Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([F:11])[C:5]([F:12])=[CH:4][CH:3]=1.CI.[C:15](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[C:7]([C:8]([O:10][CH3:15])=[O:9])=[C:6]([F:11])[C:5]([F:12])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1c(Br)ccc(F)c1F
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)c1c(Br)ccc(F)c1F
Yield: 100 %

Procedure:
A solution of 6-bromo-2,3-difluorobenzoic acid (7.66 g, 32.3 mmol), methyl iodide (10 mL, 160 mmol) and potassium carbonate (5.36 g, 38.8 mmol) in N,N-dimethylformamide (30 mL) was stirred at room temperature for 1 hour. The solution was poured into water, and organic matter was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (8.11 g, 100% yield).
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][O:8][NH:9][C:10](=[O:29])[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[C:12]=2[NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH3:27])=[CH:22][C:21]=2[F:28])[CH2:4][O:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.O>[OH:6][C@H:5]([CH2:4][OH:3])[CH2:7][O:8][NH:9][C:10](=[O:29])[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[C:12]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH3:27])=[CH:22][C:21]=1[F:28]
Reactant: CCc1ccc(Nc2c(C(=O)NOC[C@H]3COC(C)(C)O3)ccc(F)c2F)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CCc1ccc(Nc2c(C(=O)NOC[C@H](O)CO)ccc(F)c2F)c(F)c1
Reaction time: 17 h
Yield: 94.4 %

Procedure:
To a stirring solution of the product of Example 31, Step E, N-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-2-(4-ethyl-2-fluoro-phenylamino)-3,4-difluoro-benzamide (0.515 g, 1.213 mmol) in methanol (10 mL) and water (1 mL) was added p-toluenesulfonic acid (0.115 g, 0.607 mmol). After stirring for 17 hours the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed twice saturated sodium carbonate solution and twice with brine. The organic layer was collected, dried over sodium sulfate, filtered and concentrated in vacuo to afford N-[(R)-2,3-dihydroxy-propoxy]-2-(4-ethyl-2-fluoro-phenylamino)-3,4-difluoro-benzamide (0.440 g, 94.4%) as a clear oil/foam. 1NMR (400 MHz; CD3OD) δ 7.35 (1H, m), 6.84–6.95 (3H, m), 6.76–6.79 (1H, m), 3.91–3.94 (1H, m), 3.81–3.85 (2H, m), 3.53–3.55 (2H, m), 2.57 (2H, q, J=15.1, 7.6 Hz), 1.19 (3H, t, J=7.6 Hz); 19F-NMR (376 MHz; CD3OD) δ −132.3, −134.8, −147.3; MS(APCI+)=385; Anal. calcd/found for C18H19F3N2O4: C, 56.25/56.22; H, 4.98/4.93; N, 7.29/7.17; [α]25D −5.6° (c 10.8, EtOH).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:23]2[CH2:28]COC[CH2:24]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=[CH:47][C:46]([O:49][CH3:50])=CC=3)C=2N=1)(C)(C)C.C(O)(=O)C(O)=O.C1C2(CNC2)CO1>>[C:1]([C:5]1[N:6]=[C:7]([N:23]2[CH2:24][C:47]3([CH2:46][O:49][CH2:50]3)[CH2:28]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:9]=2[N:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccc(Cn2nnc3c(Cl)nc(C(C)(C)C)nc32)cc1
Reactant: COc1ccc(Cn2nnc3c(N4CCOCC4)nc(C(C)(C)C)nc32)cc1
Agent: C1NCC12COC2
Agent: O=C(O)C(=O)O
Product: COc1ccc(Cn2nnc3c(N4CC5(COC5)C4)nc(C(C)(C)C)nc32)cc1

