Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]([CH2:29][CH2:30][O:31][CH3:32])[C:24]([O:26]CC)=[O:25])[CH:5]=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.CO.O.O[Li].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]([CH2:29][CH2:30][O:31][CH3:32])[C:24]([OH:26])=[O:25])[CH:5]=[C:6]([C:13]2[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=2)[C:7]=1[O:8][CH2:9][CH:10]1[CH2:11][CH2:12]1
Reactant: CCOC(=O)C(CCOC)c1cc(Cl)c(OCC2CC2)c(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COCCC(C(=O)O)c1cc(Cl)c(OCC2CC2)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.4 %

Procedure:
To a stirred solution of ethyl 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methoxybutanoate (0.3 g, 0.638 mmol) in a mixture of THF (10 mL), methanol (10 mL) and water (5 mL) was added LiOH.H2O (53 mg, 12.030 mmol) at room temperature and the mixture was stirred at RT for 2 h. After complete consumption of starting material as monitored by TLC, the reaction mixture was diluted with water (10 mL) and acidified using 1 N HCl at 0° C. The aqueous layer was extracted with EtOAc (2×20 mL); combined organic extracts were washed with water (20 mL), brine (30 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude material was purified by column chromatography to afford 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methoxybutanoic acid (100 mg) as an off white solid. 1HNMR (500 MHz) (CDCl3): δ ppm 7.68 (m, 4H), 7.40 (s, 1H), 7.20 (s, 1H), 3.80 (t, 1H), 3.41 (d, 2H), 3.25 (m, 5H), 2.39 (m, 1H), 1.99 (m, 1H), 0.95 (m, 1H), 0.4 (d, 2H), 0.0 (m, 2H).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26](ON3C(=O)CCC3=O)=[O:27])=[C:24]([CH2:36][OH:37])[N:23]=[C:22]2[CH2:38][CH2:39][CH2:40][CH3:41])=[CH:16][CH:15]=1)=[O:7])(C)(C)C.Cl.[NH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46]>C(N(CC)CC)C>[CH2:48]([O:47][C:45]([CH2:44][NH:43][C:26]([C:25]1[N:21]([CH2:20][C:17]2[CH:16]=[CH:15][C:14]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[C:6]([OH:7])=[O:5])=[CH:19][CH:18]=2)[C:22]([CH2:38][CH2:39][CH2:40][CH3:41])=[N:23][C:24]=1[CH2:36][OH:37])=[O:27])=[O:46])[CH3:49]
Reactant: CCOC(=O)CN
Reactant: CCCCc1nc(CO)c(C(=O)ON2C(=O)CCC2=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: CCCCc1nc(CO)c(C(=O)NCC(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Following a procedure similar to that described in Example 53, but using 0.307 g of succinimido 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-hydroxymethylimidazole-5-carboxylate [prepared as described in Example 52(a)], 89 mg of ethyl glycinate hydrochloride and 0.089 ml of triethylamine, 0.202 g of the
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:13]([CH3:14])[C:12]2[CH:15]=[CH:16][C:17]([N:19]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=3)[CH3:20])=[CH:18][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:28][C:29]1[CH:30]=[CH:31][C:32]([CH3:41])=[C:33]([S:35]([NH:38][O:39][CH3:40])(=[O:37])=[O:36])[CH:34]=1.CO>ClCCl>[CH2:1]([NH:8][C:9]1[N:13]([CH3:14])[C:12]2[CH:15]=[CH:16][C:17]([N:19]([CH3:20])[C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:28][C:29]4[CH:30]=[CH:31][C:32]([CH3:41])=[C:33]([S:35]([NH:38][O:39][CH3:40])(=[O:36])=[O:37])[CH:34]=4)[N:22]=3)=[CH:18][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(c1ccc2c(c1)nc(NCc1ccccc1)n2C)c1ccnc(Cl)n1
Reactant: CONS(=O)(=O)c1cc(N)ccc1C
Solvent: ClCCl
Solvent: CO
Product: CONS(=O)(=O)c1cc(Nc2nccc(N(C)c3ccc4c(c3)nc(NCc3ccccc3)n4C)n2)ccc1C

