Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[CH:41]=[C:40]([C:42]([NH:44][CH2:45][C:46]([OH:48])=O)=[O:43])[N:39]=[N:38]2)[CH:32]=1.NC1C=NC=CC=1.Cl.[NH:57]1[CH2:62][CH2:61][CH:60]([O:63][C:64]2[CH:65]=[C:66]([CH:69]=[CH:70][CH:71]=2)[C:67]#[N:68])[CH2:59][CH2:58]1>CN(C=O)C.O>[C:67]([C:66]1[CH:65]=[C:64]([CH:71]=[CH:70][CH:69]=1)[O:63][CH:60]1[CH2:61][CH2:62][N:57]([C:46](=[O:48])[CH2:45][NH:44][C:42]([C:40]2[N:39]=[N:38][N:37]([C:33]3[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=3)[CH:41]=2)=[O:43])[CH2:58][CH2:59]1)#[N:68]
Reactant: O=C(O)CNC(=O)c1cn(-c2cccnc2)nn1
Reactant: N#Cc1cccc(OC2CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1cccnc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cccc(OC2CCN(C(=O)CNC(=O)c3cn(-c4cccnc4)nn3)CC2)c1
Reaction time: 0.03 h
Yield: 11.5 %

Procedure:
DIPEA (156.8 mg, 1.2 mmol) followed by HOBt (45 mg, 0.33 mmol) and EDCI (116 mg, 0.6 mmol) were added to a stirred solution of [(1-pyridin-3-yl-1H-[1,2,3]triazole-4-carbonyl)-amino]-acetic acid (prepared by the method used for the synthesis of Intermediate 64, starting from 3-aminopyridine, and subsequently, application of Step 3 of the General Scheme) (75 mg, 0.3 mmol) in DMF (3 mL). After 2 minutes of stirring, 3-(piperidin-4-yloxy)-benzonitrile hydrochloride (prepared by the method used for the synthesis of Intermediate 15) (72.4 mg, 0.3 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was added and formed precipitate was collected. Purification by preparative HPLC afforded 15 mg (11.5% Yield) of 1-pyridin-3-yl-1H-[1,2,3]triazole-4-carboxylic acid {2-[4-(3-cyano-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 432.19, 99.3%. 1H NMR (300 MHz, DMSO-d6): δ 9.5 (s, 1H), 9.22 (d, 1H), 8.8 (d, 1H), 8.58 (t, 1H), 8.44 (d, 1H), 7.7 (q, 1H), 7.58-7.44 (d, 2H), 7.44 (dd, 2H), 4.8 (m, 1H), 4.3 (d, 2H), 4.0 (bs, 1H), 3.8 (d, 1H), 2.5 (b, 2H), 2.1 (t, 2H), 1.7 (bd, 2H).
Reaction SMILES: CO[CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]2[CH:18]=[C:19]([CH2:23][S:24]([NH2:27])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[N:11]=1.ClC1N=CN=C(N[C:36]2[CH:37]=C(CS(N)(=O)=O)C=C[CH:41]=2)N=1.C1(C2CCN2)C=CC=CC=1>>[C:9]1([CH:4]2[CH2:3][CH2:6][N:5]2[C:10]2[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]3[CH:18]=[C:19]([CH2:23][S:24]([NH2:27])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=3)[N:11]=2)[CH:37]=[CH:36][CH:41]=[CH:7][CH:8]=1
Reactant: COCC1CCCCN1c1ncnc(Nc2cccc(CS(N)(=O)=O)c2)n1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Agent: c1ccc(C2CCN2)cc1
Product: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCC3c3ccccc3)n2)c1

