Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:39][C:40]1[CH:48]=[C:47]([Cl:49])[CH:46]=[CH:45][C:41]=1[C:42](Cl)=[O:43]>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:18])([F:19])[F:17])[CH2:11][CH2:10][N:9]1[C:42](=[O:43])[C:41]1[CH:45]=[CH:46][C:47]([Cl:49])=[CH:48][C:40]=1[Cl:39])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Cl)cc1Cl)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Yield: 85.4 %

Procedure:
200 mg (0.468 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted in analogy to Example 35a with 91 μl (0.655 mmol) of triethylamine and 78 μl (0.561 mmol) of 2,4-dichlorobenzoyl chloride to give the title compound (240 mg, 86%). TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.57, FD-MS: M+ =599, 601.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([F:16])[CH:9]=2)=[CH:6][CH:7]=1.[NH2:17][CH:18]1[CH2:23][CH2:22][N:21]([CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[CH2:20][CH2:19]1>>[CH2:25]([CH:24]([N:21]1[CH2:22][CH2:23][CH:18]([NH:17][C:2]2[N:3]=[N:4][C:5]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([F:16])[CH:9]=3)=[CH:6][CH:7]=2)[CH2:19][CH2:20]1)[CH2:27][CH3:28])[CH3:26]
Reactant: CCC(CC)N1CCC(N)CC1
Reactant: COc1ccc(-c2ccc(Cl)nn2)cc1F
Product: CCC(CC)N1CCC(Nc2ccc(-c3ccc(OC)c(F)c3)nn2)CC1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 1, starting from 3-chloro-6-(4-methoxy-3-fluorophenyl)pyridazine and 4-amino-1-(1-ethylpropyl)piperidine.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[CH:8]=[C:9]([Cl:16])[CH:10]=[C:11]2[C:15]=1[NH:14][CH:13]=[CH:12]2.CN([CH:20]=[O:21])C>>[Br:6][C:7]1[CH:8]=[C:9]([Cl:16])[CH:10]=[C:11]2[C:15]=1[NH:14][CH:13]=[C:12]2[CH:20]=[O:21]
Reactant: CN(C)C=O
Reactant: Clc1cc(Br)c2[nH]ccc2c1
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2c(Br)cc(Cl)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
Phosphorus oxychloride (3.11 mL, 33.4 mmol) was added dropwise to a 0° C sample of DMF (30 mL). The reaction was stirred 30 min at 0° C., then 7-bromo-5-chloro-1H-indole (7.0 g, 30.4 mmol) in DMF (5 mL)was added and the reaction was warmed to ambient temperature and stirred 20 hours. Ice water (300 mL) was added, and the resulting thick solid was filtered. The product was detected by TLC in both filtrate and cake. Cake and filtrate were combined, and sodium hydroxide (10N) was added until most solids disappeared, then the mixture was extracted with ethyl acetate (4×100 mL). The organic layers were dried with MgSO4 and evaporated to a solid that weighed 10.5 g. The residue was dissolved in 400 mL boiling ethyl acetate, the insoluble material was filtered away and the filtrate was evaporated. 7-bromo-5-chloro-1H-indole-3-carbaldehyde (6.45 g, 24.95 mmol, 82% yield) was obtained as an off-white solid. 1H-NMR (CDCl3, 400 MHz) δ 9.99 (s, 1H), 8.35 (s, 1H), 8.32 (s, 1H), 7.92 (s, 1H), 7.47 (d, J=2.0 Hz, 1H). LC/MS (HPLC method 4): tR=2.87 min, 257.91(MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[O:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[C:12]([CH:13]=O)=[CH:11][N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1.[CH2:38]([P:47](=[O:54])([O:51][CH2:52][CH3:53])[O:48][CH2:49][CH3:50])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[O:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[C:12](/[CH:13]=[CH:38]/[P:47](=[O:54])([O:48][CH2:49][CH3:50])[O:51][CH2:52][CH3:53])=[CH:11][N:10]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:9]=1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2cccnc2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3cccnc3)oc2C)c(OC)c1)OCC
Reaction time: 15 h
Yield: 75.9 %