Procedure:
The title compound was prepared following the procedure of Example 2 with N2-benzyl-N5-(2-chloropyrimidin-4-yl)-N5,1-dimethyl-1H-benzimidazole-2,5-diamine (50 mg, 0.13 mmol) and 5-amino-N-methoxy-2-methylbenzenesulfonamide (30 mg, 0.14 mmol) as a white solid (58 mg, 0.10 mmol) after silica gel chromatography with methanol in dichloromethane. 1H NMR (300 MHz, d6-DMSO) δ 10.3 (s, 1H), 9.42 (s, 1H), 8.73 (s, 1H), 7.76-7.80 (m, 2H), 7.40-7.23 (m, 8H), 7.09 (br s, 1H), 6.84 (d, J=7.4 Hz, 1H), 5.61 (d, J=5.3 Hz, 1H), 4.60 (br s, 2H), 4.34 (s, 2H), 3.58 (s, 6H), 3.46 (s, 3H). MS (ESI) m/z=559 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](I)=[CH:9][N:10]=2)[CH:7]=1.[CH3:12][S:13]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)(=[O:15])=[O:14]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:19]3[CH:20]=[CH:21][C:16]([S:13]([CH3:12])(=[O:15])=[O:14])=[CH:17][CH:18]=3)=[CH:9][N:10]=2)[CH:7]=1
Reactant: Brc1ccc2ncc(I)n2c1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Product: CS(=O)(=O)c1ccc(-c2cnc3ccc(Br)cn23)cc1

Procedure:
The title compound, brown solid (0.53 g, 69%), MS (ISP) m/z=353.4 [(M+H)+], mp 194° C., was prepared in accordance with the general method of intermediate E from commercially available 6-bromo-3-iodoimidazo[1,2-a]pyridine (0.7 g, 2.17 mmol) and commercially available 4-methanesulfonyl-phenylboronic acid (0.48 g, 2.38 mmol).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)[N:4]=[CH:3]1>CO>[NH2:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[N:4]=[CH:3][N:2]([CH3:1])[CH:6]=2)=[CH:12][CH:11]=1
Reactant: Cn1cnc(-c2ccc([N+](=O)[O-])cc2)c1
Solvent: CO
Product: Cn1cnc(-c2ccc(N)cc2)c1

Procedure:
Prepared by hydrogenation of 1-methyl-4-(4-nitro-phenyl)-imidazole in MeOH on palladium/charcoal (10%) at 20° C. and 3.5 bar.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]([O:16][C:17](=[O:36])[NH:18][CH:19]1[CH2:24][CH2:23][N:22]([S:25]([C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[C:30]([Cl:35])[CH:29]=2)(=[O:27])=[O:26])[CH2:21][CH2:20]1)([CH3:15])([CH3:14])[CH3:13]>N1C=CC=CC=1.C(Cl)Cl>[C:12]([O:16][C:17](=[O:36])[NH:18][CH:19]1[CH2:20][CH2:21][N:22]([S:25]([C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:9](=[O:10])[CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:30]([Cl:35])[CH:29]=2)(=[O:27])=[O:26])[CH2:23][CH2:24]1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc(N)c(Cl)c2)CC1
Reactant: O=C(Cl)CCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc(NC(=O)CCc3ccccc3)c(Cl)c2)CC1
Temperature: 60 °C
Reaction time: 12 h
Yield: 12.3 %

Procedure:
3-Phenyl propionyl chloride (0.29 g, 1.76 mmol) was added in one portion to a solution of [1-(4-amino-3-chloro-benzenesulfonyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (0.57 g, 1.4 mmol) in Pyridine (5 ml) and the mixture was heated to 60° C. The mixture was stirred at this temperature under a nitrogen atmosphere for 12 hours. After this time the mixture was diluted with DCM (100 ml) and washed sequentially with HCl (1M solution, 50 ml), NaOH (1M solution, 50 ml) and brine (50 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated. The resulting residue was purified by flash column chromatography (elution: 98% DCM, 2% Methanol) to give the title compound (0.09 g, 8% yield) as a white powder. Tr=2.41 min, m/z (ES+) (M+Na)+ 545.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:12][CH2:13][CH:14]([OH:19])[CH2:15][CH:16]([CH3:18])[CH3:17])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.CCN(CC)CC.N#N>CS(C)=O>[Cl:1][C:2]1[C:3]([NH:12][CH2:13][C:14](=[O:19])[CH2:15][CH:16]([CH3:17])[CH3:18])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CC(C)CC(O)CNc1nc2ccccc2nc1Cl
Agent: N#N
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)CC(=O)CNc1nc2ccccc2nc1Cl
Temperature: 0 °C
Yield: 60.7 %