Procedure:
In analogy to the procedure described for the synthesis of 4-(5-tert-butyl-3-(4-methoxy benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)morpholine (example 58, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(4-methoxybenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-oxa-6-azaspiro[3.3]heptane oxalate and used without further purification in the consecutive step.
Reaction SMILES: [C:1]([C:9]1[N:10]=[CH:11][C:12]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=2[O:26][CH3:27])=[O:17])=[N:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.C(OCC)(=O)C>[OH:8][CH:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[N:10]=[CH:11][C:12]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=2[O:26][CH3:27])=[O:17])=[N:13][CH:14]=1
Reactant: COc1ccc(C)cc1NC(=O)Nc1cnc(C(=O)c2ccccc2)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(C)cc1NC(=O)Nc1cnc(C(O)c2ccccc2)cn1
Reaction time: 12 h
Yield: 91 %

Procedure:
To a stirred solution of 1-(5-benzoyl-pyrazin-2-yl)-3-(2-methoxy-5-methyl-phenyl)-urea (22 mg; 0.061 mmol) in methanol (1 mL) was added sodium borohydride (10 mg; 0.3 mmol). After stirring for 12 hours, the reaction diluted with 30 mL of ethyl acetate and washed with aqueous 10% sodium carbonate (1×30 mL), brine (30 mL), then dried (MgSO4), and filtered. The filtered material was concentrated under reduced pressure to yield a white solid (91% yield). 1H NMR (400 MHz, CDCl3) δ8.48 (br s, 1H), 8.39 (s, 1H), 8.22 (s, 1H), 8.12 (s, 1H), 7.25-7.45 (m, 5H), 6.89 (d, 1H), 6.80 (d, 1H), 5.85 (d, 1H), 3.88 (s, 3H), 2.37 (s, 3H). LRMS (ESI, Positive) m/e 365.24 (M+1).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.C([Mg]Cl)(C)C.[C:15]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=[O:21])#[N:16]>C1COCC1>[OH:21][CH:20]([C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1)[C:19]1[CH:18]=[C:17]([CH:24]=[CH:23][CH:22]=1)[C:15]#[N:16]
Reactant: CSc1nccc(I)n1
Reactant: N#Cc1cccc(C=O)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CSc1nccc(C(O)c2cccc(C#N)c2)n1
Reaction time: 1 h

Procedure:
To the solution of 4-iodo-2-(methylthio)pyrimidine (2.52 g, 10 mmol) in THF (50 mL) at 0 ° C. was added i-PrMgCl (5 mL, 2.0 M, 10 mmol) and stirred for 1 h. 3-cyanobenzaldehyde (1.31 g, 10 mmol) was added. The mixture was stirred at 0° C. for 2 h. The reaction was quenched with saturated aqueous NH4Cl solution and extracted with CH2Cl2. The combined organic layer was dried, filtered, and concentrated. The residue was purified by silica gel chromatography (20-50% EtOAc in hexane) to give 3-{hydroxy[2-(methylthio)pyrimidin-4-yl]methyl}benzonitrile. 1H-NMR (500 MHz, CDCl3) δ 8.46 (d, 1H, J=5.1), 7.72 (s, 1H), 7.65 (d, 1H, J=7.9), 7.61 (d, 1H, J=7.8), 7.48 (t, 1H, J=7.6), 6.84 (d, 1H, J=5.1), 5.69 (d, 1H, J=3.7), 4.58 (d, 1H, J=4.1), 2.60 (s, 3H). LRMS m/z (M+H) Calcd: 258.3, found: 258.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[NH:7][C:6](=[O:8])[C:5]2[S:9][C:10]([N:12]3[C:17]4[CH:18]=[C:19]([OH:22])[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13]3)=[N:11][C:4]=2[CH2:3]1.[Cl:24][C:25]1[CH:30]=[C:29](Cl)[N:28]=[C:27]([CH3:32])[N:26]=1.CC(C)([O-])C.[Na+]>C1COCC1>[Cl:24][C:25]1[N:26]=[C:27]([CH3:32])[N:28]=[C:29]([O:22][C:19]2[CH:20]=[CH:21][C:16]3[O:15][CH2:14][CH2:13][N:12]([C:10]4[S:9][C:5]5[C:6](=[O:8])[NH:7][C:2]([CH3:23])([CH3:1])[CH2:3][C:4]=5[N:11]=4)[C:17]=3[CH:18]=2)[CH:30]=1
Reactant: Cc1nc(Cl)cc(Cl)n1
Reactant: CC1(C)Cc2nc(N3CCOc4ccc(O)cc43)sc2C(=O)N1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(Cl)cc(Oc2ccc3c(c2)N(c2nc4c(s2)C(=O)NC(C)(C)C4)CCO3)n1
Temperature: 155 °C
Yield: 33.1 %