Procedure:
To a mixture of 3-({3-methoxy-4-[(5-methyl-2-pyridin-3-yl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (0.55 g), tetraethyl methylenediphosphonate (0.35 g) and N,N-dimethylformamide (30 mL) was added sodium hydride (60% in oil, 0.050 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl (E)-2-[3-({3-methoxy-4-[(5-methyl-2-pyridin-3-yl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazol-4-yl]ethenylphosphonate as colorless crystals (0.53 g, yield 77%) from a fraction eluted with ethyl acetate-hexane (19:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 128-129° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:28]([O:30]C)=O)=[N:11][N:12]2[CH2:17][CH:16]([CH3:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:14](=[O:27])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][NH2:33]>>[CH2:1]([O:8][C:9]1[C:10]([C:28]([NH:33][CH3:32])=[O:30])=[N:11][N:12]2[CH2:17][CH:16]([CH3:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:14](=[O:27])[C:13]=12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(Cc1ccc(F)cc1)C(C)C2
Reactant: CN
Product: CNC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(Cc1ccc(F)cc1)C(C)C2

Procedure:
The title compound was prepared from methyl 3-benzyloxy-5-(4-fluorobenzyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate using a procedure similar to that described in Example 5, Step 3, except that methylamine (2M in MeOH) was used in place of 4-fluorobenzylamine, and the reaction was heated to reflux overnight. The solvent was removed in vacuo, and the material was used without purification. ES MS (M+1)=423.
Reaction SMILES: [H][H].[BrH:3].[NH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:16])[C:11]=2[OH:15])[C:6]1=[O:17]>O.[Pt](=O)=O>[BrH:3].[NH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:16])[C:11]=2[OH:15])[CH:6]1[OH:17]
Reactant: [H][H]
Reactant: NC1CCc2c(ccc(O)c2O)C1=O
Agent: O=[Pt]=O
Agent: Br
Solvent: O
Product: NC1CCc2c(ccc(O)c2O)C1O

Procedure:
In 5 volume parts of water is dissolved 0.200 part of 3,4-dihydro-2-amino-5,6-dihydroxy-1(2H)-naphthalenone hydrobromide and, using 0.050 part of platinum dioxide, the catalytic reduction is carried out in a current of hydrogen gas until a substantially stoichiometric amount of hydrogen gas is absorbed. The catalyst in the reaction mixture is filtered off and to the filtrate is added a mixture of ethyl ether, methanol and water. The procedure gives white prisms of 2-amino-1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide. Melting point: 190° to 200° C.(decomp.)
Reaction SMILES: [OH:1][P:2]([O:4][P:5]([OH:7])[OH:6])[OH:3].Cl[C:9](Cl)([C:11]([CH2:16][OH:17])([CH2:14][OH:15])[CH2:12][OH:13])[OH:10].C1(C)C=CC=CC=1>C(N(CC)CC)C>[OH:1][P:2]([O:4][P:5]([OH:7])[OH:6])[OH:3].[OH:10][CH2:9][C:11]([CH2:16][OH:17])([CH2:14][OH:15])[CH2:12][OH:13]
Reactant: OCC(CO)(CO)C(O)(Cl)Cl
Agent: OP(O)OP(O)O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: OCC(CO)(CO)CO

Procedure:
Dichloro pentaerythritol diphosphite (1 mol) was reacted with 2.05 mol of ABITOL in toluene using 2.1 mol of triethyl amine as an acid acceptor. The very viscous liquid product, bis abietyl pentaerythritol diphosphite, was obtained after filtering the triethylamine hydrochloride and stripping the toluene.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15](O)=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[SH:32].[OH-].[NH4+]>O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[S:32][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[N:25]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1S
Reactant: O=C(O)CC1CCN(Cc2ccccc2)CC1
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: c1ccc(CN2CCC(Cc3nc4ccccc4s3)CC2)cc1
Temperature: 120 °C
Reaction time: 18 h
Yield: 86.3 %