Procedure:
B37 was prepared following the general procedure reported for B4 using A1 and rac-2-phenylazetidine and obtained as white crystals; yield: 120 mg (34%). 1H NMR (300 MHz, d6-DMSO, 300K) δ 2.05-2.20 (m, 1H), 2.69-2.90 (m, 1H), 3.88-4.29 (m, 4H), 5.42 (bs, 1H), 6.72-7.08 (m, 3H), 7.20-7.55 (m, 6H), 7.58-7.72 and 7.82-8.00 (2 m, 1H), 8.11 and 8.25 (2bs, 1H), 9.65 and 9.78 (2bs, 1H). MS (ES) C19H20N6O2S requires: 396. found: 397 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH2:15]C)[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:39])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[CH:33]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:14]([C:12]1[C:11]([C:17]([F:18])([F:19])[F:20])=[CH:10][C:9]2[NH:21][C:22](=[O:39])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[CH:33]=4)[CH:27]=3)=[N:7][C:8]=2[CH:13]=1)[CH3:15]
Reactant: CCCc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C)c3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(C)c3)c1)=N2

Procedure:
The title compound was prepared from (2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-propyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M203) (204 mg, 0.38 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (94 mg, 58%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24]#[N:25])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH:20]([CH3:22])[CH3:21])[C:17](O)=[O:18])[C:10](=[O:23])[CH:9]=2)[CH:7]=1.[NH2:26][C:27]1[CH:28]=[CH:29][C:30]2[N:34]=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[NH:32][C:31]=2[CH:40]=1.CC(C)N=C=NC(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24]#[N:25])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH:20]([CH3:21])[CH3:22])[C:17]([NH:26][C:27]3[CH:28]=[CH:29][C:30]4[N:34]=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[NH:32][C:31]=4[CH:40]=3)=[O:18])[C:10](=[O:23])[CH:9]=2)[CH:7]=1
Reactant: CCOC(=O)c1nc2ccc(N)cc2[nH]1
Reactant: COc1cn(C(C(=O)O)C(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc2ccc(NC(=O)C(C(C)C)n3cc(OC)c(-c4cc(Cl)ccc4C#N)cc3=O)cc2[nH]1

Procedure:
100 mg (277 μmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-methylbutanoic acid (racemate), 57 mg (277 μmol, 1.0 eq.) of ethyl 6-amino-1H-benzimidazole-2-carboxylate, 39.4 mg (277 μmol) of Oxima and 42.9 μl (277 μmol) of DIC in 5.4 ml of dimethylformamide were reacted according to General Method 5B. The crude product was purified by flash chromatography (silica gel 50, cyclohexane/ethyl acetate mixtures). Yield: 139 mg (91% of theory)
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].CN.[CH2:14]([N:16](CC)CC)C>C(Cl)Cl>[Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:16][CH3:14])=[O:7]
Reactant: O=C(Cl)c1cccc(CCl)c1
Reactant: CCN(CC)CC
Agent: CN
Solvent: ClCCl
Product: CNC(=O)c1cccc(CCl)c1
Temperature: 25 °C

Procedure:
A solution of 3-chloromethylbenzoyl chloride (7.4 g, Aldrich) in DCM (35 ml) was added dropwise at 0° C. over 30 minutes to a stirred mixture of 30% aqu. methylamine (4.5 ml) and triethylamine (3.6 g) in DCM (50 ml). When addition was complete, the mixture was allowed to warm to room temperature over 1 hour with stirring. Further methylamine (0.5 ml) was added and the mixture stirred for a further 10 minutes, then washed with water, 1N aqu. HCl, 1N aqu. NaOH and brine, dried over MgSO4 and evaporated in vacuo to give the desired product as a colourless oil which solidified to a white solid on standing.
Reaction SMILES: [C:1](OC(N1CCN(CC(C2C=CC(Cl)=CC=2)C2C=CC(Cl)=CC=2)CC1)=O)(C)(C)C.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]([C:45]2[CH:50]=[CH:49][C:48]([C:51]3[CH:52]=[N:53][NH:54][CH:55]=3)=[CH:47][CH:46]=2)[CH2:38][N:39]2[CH2:44][CH2:43]N[CH2:41][CH2:40]2)=[CH:33][CH:32]=1.C(N1CCNCC1)(OC(C)(C)C)=O>>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]([C:45]2[CH:50]=[CH:49][C:48]([C:51]3[CH:52]=[N:53][NH:54][CH:55]=3)=[CH:47][CH:46]=2)[CH2:38][N:39]2[CH2:40][CH2:41][CH2:1][CH2:43][CH2:44]2)=[CH:33][CH:32]=1
Reactant: Clc1ccc(C(CN2CCNCC2)c2ccc(-c3cn[nH]c3)cc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(c2ccc(Cl)cc2)c2ccc(Cl)cc2)CC1
Agent: CC(C)(C)OC(=O)N1CCNCC1
Product: Clc1ccc(C(CN2CCCCC2)c2ccc(-c3cn[nH]c3)cc2)cc1