Procedure:
To a suspension of Example 57 (70 mg, 0.211 mmol) in THF (4 mL) was added 4,6-dichloro-2-methylpyrimidine (86 mg, 0.529 mmol) and sodium tert-butoxide (81 mg, 0.846 mmol). The reaction was heated to 155° C. under microwave irradiation for 30 minutes then cooled to room temperature. The mixture was partitioned between DCM (50 mL) and water (50 mL); the organic phase was washed with brine (50 mL), dried (MgSO4), and concentrated in vacuo. The residue was purified by preparative HPLC (Method 6) to give the title compound (32 mg, 35%) as an off-white solid. δH (CDCl3) 8.02 (1H, d, J 2.8 Hz), 6.99 (1H, d, J 8.9 Hz), 6.82 (1H, dd, J 8.9 and 2.6 Hz), 6.66 (1H, s), 5.50 (1H, s), 4.47-4.26 (2H, m), 4.19-4.04 (2H, m), 2.86 (2H, s), 2.61 (3H, s), 1.38 (6H, s). LCMS (ES+) 458.0 (M+H)+, RT 3.50 minutes (Method 1).
Reaction SMILES: Cl.[CH3:2][C:3]1[N:4]=[N:5][N:6]([CH:8]2[CH2:12][CH2:11][NH:10][CH2:9]2)[CH:7]=1.[NH2:13][C:14]1[C:23]([F:24])=[C:22](F)[C:21]([O:26][CH3:27])=[C:20]2[C:15]=1[C:16](=[O:34])[C:17]([C:31]([OH:33])=[O:32])=[CH:18][N:19]2[CH:28]1[CH2:30][CH2:29]1>N1C=CC=CC=1>[NH2:13][C:14]1[C:23]([F:24])=[C:22]([N:10]2[CH2:11][CH2:12][CH:8]([N:6]3[CH:7]=[C:3]([CH3:2])[N:4]=[N:5]3)[CH2:9]2)[C:21]([O:26][CH3:27])=[C:20]2[C:15]=1[C:16](=[O:34])[C:17]([C:31]([OH:33])=[O:32])=[CH:18][N:19]2[CH:28]1[CH2:30][CH2:29]1
Reactant: COc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: Cc1cn(C2CCNC2)nn1
Agent: Cl
Solvent: c1ccncc1
Product: COc1c(N2CCC(n3cc(C)nn3)C2)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 120 °C

Procedure:
3-(4-methyl-1,2,3-triazol-1-yl)pyrrolidine hydrochloride (159 mg, 0.85 mmol) were added to a suspension of 5-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (100 mg, 0.34 mmol) in pyridine (5 ml). The reaction mixture was heated at 120° C. for 30 hrs, concentrated and the residue was triturated with water. The separated solid was filtered, washed with water and recrystallized from chloroform-hexane. Yield 52 mg; m.p. 255.6°-256.2 ° C. 1H NMR (TFA) δ: 9.39 (s, 1H), 8.40 (s, 1H), 5.77 (s, 1H), 4.34-4.83 (m, 4H), 4.10 (m, 1H), 3.79 (s, 3H), 2.89 (m, 2H), 2.68 (s, 3H), 1.22-1.67 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[N:17])=[CH:4][CH:3]=1.[C:18]([O-])(=[O:20])[CH3:19].[Na+].C(OC(=O)C)(=O)C.C(=O)(O)[O-].[K+]>O.C(O)C.C(OCC)(=O)C>[C:18]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[N:17])=[CH:6][CH:7]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)[O-]
Reactant: N#CCCCCCCNCc1ccc(O)cc1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Oc1ccc(CNCCCCCCC#N)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.9 %