Procedure:
A mixture of 1.2 g of (1-benzyl-piperidin-4-yl)acetic acid.TFA, (from EXAMPLE 163, Step C) and 433 mg of 2-aminothiophenol was treated with 10 mL of polyphosphoric acid. After stirring at 120° C. for 18 h, the syrup was poured onto ice and H2O, maintaining the temperature of the aqueous mixture below 10° C. The resulting dark brown solution was made basic with ammonium hydroxide. The aqueous mixture was extracted with EtOAc (3×). The combined organic extracts were washed with sat'd NaCl and dried over MgSO4. Concentration afforded 962 mg of the title compound as a oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([CH2:14][O:15][C:16]2[C:24]3[N:23]=[C:22]([O:25][CH3:26])[N:21]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[C:20]=3[CH:19]=[CH:18][CH:17]=2)[C:8]=1[Cl:34])[CH3:6])=[O:4].[C:35]([NH:38][C:39]1[N:44]=[CH:43][C:42]([CH2:45][CH2:46][C:47](O)=[O:48])=[CH:41][CH:40]=1)(=[O:37])[CH3:36].ClC1C(COC2C3N=C(OC)N(CC4C=CC=CN=4)C=3C=CC=2)=C(Cl)C=CC=1N(C)C(=O)CNC(=O)CCC1C=CC(C(NCCOC)=O)=CC=1>>[C:35]([NH:38][C:39]1[N:44]=[CH:43][C:42]([CH2:45][CH2:46][C:47]([NH:1][CH2:2][C:3]([N:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([CH2:14][O:15][C:16]3[C:24]4[N:23]=[C:22]([O:25][CH3:26])[N:21]([CH2:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=5)[C:20]=4[CH:19]=[CH:18][CH:17]=3)[C:8]=2[Cl:34])[CH3:6])=[O:4])=[O:48])=[CH:41][CH:40]=1)(=[O:37])[CH3:36]
Reactant: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccc2n1Cc1ccccn1
Reactant: CC(=O)Nc1ccc(CCC(=O)O)cn1
Agent: COCCNC(=O)c1ccc(CCC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c3nc(OC)n4Cc3ccccn3)c2Cl)cc1
Product: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)CCc4ccc(NC(C)=O)nc4)c3Cl)cccc2n1Cc1ccccn1

Procedure:
Compound 32 is prepared 2-amino-N-(2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)-N-methylacetamide and 3-(6-acetamidopyridin-3-yl)propanoic acid as described for compound 1. MS (APCI) 690 (M+), 1H NMR 2.18 (s, 3H), 2.49 (t, 2H, J=7.4 Hz), 2.89 (t, 2H, J=7.4 Hz), 3.32 (s, 3H), 3.4-3.55 (m, 1H), 3.7-3.82 (m, 1H), 4.21 (s, 3H), 5.28 (s, 2H), 5.66 (s, 2H), 6.45-6.52 (m, 1H), 6.81 (t, 2H, J=8.2 Hz), 6.92 (d, 1H, J=7.86 Hz), 7.01-7.06 (m, 1H), 7.17-7.19 (m 1H), 7.4-7.6 (m, 4H), 7.9-7.95 (m, 1H), 8.06-8.09 (m, 2H), 8.55-8.59 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:17]2[C:25](O)=[CH:24][C:20]3[O:21][CH2:22][O:23][C:19]=3[CH:18]=2)([CH2:15][OH:16])[C:7]1=[O:27])[CH3:2].C1(CCN2C3C(=CC=CC=3)C(C3C(O)=CC4OCOC=4C=3)(CO)C2=O)CC1>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([C:17]3=[CH:18][C:19]4[O:23][CH2:22][O:21][C:20]=4[CH:24]=[C:25]3[O:16][CH2:15]2)[C:7]1=[O:27])[CH3:2]
Reactant: CCOC(=O)CN1C(=O)C(CO)(c2cc3c(cc2O)OCO3)c2ccccc21
Agent: O=C1N(CCC2CC2)c2ccccc2C1(CO)c1cc2c(cc1O)OCO2
Product: CCOC(=O)CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Yield: 90 %