Procedure:
By following the procedure described in Example 33A, 33B and 33D but substituting piperidine for N—BOC-piperazine, the title compound was obtained. LC/MS: (PS-A2) Rt 2.21 [M+H]+366.09. 1H NMR (Me-d3-OD) δ 1.44 (2H, m), 1.53 (4H, m), 2.39-2.57 (4H, m), 2.94-3.09 (2H, m), 4.26 (1H, t), 7.22-7.35 (6H, m), 7.50 (2H, d), 7.91 (2H, s).
Reaction SMILES: [Si:1]([N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][CH:10]=[CH2:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:19][O:20][SiH:21]([O:24][CH3:25])[O:22][CH3:23]>[Pt].C([Si](C)(C)O[Si](C=C)(C)C)=C.C1(C)C=CC=CC=1>[Si:1]([N:8]([CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:9][CH2:10][CH2:11][Si:21]([O:24][CH3:25])([O:22][CH3:23])[O:20][CH3:19])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CO[SiH](OC)OC
Reactant: C=CCN(Cc1ccccc1)[Si](C)(C)C(C)(C)C
Agent: [Pt]
Agent: C=C[Si](C)(C)O[Si](C)(C)C=C
Solvent: Cc1ccccc1
Product: CO[Si](CCCN(Cc1ccccc1)[Si](C)(C)C(C)(C)C)(OC)OC
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A flask equipped with a stirrer, reflux condenser, dropping funnel and thermometer was charged with 26.2 g (0.1 mol) of N-t-butyldimethylsilyl-N-benzyl-N-allylamine and 0.07 g of a toluene solution of platinum/1,3-divinyl-1,1,3,3-tetramethyldisiloxane complex (Pt concentration 3 wt %) and heated at 50° C. Once the internal temperature became steady, 12.2 g (0.1 mol) of trimethoxysilane was added dropwise over 1 hour. Stirring was continued at the temperature for a further 1 hour. The reaction solution was distilled, collecting 32.6 g of a fraction having a boiling point of 165-166° C./0.4 kPa.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([NH:12][CH2:13][C:14]3[O:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[N:7]=1.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>ClC1N=C(N2CCS(=O)CC2)C2N=CN=C(Cl)C=2N=1>[CH2:13]([NH:12][C:8]1[C:6]2[N:7]=[C:2]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[N:3]=[C:4]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:5]=2[N:11]=[CH:10][N:9]=1)[C:14]1[O:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S1CCN(c2nc(Cl)nc3c(NCc4ccco4)ncnc23)CC1
Reactant: C1CNCCN1
Agent: O=S1CCN(c2nc(Cl)nc3c(Cl)ncnc23)CC1
Product: O=S1CCN(c2nc(N3CCNCC3)nc3c(NCc4ccco4)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 118 from 2-chloro-8-furfurylamino-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 203°-205° C.) and piperazine in dioxane at 80° C.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH2:15]([O:17][C:18](=[O:29])[CH2:19][NH:20][C:21](=O)[CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH3:16]>C(#N)C.[Cl-].[Na+].O>[CH2:15]([O:17][C:18]1[O:29][C:21]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[N:20][CH:19]=1)[CH3:16]
Reactant: CCOC(=O)CNC(=O)CCC(=O)OC
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCOc1cnc(CCC(=O)OC)o1
Temperature: 60 °C
Reaction time: 1 h
Yield: 38.5 %