Procedure:
A solution of 4 g (0.017 mol) of 7-[(4-hydroxyphenyl)methylamino]heptanenitrile and 2.1 g (0.026 mol) anhydrous sodium acetate in 14 mL (0.17 mol) of acetic anhydride was stirred under nitrogen at room temperature. After 11/2 hours 15 mL of ethyl acetate was added followed by 49 mL of absolute ethanol. The reaction was stirred 18 hours at room temperature, cooled, and 61 mL of water was added followed by about 11 g of solid potassium bicarbonate. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The ethyl acetate extracts were combined, washed three times with saturated sodium bicarbonate solution, two times with saturated sodium chloride solution, and dried over magnesium sulfate. The solution was concentrated in vacuo to 3.4 gm of amber oil which was distilled at 170°-172°/0.08 mm in a Kugelrohr to yield 2.7 g (59%) of 7-[[4-(acetyloxy)phenyl]methylamino]heptanenitrile.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]([C:17](OCC)=O)=[C:7]([CH3:16])[C:8]=1[CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])[CH2:2][CH3:3].C=O>>[CH2:1]([C:4]1[NH:5][C:6]([CH3:17])=[C:7]([CH3:16])[C:8]=1[CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH2:2][CH3:3]
Reactant: CCCc1[nH]c(C(=O)OCC)c(C)c1CCC(=O)OCC
Agent: C=O
Product: CCCc1[nH]c(C)c(C)c1CCC(=O)O

Procedure:
2-n-propyl-3-carbethoxyethyl-4-methyl-5-carbethoxy-pyrrole was reductively alkylated with paraformaldehyde to yield 2-n-propyl-3-carboxyethyl-4,5-dimethyl-pyrrole. ##STR112##
Reaction SMILES: [Na].[C:2]([NH:4][C:5](=[N:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)S)#[N:3].[CH3:23][C:24]1[NH:25][C:26]([CH3:46])=[C:27]([C:42]([O:44][CH3:45])=[O:43])[CH:28]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([NH:40][CH3:41])[CH:35]=2)[C:29]=1[C:30]([O:32][CH3:33])=[O:31].O>C1COCC1.Cl[Hg]Cl>[C:2]([N:4]=[C:5]([N:40]([CH3:41])[C:36]1[CH:35]=[C:34]([CH:28]2[C:29]([C:30]([O:32][CH3:33])=[O:31])=[C:24]([CH3:23])[NH:25][C:26]([CH3:46])=[C:27]2[C:42]([O:44][CH3:45])=[O:43])[CH:39]=[CH:38][CH:37]=1)[NH:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)#[N:3]
Reactant: N#CNC(S)=NCCCN1CCC(c2ccccc2)CC1
Reactant: CNc1cccc(C2C(C(=O)OC)=C(C)NC(C)=C2C(=O)OC)c1
Agent: Cl[Hg]Cl
Agent: [Na]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cccc(N(C)C(=NC#N)NCCCN2CCC(c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 4.5 %