Procedure:
Following the procedure as described in EXAMPLE 1, and making non-critical variations using ethyl[3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate to replace 1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained as a white powder in 90% yield: 1H NMR (300 MHz, DMSO-d6) δ 7.31-7.26 (m, 1H), 7.17-7.00 (m, 3H), 6.67 (s, 1H), 6.18 (s, 1H), 5.90-5.89 (m, 2H), 4.76-4.66 (m, 2H), 4.59 (s, 2H), 4.13 (q, 2H), 1.17 (t, 3H); 13C NMR (75 MHz, DMSO-d6) δ 177.3, 168.3, 155.6, 148.8, 142.4, 142.1, 132.0, 129.3, 124.1, 123.7, 120.4, 109.6, 103.3, 101.9, 93.8, 79.8, 61.8, 57.8, 41.8, 14.5; MS (ES+) m/z 390.2 (M+23).
Reaction SMILES: OC(C(F)(F)F)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][CH:17]=[C:18]([CH2:20][N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:19]=2)=[CH:11][CH:10]=1.[F:27][C:28]([F:44])([F:43])[C:29]1[O:33][N:32]=[C:31]([C:34]2[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=2)[C:37](O)=[O:38])[N:30]=1>>[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][CH:17]=[C:18]([CH2:20][N:21]3[CH2:22][CH2:23][N:24]([C:37]([C:36]4[CH:40]=[CH:41][CH:42]=[C:34]([C:31]5[N:30]=[C:29]([C:28]([F:43])([F:27])[F:44])[O:33][N:32]=5)[CH:35]=4)=[O:38])[CH2:25][CH2:26]3)[N:19]=2)=[CH:11][CH:10]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: Fc1ccc(-c2nc(CN3CCNCC3)co2)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cccc(-c2noc(C(F)(F)F)n2)c1)N1CCN(Cc2coc(-c3ccc(F)cc3)n2)CC1
Yield: 14 %

Procedure:
This compound was synthesized from 2-(4-fluorophenyl)-4-(piperazin-1-ylmethyl)oxazole TFA salt and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (34 mg, yield 14%). 1H NMR (400 MHz, CDCl3) δ 8.19-8.17 (m, 2H), 8.06-8.03 (dd, J=8.7 Hz, 5.1 Hz, 2H), 7.63-7.57 (m, 3H), 7.17-7.12 (t, J=8.7 Hz, 2H), 3.87 (m, 2H), 3.59 (s, 2H), 3.50 (m, 2H), 2.68 (m, 2H), 2.54 (m, 2H). MS (ESI) m/z: Calculated for C24H19F4N6O3: 501.14. found: 502.1 (M+H)+
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C=O)C>[OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:9])[CH2:4][CH2:3]1
Reactant: O=C(O)C1CCC(O)CC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)C1CCC(O)CC1
Reaction time: 16 h

Procedure:
To a solution of 4-hydroxycyclohexane carboxylic acid (19.95 g, 138.4 mmol) in 100 mL of degassed DMF was added potassium carbonate (21.0 g, 152.2 mmol) and benzyl bromide (15.61 mL, 131.4 mmol). After 16 hours at room temperature, the reaction mixture was poured into 500 mL of water and extracted 3 times with EtOAc. The combined organic layers were washed with water and brine prior to drying over sodium sulfate. Filtration and solvent removal provided benzyl 4-hydroxycyclohexane carboxylate as a clear oil.
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.C[O:20][C:21](=[O:25])[CH2:22][CH2:23][NH2:24].[OH-].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:24][CH2:23][CH2:22][C:21]([OH:25])=[O:20])=[CH:13][CH:12]=1
Reactant: COC(=O)CCN
Reactant: O=Cc1ccc(Oc2nc3ncccc3s2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCNCc1ccc(Oc2nc3ncccc3s2)cc1
Reaction time: 4 h
Yield: 31.1 %

