]3[CH:47]=[C:46]([CH3:48])[C:45]([NH2:49])=[C:44]([CH3:50])[CH:43]=3)[C:21]([N:23]3[CH2:24][CH2:25][CH:26]([CH:29]4[CH2:34][CH2:33][N:32]([CH2:35][C:36]([OH:38])=[O:37])[CH2:31][CH2:30]4)[CH2:27][CH2:28]3)=[O:22])=[O:18])[CH2:15][CH2:16]2)[CH2:9][CH2:8][C:7]2[CH:51]=[CH:52][CH:53]=[CH:54][C:6]=2[NH:5]1
Reactant: CCOC(=O)CN1CCC(C2CCN(C(=O)[C@@H](Cc3cc(C)c(N)c(C)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(CC(=O)O)CC3)CC2)cc(C)c1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3.1 mg (0.13 mmol) LiOH in 1 mL water was added to a solution of 55 mg (0.08 mmol) of (R)-1-(4-amino-3,5-dimethyl-benzyl)-2-(1′-ethoxycarbonylmethyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 90) in 5 mL THF and the reaction mixture was stirred overnight at RT. The mixture was evaporated down i.vac., the residue was taken up in 1 mL DMF and the crude product was purified by HPLC. The fractions containing the product were combined and lyophilised.
Reaction SMILES: [N:1]1([C:6]2[S:7][C:8]([C:12]#[N:13])=[C:9]([NH2:11])[N:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[SH2:14].CN(C)C=O>C(N(CC)CC)C>[N:1]1([C:6]2[S:7][C:8]([C:12](=[S:14])[NH2:13])=[C:9]([NH2:11])[N:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1sc(N2CCCC2)nc1N
Reactant: S
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=S)c1sc(N2CCCC2)nc1N
Yield: 53 %

Procedure:
25 parts of 2-pyrrolidino-4-amino-5-cyanothiazole are reacted with 8 parts of hydrogen sulfide in 150 parts of dimethylformamide and 2 parts of triethylamine, by the method described in Example 1(a). 15.6 parts of 2-pyrrolidino-4-amino-5-thiocarbamoyl-thiazole (53% of theory) of melting point 264°-265° C. are obtained.
Reaction SMILES: [O:1]([CH2:8][CH:9]([OH:12])[CH2:10][NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=[C:14]([CH3:31])[CH2:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]2[S:26][C:25](=[O:27])[NH:24][C:23]2=[O:28])=[CH:19][CH:18]=1.C([BH3-])#N.[Na+]>CO>[O:1]([CH2:8][CH:9]([OH:12])[CH2:10][NH:11][CH:14]([CH3:31])[CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][CH:22]2[S:26][C:25](=[O:27])[NH:24][C:23]2=[O:28])=[CH:29][CH:30]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCC(O)COc1ccccc1
Reactant: CC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(COc1ccc(CC2SC(=O)NC2=O)cc1)NCC(O)COc1ccccc1
Yield: 76.1 %

Procedure:
A procedure similar to that described in Example 2 was repeated, except that 0.98 g of 3-phenoxy-2-hydroxypropylamine (prepared as described in Preparation 15), 3.39 g of 5-[4-(2-oxopropoxy)benzyl]thiazolidine-2,4-dione, 1.11 g of sodium cyanoborohydride and 60 ml of anhydrous methanol were used. The resulting crude product was purified by silica gel column chromatography (using a 10:1 by volume mixture of ethyl acetate and ethanol as the eluent) to give 1.92 g of the title compound, melting at 64° C. to 68° C.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[CH3:13][O:14][C:15]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18]>ClCCl>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][S:7]([NH:18][CH2:17][C:16]2[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:15]=2[O:14][CH3:13])(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)Cc1ccc(Br)cc1
Reactant: COc1ccc(CN)c(OC)c1
Solvent: ClCCl
Product: COc1ccc(CNS(=O)(=O)Cc2ccc(Br)cc2)c(OC)c1
Reaction time: 2 h