Procedure:
A mixture of 2a (6.96 g, 24.8 mmol), 28.4 ml Et3N and sulphur trioxide trimethylamine complex (7.9 g, 56.8 mmol) in 28.4 ml DMSO, is stirred overnight (under N2) at room temperature, then ice water (50 ml) is added. The aqueous phase is extracted in CH2Cl2 (3×30 ml). The collected organic phases are dried (CaCl2) and then evaporated under reduced pressure. The residues are purified by chromatography on a silica column, eluent: C6H12/Et2O (85:15) to give a beige solid (4.18 g, 61%); 1H NMR (100 MHz, CDCl3) δ: 0.93 (s, 3H), 1.00 (s, 3H), 2.34 (m, 1H), 2.40 (s, 2H), 4.38 (d, 2H), 6.39 (t, 1H), 7.59 (m, 4H); 13C NMR (25 MHz, CDCl3) δ: 22.56, 25.01, 49.28, 51.55, 125.34, 125.87, 127.98, 130.14, 136.65, 137.92, 140.99, 147.30, 205.01. Analysis calculated for C14H16N3OCl: C, 60.54; H, 5.81; N, 15.13. Experimental: C, 60.32; H, 6.06; N, 14.95.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:9].C(N(CC)CC)C.[C:17](Cl)(Cl)=[S:18].[OH-].[K+]>CCOCC>[NH:9]1[C:4]2[C:3](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:2][NH:1][C:17]1=[S:18]
Reactant: S=C(Cl)Cl
Reactant: NCc1ccccc1N
Agent: [K+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: S=C1NCc2ccccc2N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a solution of 2-aminomethyl-phenylamine (6.35 g, 52 mmol) and triethylamine (16.8 ml, 120 mmol) in ether (150 ml) was added dropwise a solution of thiophosgene (4.6 ml, 60 mmol) in ether (40 mL), at −78° C. over 1 h. After warming to rt a precipitate was filtered, washed thoroughly with ether, dissolved in methanol (200 mL) and treated with solid KOH (6.7 g, 120 mmol). The mixture was stirred for 15 min, filtered, and the filtrate was concentrated under reduced pressure to obtaine a residue which was recrystallized from methanol/water to give an off-white solid 7.43 g (87%). 1H NMR (500 MHz, DMSO-D6) δ 4.35 (s, 1H) 6.92 (d, J=7.93 Hz, 1H) 6.96 (m, 1H) 7.08 (d, J=7.32 Hz, 1H) 7.15 (m, 1H) 8.59 (s, 1H) 10.36 (s, 1H). MS (ESI) m/z 165 (MH+); HPLC (Column YMC Xterra OSD 4.6×33 mm S 7) Rt 0.81 min; Purity (96%).
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[C:8]2[C@@H:11]2[CH2:13][C@H:12]2[CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[N:3]1.[Xe](F)[F:20]>C(#N)C.C(OCC)(=O)C>[F:20][C:10]1[N:2]([CH3:1])[N:3]=[C:4]2[C:9]=1[C:8]([C@@H:11]1[CH2:13][C@H:12]1[CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:7][CH:6]=[CH:5]2
Reactant: CC(=O)NC[C@@H]1C[C@H]1c1cccc2nn(C)cc12
Reactant: F[Xe]F
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)NC[C@@H]1C[C@H]1c1cccc2nn(C)c(F)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 12.9 %

Procedure:
To a solution of N-{[(1R,2R)-2-(2-methyl-2H-indazol-4-yl)cyclopropyl]methyl}acetamide (100 mg, 0.411 mmol) in acetonitrile (4.1 mL) was added xenon difluoride (76.5 mg, 0.452 mmol), and the mixture was stirred at room temperature for 4 hr. The reaction solution was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate is solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane=50/50→100/0) and preparative TLC (methanol/ethyl acetate=10/90) to give the title compound (13.9 mg, yield 11%).
Reaction SMILES: [C:1]12([CH2:8][N:9]3[CH2:13][CH2:12][C@@H:11]([NH:14]C(=O)OC(C)(C)C)[CH2:10]3)[O:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[ClH:22].CCOC(C)=O>CCOC(C)=O>[ClH:22].[ClH:22].[C:1]12([CH2:8][N:9]3[CH2:13][CH2:12][C@@H:11]([NH2:14])[CH2:10]3)[O:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(CC23CCC(CC2)O3)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@@H]1CCN(CC23CCC(CC2)O3)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of tert-butyl [(3R)-1-(7-oxabicyclo[2.2.1]hept-1-ylmethyl)-3-pyrrolidinyl]carbamate (377 mg) in AcOEt (3.8 mL) was added 4N HCl—AcOEt (3.2 mL), which was stirred at room temperature for 5 hours. The solvent was evaporated. The residue was dried to give (3R)-1-(7-oxabicyclo[2.2.1]hept-1-ylmethyl)-3-pyrrolidinamine dihydrochloride (370 mg) as an orange amorphous.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].[NH:34]1[CH2:38][CH2:37][C@@H:36]([OH:39])[CH2:35]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([N:34]2[CH2:38][CH2:37][C@@H:36]([OH:39])[CH2:35]2)=[O:32])[C:25]=1[CH3:33])(=[O:11])=[O:12]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Reactant: O[C@@H]1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)N1CC[C@@H](O)C1
Temperature: 40 °C
Reaction time: 72 h