Procedure:
To a suspension of diphosphorus pentoxide (70.0 g, 433 mmol) in acetonitrile (200 mL) was added a solution of methyl 4-[(2-ethoxy-2-oxoethyl)amino]-4-oxobutanoate (20.0 g, 92.1 mmol) in acetonitrile (50 mL) at room temperature under an argon gas atmosphere. The mixture was stirred at 60° C. for 1 hr and poured into saturated brine (1.5 L), and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→30/70) to give the title compound (7.06 g, yield 38%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:12][CH:13]([CH2:21][CH3:22])[C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15]>>[CH2:17]([O:16][C:14](=[O:15])[CH:13]([NH:12][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH2:21][CH3:22])[CH:18]([CH3:19])[CH3:20]
Reactant: CCC(N)C(=O)OCC(C)C
Reactant: O=C(O)Cc1ccc(Cl)cc1
Product: CCC(NC(=O)Cc1ccc(Cl)cc1)C(=O)OCC(C)C

Procedure:
Following General Procedure BI above and using 4-chlorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24](O)=[O:25])=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH:27]1([NH2:30])[CH2:29][CH2:28]1>>[CH:27]1([NH:30][C:24]([C:23]2[CH:22]=[N:21][N:18]3[CH:19]=[CH:20][C:15]([N:11]4[CH2:12][CH2:13][CH2:14][C@@H:10]4[C:4]4[C:5]([O:8][CH3:9])=[N:6][CH:7]=[C:2]([F:1])[CH:3]=4)=[N:16][C:17]=23)=[O:25])[CH2:29][CH2:28]1
Reactant: NC1CC1
Reactant: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Product: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)NC3CC3)c2n1
Yield: 57 %

Procedure:
Prepared by the method described in Example 1 using (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation K) and cyclopropanamine. The combined organic extracts were concentrated and the residue was purified by reverse phase HPLC (0-70% acetonitrile/water) to provide the title compound (19 mg, 57% yield). MS (apci) m/z=397.0 (M+H).
Reaction SMILES: Cl[C:2]1[O:3][C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][C:6](=[O:8])[CH:7]=1.[CH3:15][O:16][C:17]([C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)=[O:18].C(=O)([O-])[O-].[K+].[K+].N#N>O1CCOCC1.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>[CH3:15][O:16][C:17](=[O:18])[C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([C:2]2[O:3][C:4]([N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[CH:5][C:6](=[O:8])[CH:7]=2)[CH:24]=1
Reactant: O=c1cc(Cl)oc(N2CCOCC2)c1
Reactant: COC(=O)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)c1cccc(-c2cc(=O)cc(N3CCOCC3)o2)c1
Temperature: 90 °C
Yield: 46.5 %

Procedure:
2-Chloro-6-morpholin-4-yl-pyran-4-one (7.98 g, 37 mmol), (3-methoxycarbonylphenyl) boronic acid (8.01 g, 44.5 mmol), and ground potassium carbonate (11.23 g, 81.40 mmol) were suspended in dioxane (50 ml) and degassed (sonication for 5 min then saturated with N2). Pd(PPh3)4 (2.13 g, 1.85 mmol) was then added and the reaction mixture was then heated at 90° C. for 24 hrs under a vigorous stirring and a N2 atmosphere. The solvent were removed in vacuo and the residue was then suspended in water 50 ml) and extracted with ethyl acetate (100 ml). The organics were combined, washed with saturated brine and dried over sodium sulphate. The solvent was removed in vaccuo and the residue was purified by column chromatography (silica; dichloromethane:methanol; 9:1) to give the title compound as a white solid (5.42 g, 46%). m/z (LC-MS, ESP): 316 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([OH:11])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[C:13]=[O:14]>CN(C=O)C>[CH2:15]([NH:12][C:13]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([OH:11])=[N:7]1)=[O:14])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCN=C=O
Reactant: Oc1n[nH]c2cc(Cl)ccc12
Solvent: CN(C)C=O
Product: CCCCCCNC(=O)n1nc(O)c2ccc(Cl)cc21
Temperature: 50 °C
Reaction time: 1 h