Procedure:
While cooling with ice, 20.0 g of 4-bromobenzylsulfonyl chloride were initially charged in 200 ml of dichloromethane, and a solution of 24 ml of 2,4-dimethoxybenzylamine in 100 ml of dichloromethane was slowly added dropwise. For improved stirrability, a further 100 ml of dichloromethane were added, and the reaction mixture was allowed to come to room temperature. After stirring for 2 hours, the reaction mixture was washed with 100 ml of water, with 100 ml of 0.2 N aqueous hydrochloric acid, with 100 ml of saturated aqueous sodium hydrogencarbonate solution and finally once more with 100 ml of water. The organic phase was dried over Na2SO4, concentrated by rotary evaporation and dried under high vacuum. The residue (30 g) was used in the next reaction without further purification.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:27]=[CH:28][N:29]=3)[N:17]=[C:18]([C:20]3[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].CS(O[CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1)(=O)=O.O>CN(C=O)C>[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:27]=[CH:28][N:29]=3)[N:17]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:41][CH2:42][N:43]4[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]4)[CH:21]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)OCCN1CCCCC1
Reactant: CC1CCCN1c1cccc(Nc2cc(-c3cccc(O)c3)nn3ccnc23)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1CCCN1c1cccc(Nc2cc(-c3cccc(OCCN4CCCCC4)c3)nn3ccnc23)n1
Temperature: 50 °C
Yield: 40.2 %