Procedure:
A mixture of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (100 mg, 0.2 mmol), (R)-pyrrolidin-3-ol (34 mg, 0.2 mmol), HOBt (20 mg), EDAC.HCl (40 mg) and TEA (40 mg, 3 eq.) in DMF was stirred at 40° C. for 3 days. The reaction was concentrated and purified on a silica gel column to give the titled compound. MS m/z 572 [M−1].
Reaction SMILES: Cl[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:16]([CH:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])[N:3]=1.O.[C:23]([O:27][C:28]([NH:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C(COC)OC.C(O)C>[CH:19]([S:16]([CH2:15][C:4]1[CH:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]2[CH3:14])[N:7]=[C:2]([C:34]2[CH:33]=[CH:32][C:31]([NH:30][C:28](=[O:29])[O:27][C:23]([CH3:25])([CH3:24])[CH3:26])=[CH:36][CH:35]=2)[N:3]=1)(=[O:18])=[O:17])([CH3:21])[CH3:20]
Reactant: CC(C)S(=O)(=O)Cc1cc(N2CCOC[C@@H]2C)nc(Cl)n1
Reactant: CC(C)(C)OC(=O)Nc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)S(=O)(=O)Cc1cc(N2CCOC[C@@H]2C)nc(-c2ccc(NC(=O)OC(C)(C)C)cc2)n1
Temperature: 90 °C
Yield: 108.9 %

Procedure:
(3S)-4-{2-Chloro-6-[(isopropylsulfonyl)methyl]pyrimidin-4-yl}-3-methylmorpholine (2.0 g, 5.99 mmol) was dissolved in a solution of 18% DMF in a mixture of 7:3:2 dimethoxyethane:water:ethanol (16 mL). {4-[(Tert-butoxycarbonyl)amino]phenyl}boronic acid (2.13 g, 8.99 mmol), 2M sodium carbonate solution (8 mL) and dichlorobis(triphenylphosphine) palladium catalyst (211 mg, 0.30 mmol) were then added and the reaction refluxed at 90° C. for 2 hours under a nitrogen atmosphere. The reaction was allowed to cool to room temp then partitioned between ethyl acetate (20 mL) and water (20 mL). The organics were dried over magnesium sulphate, filtered and concentrated in vacuo. The cream solid obtained was chromatographed on silica, eluting with 0-50% ethyl acetate in DCM, to give the desired material as a brown solid (3.2 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[N:11]=[C:10]([C:12](O)=[O:13])[CH:9]=[CH:8][C:6]=2[N:7]=1.[Cl-].[NH4+].C[N:24](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[N:11]=[C:10]([C:12]([NH2:24])=[O:13])[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1ccc2nc(Cl)nc(N3CCOCC3)c2n1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1ccc2nc(Cl)nc(N3CCOCC3)c2n1

Procedure:
2-Chloro-4-morpholinopyrido[3,2-d]pyrimidine-6-carboxylic acid from Example 118 (0.12 g) was reacted with ammonium chloride (7 eq), HATU (1.5 eq) and DIPEA (4 eq) in DMF (5.2 mL) for 30 minutes. The reaction mixture was then diluted with water and the orange solid was collected by filtration to give 90 mg of 2-chloro-4-morpholinopyrido[3,2-d]pyrimidine-6-carboxamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2(O)[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[CH:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:7]=1.[OH-].[Na+]>>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH:13]=2)[CH:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cc(F)cc(S(C)(=O)=O)c2)CC1
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)(=O)c1cc(F)cc(C2=CCNCC2)c1
Temperature: 120 °C
Yield: 89.9 %