Procedure:
100 mg (0.59 mmol) of 6-chloro-1H-indazol-3-ol were dissolved in 5 ml of DMF. Addition of 83 mg (0.65 mmol) of 1-isocyanatohexane was followed by stirring at room temperature for 1.5 h and at 50° C. for 1 h, concentration and purification by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 17 mg (7%), M+H+: 296.14, 6-chloro-3-oxo-3H-indazole-1,2-dicarboxylic acid bishexylamide and 12 mg (5%) of 6-chloro-1-hexylcarbamoyl-1H-indazol-3-yl hexylcarbamate. It was additionally possible to isolate 6-chloro-3-hydroxyindazole-1-carboxylic acid hexylamide as compound not according to the invention.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([OH:28])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][CH:17]=2)[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].[CH2:35]([CH:37]1[O:39][CH2:38]1)Br.O>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH2:35][CH:37]4[CH2:38][O:39]4)=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][CH:17]=2)[C:5]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:7]=1[CH3:8]
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccccc3)ccnc2cc1O
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccccc3)ccnc2cc1OCC1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
4-(5,6-Dimethyl-2-phenyl-pyridin-3-yloxy)-6-methoxy-quinolin-7-ol (compound 332) (150 mg) was dissolved in N,N-dimethylformamide (4 ml) to prepare a solution, potassium carbonate (167 mg) and epibromohydrin (0.1 ml) were added to the solution, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (140 mg, yield 82%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[C@@H:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:14][O:13][C:12]3=[O:22])=[N:7][C:6]=12.[F:23][C:24]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[CH:26][C:25]=1[C:39]1[N:43]=[CH:42][N:41]([CH2:44][O:45][CH2:46][CH2:47][Si:48]([CH3:51])([CH3:50])[CH3:49])[N:40]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CCOC(C)=O>[F:23][C:24]1[CH:29]=[C:28]([C:2]2[CH:3]=[N:4][N:5]3[CH:10]=[CH:9][C:8]([N:11]4[C@@H:15]([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)[CH2:14][O:13][C:12]4=[O:22])=[N:7][C:6]=23)[CH:27]=[CH:26][C:25]=1[C:39]1[N:43]=[CH:42][N:41]([CH2:44][O:45][CH2:46][CH2:47][Si:48]([CH3:51])([CH3:50])[CH3:49])[N:40]=1
Reactant: O=C1OC[C@H](c2ccccc2)N1c1ccn2ncc(Br)c2n1
Reactant: CC1(C)OB(c2ccc(-c3ncn(COCC[Si](C)(C)C)n3)c(F)c2)OC1(C)C
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1cnc(-c2ccc(-c3cnn4ccc(N5C(=O)OC[C@@H]5c5ccccc5)nc34)cc2F)n1
Temperature: 80 °C
Yield: 92.9 %

Procedure:
To a solution of (S)-3-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)-4-phenyloxazolidin-2-one (0.20 g, 0.56 mmol), 3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole (0.35 g, 0.84 mmol) and sodium carbonate (2.0 M, 1.4 ml, 2.8 mmol) in dioxanes (30 mL) was degassed with nitrogen for 30 minutes. Pd2 dba3 (70 mg) and XPHOS (70 mg) were added and the reaction was heated to 80° C. for 4 hours. The reaction was poured into EtOAc and the layers separated. The organic layer was washed with water, brine, dried over MgSO4 and concentrated in vacuo. The crude material was purified by normal phase chromatography, using 25% EtOAc/DCM as the eluent to give (S)-3-(3-(3-fluoro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-phenyloxazolidin-2-one as a solid (0.30 g, 0.52 mmol, 94% yield).
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH2:24][CH:25]2C[CH2:29][CH2:28][CH2:27][CH2:26]2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.CN(CC1CCCCC1)C1C=CC(OC)=CC=1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:25]1([CH2:24][N:15]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:3])=[O:31])=[CH:8][N:9]=2)[CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCCC2)c2ccc(OC)cc2)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: COc1ccc(N(C)CC2CCCCC2)cc1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Product: COc1ccc(N(CC2CCCC2)C(=O)Nc2ncc(SCC(=O)O)s2)cc1