Procedure:
To a mixture of 3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)phenol (40 mg, 0.1 mmol) and K2CO3 (28 mg, 0.2 mmol) in DMF (5 mL) was added 2-(piperidin-1-yl)ethyl methanesulfonate (25 mg, 0.12 mmol). The mixture was heated at 50° C. for 16 h. After cooling, the mixture was poured into water and extracted with EtOAc (8 mL 3). The combined organic layers were washed with brine, then dried over MgSO4. After filtration and concentration, the residue was purified by chromatography (silica gel, EtOAc) to give N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)-6-(3-(2-(piperidin-1-yl)ethoxy)phenyl)imidazo[1,2-b]pyridazin-8-amine (20 mg, 40%). 1H NMR (300 MHz, CDCl3): δ 8.67 (s, 1H), 8.08 (s, 1H), 7.93 (s, 1H), 7.60-7.53 (m, 3H), 7.45-7.37 (m, 2H), 7.05-7.01 (m, 1H), 6.23 (d, 1H, J=7.5 Hz), 6.04 (d, 1H, J=8.4 Hz), 4.31-4.21 (m, 3H), 3.71-3.65 (m, 1H), 3.54-3.48 (m, 1H), 2.85 (t, 2H, J=6.0 Hz), 2.57 (brs, 4 h), 2.17-2.04 (m, 3H), 1.76-1.62 (m, 5H), 1.48 (brs, 2H), 1.26 (d, 3H, J=6.6 Hz). LC/MS: 498 [M+H]+, tR=1.15 min. HPLC: 99.14% at 214 nm, 99.51% at 254 nm, tR=3.97 min.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:8]=1)=[O:2].[Cl:16]N1C(=O)CCC1=O.O>CN(C=O)C>[CH:1]([NH:3][C:4]1[S:5][C:6]([Cl:16])=[C:7]([C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:8]=1)=[O:2]
Reactant: CCOC(=O)C(=O)c1csc(NC=O)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(=O)c1nc(NC=O)sc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethyl 2-(Formylaminothiazol-4-yl)-2-oxoacetate (9.1 g, 39.87 mmol) (obtained from Aldrich, Milwaukee, Wis.) was slurried in 50 mL of anhydrous DMF. N-Chlorosuccinimide (5.6 g, 41.86 mmol) was added as a solid and the suspension was stirred at room temperature. After 18 hours, the reaction mixture was poured into 500 mL of water. The resulting white precipitate was filtered, washed with water and air dried to afford the title intermediate as a white solid.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[N:14][CH:13]=[CH:12]3)[CH2:4][CH2:3]1.[Cl:19][C:20]1[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][N:21]=1>N1C=CC=CC=1.CN(C=O)C>[ClH:19].[F:27][C:26]([F:29])([F:28])[C:24]1[CH:23]=[CH:22][N:21]=[C:20]([N:2]2[CH2:7][CH2:6][CH:5]([O:8][C:9]3[CH:10]=[C:11]4[C:16](=[CH:17][CH:18]=3)[CH:15]=[N:14][CH:13]=[CH:12]4)[CH2:4][CH2:3]2)[N:25]=1
Reactant: c1cc2cc(OC3CCNCC3)ccc2cn1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: FC(F)(F)c1ccnc(N2CCC(Oc3ccc4cnccc4c3)CC2)n1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
75 mg of 6-(Piperidine-4-yloxy)-isoquinoline-Hydrochloride (124) are dissolved in 5 mL of dry pyridine and 5 mL of DMF. 55 mg 2-Chlor-4-trifluoromethyl-pyrimidine are added and the solution is stirred at 60° C. for 3 hours. The solvents are removed in vacuo and the residue is taken up in brine and extracted three times with ethyl acetate. The combined organic layers are dried over magnesium sulfate, evaporated to dryness and the crude product is purified by preparative HPLC. The product is converted into the corresponding HCl salt by taking up the product in 20 mL of 1 N hydrochloric acid followed by lyophilization. Yield: 29 mg. Rt=1.69 min (Method #2). Detected mass: 375.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][N:21](C3CCCCO3)[C:15]=2[CH:14]=1.O1CCCCC1[O:35][CH2:36][CH2:37][N:38]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[N:39]1>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:41]3[CH:40]=[N:39][N:38]([CH2:37][CH2:36][OH:35])[CH:42]=3)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: COc1cc(OC)c(F)c(-c2cc3c(cn2)c(I)nn3C2CCCCO2)c1F
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Product: COc1cc(OC)c(F)c(-c2cc3[nH]nc(-c4cnn(CCO)c4)c3cn2)c1F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 52, Step 8 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine and 1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. LCMS (M+H)+=402.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=2)[NH:9]1.N1C=CC=CC=1.[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[CH3:19][C:17]1([CH3:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=2)[NH:9][CH:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][S:36]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:38])=[O:37]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccccc1N)N2
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccccc1NS(=O)(=O)c1ccccc1)N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
To an ice-cold mixture of methyl 2-(2-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (60 mg, 0.19 mmol, 1.0 eq.) and pyridine (0.3 mL, 3.8 mmol, 20 eq.) in dichloro methane (5 mL) was added benzenesulfonyl chloride (51 mg, 0.29 mmol, 1.5 eq.) under nitrogen. Then the reaction mixture was stirred at room temperature for two hours. Thin layer chromatography and LC-MS indicated that the starting material was consumed completely. The reaction was quenched with 20 mL water extracted with ethyl acetate (20 mL×2). The combined organic layers were concentrated and the residue was purified by silica gel (petroleum ether/ethyl acetate=2:1) to afford 70 mg of methyl 3,3-dimethyl-2-(2-(phenylsulfonamido)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate as a pale yellow solid; yield: 85%; MS (ESI+APCI) M+1=451.
Reaction SMILES: C([N:8]1[CH2:16][CH:15]2[CH:10]([CH2:11][CH:12]([CH3:17])[CH2:13][NH:14]2)[CH2:9]1)C1C=CC=CC=1>CO.[Pd].C>[CH3:17][CH:12]1[CH2:11][CH:10]2[CH:15]([CH2:16][NH:8][CH2:9]2)[NH:14][CH2:13]1
Reactant: CC1CNC2CN(Cc3ccccc3)CC2C1
Agent: [Pd]
Solvent: CO
Product: CC1CNC2CNCC2C1