Procedure:
To a mixture of 4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)-benzaldehyde (100 mg, 0.39 mmol) and β-alanine methyl ester (54 mg, 0.39 mmol, 1 equiv.) was added methanol (2 mL) followed by 1N NaOH (430 μL). The reaction was allowed to stir at rt for 1 h before the addition of sodium triacetoxyborohydride (95 mg, 0.39 mmol, 1 equiv.). Stirring was allowed to continue for 4 h before the reaction was concentrated and purified using preparative reversed phase HPLC to afford the product as white powder (40 mg, 31%). 1H NMR (400 MHz, CD3OD): 8.49 (d, J=4.8, 1H), 8.33 (d, J=7.9, 1H), 8.27 (s, 1H), 7.65 (d, J=8.2, 2H), 7.55 (d, J=8.2, 2H), 7.38-7.33 (m, 1H), 4.28 (s, 2H), 3.24 (t, J=6.4, 2H), 2.58 (t, J=6.4, 2H). MS (ESI): Mass calcd for C16H16N3O3S, 329.08; m/z found, 330.1 [M+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]([NH2:26])=[N:9][C:10]3[C:15]([CH:16]=2)=[CH:14][C:13](B2OC(C)(C)C(C)(C)O2)=[CH:12][CH:11]=3)[CH2:3][CH2:2]1.[Cl:27][C:28]1[C:29]([CH3:41])=[N:30][N:31]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[C:34]=2I)[CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+].O>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>[Cl:27][C:28]1[C:29]([CH3:41])=[N:30][N:31]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[C:34]=2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([NH2:26])[C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[CH:16]3)[CH:32]=1
Reactant: CC1(C)OB(c2ccc3nc(N)c(N4CCOCC4)cc3c2)OC1(C)C
Reactant: Cc1cccc(-n2cc(Cl)c(C)n2)c1I
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: C1COCCO1
Solvent: O
Product: Cc1cccc(-n2cc(Cl)c(C)n2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Temperature: 140 °C

Procedure:
A glass microwave reaction vessel was charged with 3-morpholino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-amine (0.150 g, 0.422 mmol, prepared as in Example 2, Step 1-2) and 4-chloro-1-(2-iodo-3-methylphenyl)-3-methyl-1H-pyrazole (0.281 g, 0.845 mmol) in dioxane (3 mL) and 2 M aqueous sodium carbonate (1.0 mL, 2.0 mmol). The vessel was capped with a septum and the solution was degassed by bubbling nitrogen gas through the solution for 10 min. Next, Pd (PPh3)4 (0.049 g, 0.042 mmol) was added and the vessel was sealed. The reaction mixture was stirred and heated in a microwave reactor at 140° C. for 15 min. The reaction was poured into water and the mixture was extracted with EtOAc. The combined organic extracts were washed with water, saturated sodium chloride, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give the crude material. The crude material was purified by reverse-phase preparative HPLC with 0.1% TFA in CH3CN/H2O, gradient 5-70% over 20 min to provide 6-(2-(4-chloro-3-methyl-1H-pyrazol-1-yl)-6-methylphenyl)-3-morpholinoquinolin-2-amine as a white solid. The purified compound was portioned between DCM and saturated sodium bicarbonate. The layers were separated and the aqueous layer was extracted with DCM. The combined organic extracts were washed with saturated sodium chloride and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give 6-(2-(4-chloro-3-methyl-1H-pyrazol-1-yl)-6-methylphenyl)-3-morpholinoquinolin-2-amine as a white solid. MS (ESI, pos. ion) m/z: 434 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][C:14]#[N:15])=[CH:5][CH:4]=1.N.[H][H]>C(O)C.[Ni]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][CH2:14][NH2:15])=[CH:5][CH:4]=1
Reactant: COc1ccc2cccc(CC#N)c2c1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CCO
Product: COc1ccc2cccc(CCN)c2c1