Procedure:
To a solution of N-cyano-N'-[3-(4-phenyl-1-piperidinyl)propyl]isothiourea sodium salt (IX) (115 mg, 0.35 mmol) and the aniline intermediate (XIV) from Example 12 (115 mg, 0.35 mmol) in THF (7 mL) at 0° C. was added HgCl2 (95 mg, 0.35 mmol). The reaction mixture was then refluxed for 3 h. After cooling to room temperature, H2O (1 mL) was added, and the mixture was stirred for 30 min. A gray precipitate was collected by filtration, and rinsed with CH2Cl2, the organic extract was dried (Na2SO4), and the solvent was removed in vacuo. The residue was subjected twice to flash chromatography (silica gel, MeOH:CH2Cl2, 4:96) to afford the compound as a white solid (15 mg, 4.5%). mp 85-90° C.; MS (ESI) m/z 599 (MH+); 1H NMR (CDCl3) δ 7.30 (m, 8 h), 6.98 (d, 1H, J=7.8 Hz), 6.91 (s, 1H), 5.29 (br s, 1H), 5.09 (s, 1 H), 3.67 (s, 6H), 3.63 (m, 2H), 3.47 (m, 2H), 3.37 (s, 3H), 3.00 (m, 2H), 2.73 (m, 4H), 2.45 (s, 6H), 2.38 (m, 1H), 2.26 (m, 2H), 2.03 (m, 2H); 13C NMR (CDCl3) δ 168.2, 150.4, 146.8, 130.6, 129.0, 128.0, 127.4, 127.0, 124.9, 124.1, 117.3, 102.3, 54.1, 51.4, 51.3, 40.8, 40.3, 39.9, 38.9, 30.4, 25.4, 19.3. HRMS (FAB) Calcd. for C34H43N6O4 (MH+): m/z 599.3346. Found: 599.3362.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][C:14]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:20][CH:19]=2)([OH:17])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CO>[CH2:25]([O:24][C:21]1[CH:22]=[CH:23][C:18]([C:14]2([OH:17])[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]2)=[CH:19][CH:20]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCOc1ccc(C2(O)CCN(C(=O)OCc3ccccc3)CC2)cc1
Solvent: CO
Product: CCCCCCOc1ccc(C2(O)CCNCC2)cc1
Reaction time: 6 h
Yield: 78.4 %

Procedure:
To a solution of 1-benzyloxycarbonyl-4-(4-hexyloxyphenyl)-4-hydroxypiperidine (1.4 g) in methanol (28 ml) was added dry 10% palladium on carbon (0.7 g) and stirred for 6 hours under hydrogen atmosphere. The palladium on carbon was filtered off, and the filtrate was evaporated under reduced pressure to give 4-(4-hexyloxyphenyl)-4-hydroxypiperidine (0.74 g).
Reaction SMILES: [CH3:1][O:2][CH2:3]/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]([C:16]([O:18][CH3:19])=[O:17])[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2.C>CO.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([C:16]([O:18][CH3:19])=[O:17])[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: COC/C=C/c1cc(C(=O)OC)c2ccccc2c1
Agent: [Pd]
Solvent: CO
Product: COCCCc1cc(C(=O)OC)c2ccccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl 3-[(1E)-3-(methyloxy)-1-propen-1-yl]-1-naphthalenecarboxylate (1 eq.) from the previous step and 10% w/w palladium over charcoal (0.1 eq.) were suspended in MeOH (0.08 M). The vessel was then evacuated and purged with H2. Under a balloon-filled H2 atmosphere, the reaction suspension was stirred at RT for 2 h. The reaction was then quenched with CH2Cl2, filtered through a bed of celite and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex→1:1 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([OH:3])=O.C(N(CC)CC)C.ClC(OCC)=O.[C:27]1([CH2:33][CH2:34][NH2:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1>[C:27]1([CH2:33][CH2:34][NH:35][C:1]([C:4]2[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=2)=[O:3])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: NCCc1ccccc1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1ccc(C(=O)NCCc2ccccc2)cc1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
20.1 g (0.1 mol) of 4-carboxy-benzenesulfonamide were suspended in 300 ml of anhydrous tetrahydrofuran, and 15.2 ml (0.11 mol) of triethylamine were added dropwise at 0° C., while stirring. After 30 minutes, 10.5 ml (0.11 mol) of ethyl chloroformate were added dropwise at 0° C., the mixture was stirred at this temperature for 1 hour and cooled to -10° C., and 12.1 g (0.1 mol, 12.5 ml) of 2-phenylethylamine in 30 ml of anhydrous tetrahydrofuran were added dropwise. After 1 hour at 0° C., the mixture was warmed to 20° C. and concentrated in vacuo and the solid residue was treated with water, filtered off with suction and recrystallized from ethanol to give 20.4 g of product, melting point 243° to 245° C.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].NC(N)=[S:22].[OH-].[Na+].Cl>C(O)C>[SH:22][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: O=C(O)CCCCCCCCCCCCCCCI
Reactant: NC(N)=S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCCCCCCCCCCCCCCS
Temperature: 25 °C
Yield: 70 %