Procedure:
The title compound was prepared via {2-[3-(cyclohexylmethyl)-3-(4-methoxy-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using (methyl-cyclohexylmethyl-(4-methoxy-phenyl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][C:8]2([CH3:11])[CH2:10][O:9]2)=[CH:4][CH:3]=1.CC(C)=[O:16].S(=O)(=O)(O)O>O>[Br:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][C:8]([CH3:11])([OH:16])[CH2:10][OH:9])=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: CC1(COc2ccc(Br)cc2)CO1
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(O)(CO)COc1ccc(Br)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
2-[(4-Bromophenoxy)methyl]-2-methyloxirane (72.9 g, 300 mmol), acetone (360 ml), water (180 ml), and sulfuric acid (7.3 ml) were mixed and stirred at 60° C. for 1 hour. After cooling, the mixture was concentrated under reduced pressure. Ethyl acetate (360 ml) and a saturated sodium bicarbonate solution were added to the concentrated residue, followed by extraction. Thereafter, the ethyl acetate layer was dried over anhydrous sodium sulfate. Ethyl acetate (102 ml) was added to the resulting crude product and heated to dissolve the crude product. The resulting solution was cooled to room temperature, and then hexane (204 ml) was added thereto, followed by stirring at a temperature 10° C. or less for 1 hour. The precipitated crystals were collected by filtration and then washed with a mixture of ethyl acetate (24 ml) and hexane (48 ml). The resulting crystals were dried under reduced pressure, obtaining 44.0 g of the objective product (yield: 56%).
Reaction SMILES: C([O:4][CH:5]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:6]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]=O)[CH:17]=2)[N:8]([CH3:24])[N:7]=1)(=O)C.[CH2:31]([NH2:37])[C:32]1[O:36][CH:35]=[CH:34][CH:33]=1.[BH4-].[Na+].O>C(O)C>[O:36]1[CH:35]=[CH:34][CH:33]=[C:32]1[CH2:31][NH:37][CH2:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[O:15][CH2:14][CH2:13][CH2:12][NH:11][C:9]1[N:8]([CH3:24])[N:7]=[C:6]([CH:5]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[OH:4])[N:10]=1
Reactant: NCc1ccco1
Reactant: CC(=O)OC(c1ccccc1)c1nc(NCCCOc2cccc(C=O)c2)n(C)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cn1nc(C(O)c2ccccc2)nc1NCCCOc1cccc(CNCc2ccco2)c1
Reaction time: 16 h

Procedure:
A solution of 5-[[3-(3-formylphenoxy)propyl]amino]-1-methyl-α-phenyl-1H-1,2,4-triazole-3-methanol acetate (ester) (1.0 g) and furfurylamine (5 ml) in ethanol (30 ml) was stirred at 21° for 1.5 h before a suspension of sodium borohydride (1.3 g) in ethanol (10 ml) was added and stirring was continued for a further 16 h at 21°. Water (20 ml) was added, the mixture concentrated to remove ethanol and the aqueous residue extracted with 4-methylpentan-2-one. The extract was dried and evaporated to give an oil. Excess furfurylamine was removed in vacuo and the residue was dissolved in 2N hydrochloric acid, the acidic layer washed with ethyl acetate, basified (pH 9) with sodium carbonate, and extracted with 4-methylpentan-2-one. The extract was washed with water, dried and evaporated to give a brown gum (0.65 g) which was chromatographed on silica (Merck No. 7729) using System B as eluent to give the title compound (0.5 g) as a pale orange gum.
Reaction SMILES: [NH3:1].CO.Cl[S:5]([C:8]1[N:9]=[CH:10][N:11]2[CH:15]=[CH:14][S:13][C:12]=12)(=[O:7])=[O:6]>C1COCC1>[S:5]([C:8]1[N:9]=[CH:10][N:11]2[CH:15]=[CH:14][S:13][C:12]=12)(=[O:7])(=[O:6])[NH2:1]
Reactant: N
Reactant: O=S(=O)(Cl)c1ncn2ccsc12
Solvent: CO
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ncn2ccsc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A 2 M ammonia/methanol solution, (4 ml) was added to a solution of 0.44 g of 7-chlorosulfonylimidazo[5,1-b]thiazole in 10 ml of THF. The mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (dichloromethane:methanol=10:1) to give 0.34 g of 7-sulfamoylimidazo[5,1-b]thiazole.