Procedure:
A mixture of tert-butyl 4-[3-fluoro-5-(methylsulfonyl)phenyl]-4-hydroxypiperidine-1-carboxylate (3.3 g, 8.8 mmol) and polyphosphoric acid (20 ml) was heated at 120° C. for 3 h. The mixture was poured on to ice and was basified with 5 M sodium hydroxide. The mixture was extracted with ethylacetate (3×100 ml) and the combined organic phases was dried (MgSO4), evaporated and purified by flash column chromatography (methanol/ethylacetate 1:1) to give the title compound (2.02 g). MS m/z (rel. intensity, 70 eV) 255 (M+, bp), 254 (50), 251 (87), 172 (87), 146 (53).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl.[C:20]1([C:26]2[N:30]=[C:29]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[S:28][N:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:20]1([C:26]2[N:30]=[C:29]([N:31]3[CH2:36][CH2:35][N:34]([C:12]([NH:11][C:2]4[CH:3]=[CH:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[N:1]=4)=[O:19])[CH2:33][CH2:32]3)[S:28][N:27]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C(Nc1ccc2ccccc2n1)OCC(Cl)(Cl)Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc2ccccc2n1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Yield: 46.2 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl quinolin-2-ylcarbamate (236 mg, 0.738 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.129 ml, 0.738 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 3 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) and recrystallized from a mixed solvent of hexane and ethyl acetate to give 142 mg (46.0%) of the desired product as a solid.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][C:10]([CH:19]=O)=[C:9]1Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O:26][CH3:27])(=[O:25])[CH2:23][SH:24].CC(C)([O-])C.[K+]>C1COCC1>[CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][C:10]2[CH:19]=[C:23]([C:22]([O:26][CH3:27])=[O:25])[S:24][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc(-c2ccccc2)n(Cc2ccccc2)c1Cl
Reactant: COC(=O)CS
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1cc2cc(-c3ccccc3)n(Cc3ccccc3)c2s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
A solution (1.1 M) of 1-benzyl-2-chloro-5-phenyl-1H-pyrrole-3-carbaldehyde in THF at 0° C. was treated with methyl thioglycolate (1.5 eq.) and a solution (2 M) of potassium tert-butoxide (2.5 eq.) in THF. The mixture was stirred at 0° C. for 2 h then at RT for 40 h. The reaction was quenched with water and pH was turned to neutral value by addition of aqueous ammonium chloride (saturated solution). The mixture was extracted with AcOEt and the combined organic phase was washed with brine and dried. Evaporation of the solvent gave a residue that was purified by flash chromatography on silica gel (1:30 acetone/toluene) to afford the title compound (38%) as a solid.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:7][N:6]1[C:14]1[N:15]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:16]=[C:17]([CH3:19])[CH:18]=1)=[O:4].[OH-].[Li+]>>[CH2:20]([N:15]1[C:14]([N:6]2[CH2:7][C@H:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:9][C@H:5]2[C:3]([OH:4])=[O:2])=[CH:18][C:17]([CH3:19])=[N:16]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)[C@@H]1C[C@@H](S(C)(=O)=O)CN1c1cc(C)nn1Cc1ccccc1
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(N2C[C@H](S(C)(=O)=O)C[C@H]2C(=O)O)n(Cc2ccccc2)n1

Procedure:
In analogy to the procedure described in example 253e, (2S,4R)-1-(2-benzyl-5-methyl-2H-pyrazol-3-yl)-4-methanesulfonyl-pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give the title compound which was used in the next step without further purification. MS (ESI): m/z=364.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:26])/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][C:21]([CH:24]=[O:25])=[CH:20][CH:19]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:26])/[CH:16]=[CH:17]/[C:18]3[CH:19]=[CH:20][C:21]([CH2:24][OH:25])=[CH:22][CH:23]=3)=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(/C=C/C(=O)Nc2ccc(-c3ccc(Cl)cc3)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: O=C(/C=C/c1ccc(CO)cc1)Nc1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4.4 g (12.16 mmol) of (E)-N-(4′-chlorobiphenyl-4-yl)-3-(4-formylphenyl)acrylamide in 200 mL of THF is adjusted with glacial acetic acid to a pH of three, combined with 8.14 g (36.48 mmol) of sodium triacetoxyborohydride, and stirred for 18 hours at ambient temperature. Then the reaction mixture is poured into water and the precipitate is filtered off. The filtrate is extracted with ethyl acetate, washed with water, and dried over sodium sulfate. The solvent is removed and the residue is combined with the solid which has been filtered off. The purification is carried out by column chromatography on silica gel (eluant: dichloromethane/ethanol/ammonia (30:1:0.1)). Yield: 3.2 g (72.4% of theory); C22H18ClNO2 (M=363.84); calc.: molecular ion peak (M+H)+: 364/366; found: molecular ion peak (M+H)+: 364/366; Rf value: 0.2 (silica gel, dichloromethane/ethanol (20:1)).