Procedure:
A solution of (7-methoxynaphth-1-yl)acetonitrile in ethanol saturated with ammonia is placed in an autoclave. Raney nickel and hydrogen at 300 atmospheres are added.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:7][NH:8]C(=O)OC(C)(C)C)[O:5][CH:6]=1.[F:16][C:17]([F:22])([F:21])[C:18]([OH:20])=[O:19]>ClCCl>[F:16][C:17]([F:22])([F:21])[C:18]([OH:20])=[O:19].[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][NH2:8])[O:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NCc1cc(Br)co1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1cc(Br)co1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Under a nitrogen atmosphere, a solution of tert-butyl [(4-bromo-2-furyl)methyl]carbamate (153 g, 55.4 mmol) in dichloromethane (86 mL) at 0° C. was treated with trifluoroacetic acid (43 mL) over 15 minutes. The reaction mixture warmed to room temperature over 30 minutes. The solvent was removed in vacuo and chased with toluene (3×50 mL). The product was lyophilized for 18 hours to give the desired product as a brown solid (13.0 g, 81%). LCMS calculated for C5H4BrO (M−NH2)+: m/z=158.9, 160.9. 1H NMR (400 MHz, DMSO-d6): δ 8.34 (br s, 3H), 8.01 (s, 1H), 6.70 (s, 1H), 4.08 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][CH2:8][CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([C:22](=[O:27])NCOC)([CH3:21])[CH3:20])[CH:17]=2)[NH:12][C:11]=1[C:28]1[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]([CH3:35])[CH:29]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:1]([O:5][C:6](=[O:36])[NH:7][CH2:8][CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([CH3:20])([CH3:21])[CH:22]=[O:27])[CH:17]=2)[NH:12][C:11]=1[C:28]1[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]([CH3:35])[CH:29]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCNC(=O)C(C)(C)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCNC(=O)OC(C)(C)C)c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C=O)cc3c2CCNC(=O)OC(C)(C)C)c1
Reaction time: 1 h
Yield: 97.1 %

Procedure:
To a solution of (2-{2-(3,5-dimethylphenyl)-5-[1-(methoxymethylcarbamoyl)-1-methyl-ethyl]-1H-indol-3-yl}ethyl)carbamic acid tert-butyl ester (296 mg in 5 mL dry tetrahydrofuran) at 0° C. was added 1.8 mL of a 1M lithium aluminum hydride solution in tetrahydrofuran and the mixture stirred at low temperature. After 1 hour, the reaction was quenched by the careful addition of 0.3M aqueous sodium bisulfate solution. The resulting mixture was extracted with ethyl acetate and the organic portion washed successively with 0.3M aqueous sodium bisulfate, water and brine. This was then dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography on silica gel (hexane:ethyl acetate, 85:15) to give the title compound (253 mg).
Reaction SMILES: Cl[C:2]1[N:22]=[C:5]2[C:6]([C:10]3[C:11]([O:20][CH3:21])=[N:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([C:36]2[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([C:36]2[CH:41]=[CH:40][C:39]([NH:42][C:2]3[N:22]=[C:5]4[C:6]([C:10]5[C:11]([O:20][CH3:21])=[N:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=5)=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)=[CH:38][CH:37]=2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: COc1ncc(C(F)(F)F)cc1-c1cccn2nc(Cl)nc12
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: COc1ncc(C(F)(F)F)cc1-c1cccn2nc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)nc12

Procedure:
[4-{4-[8-(2-Methoxy-5-trifluoromethyl-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-(2-methoxy-5-trifluoromethyl-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine and 4-(4-amino-phenyl)-piperidine-1-carboxylic acid tert-butyl ester, with 2,2′-bis-dicyclohexylphosphanyl-biphenyl as the ligand in a manner analogous to Example 2d (0.233 g, 41%). MP=142-144° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.75 (s, 1H), 8.80 (d, 1H), 8.65 (s, 1H), 8.55 (s, 1H), 7.85 (d, 1H), 7.55 (d, 2H), 7.02 (m, 3H), 4.05 (m, 2H), 3.90 (s, 3H), 2.6-2.8 (m, 3H), 1.65 (m, 2H), 1.40 (m, 11H). MS=569 (MH)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[N+](=[CH2:14])=[N-]>C(OCC)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([O:7][CH3:14])=[O:6]
Reactant: C=[N+]=[N-]
Reactant: Cc1ccc(C(=O)O)cc1O
Solvent: CCOCC
Product: COC(=O)c1ccc(C)c(O)c1
Reaction time: 24 h

Procedure:
A solution of 3-hydroxy-4-methylbenzoic acid (26.1 g, 0.17 mol) in 200 mL of diethylether is treated with a solution of diazomethane in ether until a persistent yellow color develops. The resulting solution is stirred for 24 hours. The resulting solution is concentrated and the residue is crystallized from CH2Cl2. A white solid which is methyl 3-hydroxy-4-methylbenzoate is obtained (26.5 g, 93%).