Procedure:
8.0 g (35 mmol) of 8-benzyl-4-methyl-2,8-diazabicyclo[4.3.0]nonane are dissolved in 60 ml of methanol and hydrogenated over palladium on acitive charcoal at 100° C. and under 100 bar. Then the catalyst is filtered off, the filtrate is concentrated by evaporation and the residue is distilled.
Reaction SMILES: N[C:2]1[N:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:20]=2[NH:19][CH:18]=[C:17]3[Cl:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.N([O-])=[O:23].[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C>[Cl:21][C:17]1[C:16]2[C:20](=[C:12]([NH:11][S:8]([C:5]3[CH:6]=[N:7][C:2]([OH:23])=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH:13]=[CH:14][CH:15]=2)[NH:19][CH:18]=1
Reactant: Nc1ccc(S(=O)(=O)Nc2cccc3c(Cl)c[nH]c23)cn1
Reactant: O=N[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=S(=O)(Nc1cccc2c(Cl)c[nH]c12)c1ccc(O)nc1
Reaction time: 1 h
Yield: 53.8 %

Procedure:
Under ice-cooling, into a solution of the compound of Example 33a (100 mg, 0.31 mmol) dissolved in 2 ml of glacial acetic acid was added dropwise 1 ml of an aqueous solution containing 32 mg (0.46 mmol) of sodium nitrite. After stirring for one hour, the mixture was adjusted to about pH 8 by adding an aqueous sodium bicarbonate and further stirred for 10 minutes. The reaction mixture was extracted with ethyl acetate, and the extract was washed with water, dried over magnesium sulfate and concentrated. Then, the residue was purified by silica gel thin layer chromatography, to give 54 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Br[CH2:28][CH2:29][O:30][CH3:31].[ClH:32]>>[ClH:32].[CH3:31][O:30][CH2:29][CH2:28][N:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)[S:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)(=[O:11])=[O:10]
Reactant: COc1ccc(S(=O)(=O)Nc2ccccc2/C=C/c2ccncc2)cc1
Reactant: COCCBr
Agent: Cl
Product: COCCN(c1ccccc1/C=C/c1ccncc1)S(=O)(=O)c1ccc(OC)cc1

Procedure:
Using 1.00 g of the compound obtained in Example 3A and 1-bromo-2-methoxyethane, the reaction and after-treatment procedure of Example 9 was otherwise carried out and the product was converted to the hydrochloride. By this procedure, 0.45 g of the title compound (amorphous) was obtained.
Reaction SMILES: C([N:8]1[C:17]2[C:12](=[CH:13][N:14]=[CH:15][CH:16]=2)[C:11]([OH:18])=[CH:10][C:9]1=[O:19])C1C=CC=CC=1>FC(F)(F)S(O)(=O)=O>[NH:8]1[C:17]2[C:12](=[CH:13][N:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[CH2:10][C:9]1=[O:19]
Reactant: O=c1cc(O)c2cnccc2n1Cc1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Product: O=C1CC(=O)c2cnccc2N1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A mixture of 1-benzyl-4-hydroxy-1,6-naphthyridin-2(1H)-one (21 g, 0.08 mol) and trifluoromethanesulfonic acid (100 mL) was heated with stirring at 120° C. overnight. The reaction mixture was used for the next step directly.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]([CH3:27])[C:16](=[O:26])[CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:9]=2)=[CH:4][CH:3]=1.[CH:28]1([C:34](Cl)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.O>CCOC(C)=O.C(=O)([O-])O.[Na+]>[CH:28]1([C:34]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]([CH3:27])[C:16](=[O:26])[CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:24])[CH3:22])[CH:9]=3)=[CH:4][CH:3]=2)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CN(Cc1cccc(-c2ccc(N)cc2)c1)C(=O)CNC(=O)OC(C)(C)C
Reactant: O=C(Cl)C1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CN(Cc1cccc(-c2ccc(NC(=O)C3CCCCC3)cc2)c1)C(=O)CNC(=O)OC(C)(C)C
Reaction time: 24 h
Yield: 99.8 %