Procedure:
A mixture of 16-iodohexadecanoic acid (6) (4.0 g, 10.4 mmol) and thiourea (0.88 g, 1.1 equiv.) in ethanol (100 mL) was refluxed overnight under N2 atmosphere. The solution was cooled to room temperature. Sodium hydroxide (1.0 g in 10 mL of water) wad added and the mixture was further heated for 2 hr. After cooling to room temperature 1N HCl was added and the product was extracted using CH2Cl2. The organic extract was dried and evaporated to give a white solid Yield: 2.1 g (69%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([N:15]3[CH:19]=[CH:18][N:17]=[C:16]3SC)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1>[Ni].CO>[N:15]1([N:12]2[CH2:11][CH2:10][N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH2:14][CH2:13]2)[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: COc1ccc(N2CCN(n3ccnc3SC)CC2)cc1
Agent: [Ni]
Solvent: CO
Product: COc1ccc(N2CCN(n3ccnc3)CC2)cc1
Yield: 77 %

Procedure:
A mixture of 5.5 parts of 1-(4-methoxyphenyl)-4-[2-(methylthio)-1H-imidazol-1-yl]piperazine, 8 parts of Raney-nickel catalyst and 80 parts of methanol is stirred and refluxed overnight. The Raney-nickel is filtered off and another 8 parts of Raney-nickel catalyst are added. The whole is further stirred and refluxed overnight. The reaction mixture is filtered and the filtrate is evaporated. The residue is crystallized from 1,1'-oxybisbutane. The product is filtered off and dried, yielding 3.6 parts (77%) of 1-(1H-imidazol-1-yl)-4-(4-methoxyphenyl)piperazine, mp. 158.6° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:23])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH3:22])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH2:24]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[CH2:25][CH2:26][CH3:27]>>[CH2:24]([N:28]1[CH2:33][CH2:32][N:31]([C:1](=[NH:2])[C:3]2[CH:4]=[C:5]([NH:9][C:10](=[O:23])[NH:11][C:12]3[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH3:22])(=[O:19])=[O:20])=[CH:14][CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[CH2:30][CH2:29]1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCN1CCNCC1
Reactant: CNS(=O)(=O)c1ccc(NC(=O)Nc2cccc(C#N)c2)cc1
Product: CCCCN1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)NC)cc3)c2)CC1
Yield: 1 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-methylbenzenesulfonamide following procedure C and using 2.2 equivalents of n-butylpiperazine as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: CO[C:3](=[O:34])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:12]=[N:13][C:14]([S:17]([CH2:20][CH3:21])(=[O:19])=[O:18])=[CH:15][CH:16]=2)[CH:7]=[C:6]([O:22][C@@H:23]([CH3:33])[CH2:24][O:25][Si](C(C)(C)C)(C)C)[CH:5]=1.[NH2:35][C:36]1[CH:40]=[CH:39][N:38]([CH3:41])[N:37]=1>>[CH2:20]([S:17]([C:14]1[N:13]=[CH:12][C:11]([O:10][C:8]2[CH:9]=[C:4]([CH:5]=[C:6]([O:22][CH:23]([CH3:33])[CH2:24][OH:25])[CH:7]=2)[C:3]([NH:35][C:36]2[CH:40]=[CH:39][N:38]([CH3:41])[N:37]=2)=[O:34])=[CH:16][CH:15]=1)(=[O:18])=[O:19])[CH3:21]
Reactant: Cn1ccc(N)n1
Reactant: CCS(=O)(=O)c1ccc(Oc2cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)cc(C(=O)OC)c2)cn1
Product: CCS(=O)(=O)c1ccc(Oc2cc(OC(C)CO)cc(C(=O)Nc3ccn(C)n3)c2)cn1