Procedure:
tert-Butyl (2-{[(4′-aminobiphenyl-3-yl)methyl](methyl)amino]-2-oxoethyl}carbamate (240 mg) was dissolved in a mixed solution of EtOAc (10 ml)/saturated aqueous sodium hydrogen carbonate solution (10 ml), followed by ice-cooling. A solution of cyclohexanecarbonyl chloride (142 mg) in EtOAc (5 ml) was added dropwise thereto. The reaction mixture was returned to room temperature and stirred for 24 hours, and then to the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was dried over MgSO4 and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane=2/1) to obtain tert-butyl {2-[({4′-[(cyclohexylcarbonyl)amino]biphenyl-3-yl}methyl)(methyl)amino]-2-oxoethyl}carbamate (311 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@H:9]2[CH3:14])[CH:5]=[C:4]([CH2:15]I)[N:3]=1.[CH3:17][S-:18].[Na+]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@H:9]2[CH3:14])[CH:5]=[C:4]([CH2:15][S:18][CH3:17])[N:3]=1
Reactant: C[C@@H]1COCCN1c1cc(CI)nc(Cl)n1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCc1cc(N2CCOC[C@H]2C)nc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
(R)-4-(2-Chloro-6-(iodomethyl)pyrimidin-4-yl)-3-methylmorpholine (17.0 g, 48.08 mmol) was dissolved in DMF (150 ml), to this was added sodium methanethiolate (3.37 g, 48.08 mmol) and the reaction was stirred for 1 hour at 25° C. The reaction mixture was quenched with water (50 ml) and then extracted with Et2O (3×50 ml). The organic layer was dried over MgSO4, filtered and then evaporated. The residue was purified by flash chromatography on silica, eluting with a gradient of 50 to 100% EtOAc in iso-hexane. Pure fractions were evaporated to afford (R)-4-(2-chloro-6-(methylthiomethyl)pyrimidin-4-yl)-3-methylmorpholine (12.63 g, 96%); m/z: (ES+) MH+, 274.35.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][N:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH:20]1[CH2:22][CH2:21]1>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:19][CH:20]2[CH2:22][CH2:21]2)=[CH:7][N:6]=1)=[O:4]
Reactant: BrCC1CC1
Reactant: COC(=O)c1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OCC2CC2)cn1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A solution of 5-hydroxy-pyridine-2-carboxylic acid methyl ester (2.0 g, 13.1 mmol) in N,N-dimethylformamide was treated with potassium carbonate (2.71 g, 19.6 mmol) and 1-bromomethyl-cyclopropane (1.6 ml, 15.7 mmol). The reaction mixture was stirred at 100° C. for 16 hours. For the workup, the reaction mixture was diluted with ethyl acetate, solid material was filtered, and the filtrate evaporated at reduced pressure. The residue was purified by chromatography on silica using a gradient of n-heptane and ethyl acetate=100/0 to 20/80 as the eluent to give the 5-cyclopropylmethoxy-pyridine-2-carboxylic acid methyl ester as a yellow liquid (1.69 g, 62% of theory). Mass (calculated) C11H13NO3 [207.228]; (found) [M+H]+=208.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[Cl:7][C:8]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:9]=1[CH2:10]Br>>[Cl:7][C:8]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:9]=1[CH2:10][N:4]1[CH:5]=[CH:6][C:2]([NH2:1])=[N:3]1
Reactant: Nc1cc[nH]n1
Reactant: Clc1ccc(CBr)c(Cl)c1
Product: Nc1ccn(Cc2ccc(Cl)cc2Cl)n1

Procedure:
Prepared in analogy to example 10a) starting with 3-amino-1H-pyrazole and 2,4-dichlorobenzyl bromide. The title compound was obtained as a light yellow solid (Yield=52%). MS ISP (m/e): 242.2 (100) [(M+H)+].