Procedure:
The compound of Production Example 117 was obtained as a colorless amorphous substance using the obtained 3-((1S)-2-(t-butyldimethylsiloxy)-1-methyl-ethoxy)-5-(6-ethanesulfonyl-pyridin-3-yloxy)-benzoic acid methyl ester and 3-amino-1-methylpyrazole, by the same method as in Production Example 2, a corresponding method, or a combination thereof with an ordinary method.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH2:11])=[O:10])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[CH2:12](OC(OCC)OCC)C>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[CH:12][NH:11][C:9](=[O:10])[C:3]=2[N:4]=1
Reactant: CCOC(OCC)OCC
Reactant: NC(=O)c1nc(Cl)ccc1N
Product: O=c1[nH]cnc2ccc(Cl)nc12
Temperature: 145 °C
Reaction time: 3 h

Procedure:
3-amino-6-chloro-pyridine-2-carboxylic acid amide (7.45 g, 43.41 mmol) is taken up in triethylorthoformate (150 mL) and stirred for 3 h at 145° C. After cooling the precipitate formed is filtered off, washed with Et2O, dried and 6-chloro-3H-pyrido[3,2-d]pyrimidin-4-one (HPLC-MS: tRet=0 min; MS (M+H)+=182) is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][C:6](=[O:22])[N:7]2[CH3:21].Br[C:24]1[CH:25]=[C:26]([CH2:30][OH:31])[CH:27]=[N:28][CH:29]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:31][CH2:30][C:26]1[CH:25]=[C:24]([C:11]2[C:3]([O:2][CH3:1])=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH3:21])[C:6](=[O:22])[CH2:5]3)[CH:29]=[N:28][CH:27]=1
Reactant: OCc1cncc(Br)c1
Reactant: COc1c(B2OC(C)(C)C(C)(C)O2)ccc2c1CC(=O)N2C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: COc1c(-c2cncc(CO)c2)ccc2c1CC(=O)N2C
Temperature: 120 °C

Procedure:
To 4-methoxy-1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one, prepared as described in Example 37a (80 mg, 0.264 mmol) was added (5-bromo-pyridin-3-yl)-methanol (CAS#37669-64-0, 55 mg, 0.29 mmol), 1,2-dimethoxyethane (3.0 mL), and 2 M aqueous sodium carbonate (0.330 mL, 066 mmol). The reaction mixture was degassed and placed under an argon atmosphere, at which time resin bound tetrakis(triphenylphosphine)palladium(0), specifically polystyrene triphenylphosphine palladium (0) [PS—PPh3-Pd(0) (Biotage), 0.11 mmol/g loading, (120 mg, 0.013 mmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 120° C. for 3 hours. The reaction mixture was then cooled to room temperature, diluted with dichloromethane and filtered through glass wool. The filtrate was further diluted with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was partially purified by silica gel flash chromatography (ethanol-dichloromethane, 0 to 10%). Further purification was accomplished via reverse phase HPLC (7 to 40% acetonitrile/water w/0.1% NH4OH) to furnish 5-(5-hydroxymethyl-pyridin-3-yl)-4-methoxy-1-methyl-1,3-dihydro-indol-2-one; HRMS: (ESI) m/z 285.1240 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 3.24 (s, 3H), 3.75 (s, 3H), 3.78 (s, 2H), 4.71 (s, 2H), 6.84 (d, J=81 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 7.94 (d, J=2.0 Hz, 1H), 8.45 (d, J=1.8 Hz, 1H), 8.55 (d, J=2.0 Hz, 1H)