Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[O:8])=[CH:5][C:4]=1[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH:23]=1>C(Cl)Cl.O=[Mn]=O>[CH:2]([C:3]1[CH:21]=[CH:20][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:17])[F:18])[CH:11]=2)=[O:8])=[CH:5][C:4]=1[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH:23]=1)=[O:1]
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1ccc(CO)c(-c2ccnc(N3CCOCC3)c2)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1-c1ccnc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
MnO2 (8.0 equiv.) was added into a solution of 4-(hydroxymethyl)-3-(2-morpholinopyridin-4-yl)-N-(3-(trifluoromethyl)phenyl)benzamide (1.0 equiv.) in DCM (0.05 M). The suspension was stirred at rt for 1 hr. The mixture was filtered over celite and concentrated to yield 4-formyl-3-(2-morpholinopyridin-4-yl)-N-(3-(trifluoromethyl)phenyl)benzamide in 100% yield. LC/MS (m/z)=456.1 (MH+), Rt=0.76 min.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13](S(C)=O)[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:19][O:20][CH2:21][CH3:22])[C:7]2=[O:23])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:24]1([C:30]2[CH:31]=[CH:32][C:33]([NH2:36])=[N:34][CH:35]=2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>C1(C)C=CC=CC=1>[CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([NH:36][C:33]4[CH:32]=[CH:31][C:30]([N:24]5[CH2:25][CH2:26][O:27][CH2:28][CH2:29]5)=[CH:35][N:34]=4)[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:19][O:20][CH2:21][CH3:22])[C:7]2=[O:23])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccc(N2CCOCC2)cn1
Reactant: CCOCc1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Solvent: Cc1ccccc1
Product: CCOCc1cc2cnc(Nc3ccc(N4CCOCC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Yield: 17.6 %

Procedure:
8-Cyclopentyl-6-ethoxymethyl-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (0.60 g, 1.79 mmol) and 5-morpholin-4-yl-pyridin-2-ylamine (0.442 g, 2.47 mmol) were heated to reflux in toluene (6 mL) for 16 hours. The reaction mixture was cooled to room temperature and the precipitate that formed was filtered off and washed with toluene (2×4 mL) to give 8-cyclopentyl-6-ethoxymethyl-2-(5-morpholin-4-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (0.142 g, 17.6%). MS (APCl); M++1: Calc'd, 451.3. Found 451.3. Anal. Calc'd for C25H32N6O2: C, 63.98; H, 6.71; N, 18.65. Found; C, 64.03; H, 6.66; N, 18.49.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:18](=[O:29])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:31][C:32]([CH3:37])([CH3:36])[CH2:33][C:34]#[N:35]>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH2:31][C:32]([CH3:37])([CH3:36])[CH2:33][C:34]#[N:35])[CH:12]=[CH:11][C:10]=1[N:16]1[CH2:17][C:18](=[O:29])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[S:20]1(=[O:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Reactant: CC(C)(CI)CC#N
Product: CC(C)(CC#N)Cc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1

Procedure:
The title compound is prepared 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one and 4-iodo-3,3-dimethylbutyronitrile analogous to Example 292, step A.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=O)[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.Cl.[CH2:19]([O:22][NH2:23])[CH:20]=[CH2:21].N1C=CC=CC=1>C(O)C>[CH2:19]([O:22][N:23]=[C:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:9]([C:14]([OH:16])=[O:15])[CH2:10]1)[CH:20]=[CH2:21]
Reactant: C=CCON
Reactant: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CCO
Product: C=CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Yield: 94.3 %

Procedure:
A solution was made containing (2S)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid (5.0 g, 22 mmol) and O-allylhydroxylamine hydrochloride monohydrate (7.2 g, 65.5 mmol) in a 1:1 mixture of pyridine and ethanol (100 ml). The reaction was heated to reflux for 2.5 h before cooling and removal of solvent. The residue was dissolved in ethyl acetate and washed rapidly with 1.3N HCl (40 ml). The acidic layer was then extracted with ethyl acetate (3×20 ml) and the combined organic layers washed with brine before drying over magnesium sulfate, filtering and re-moval of solvent in vacuo. The desired product (5.9 g, 94%) was isolated as a pale yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3]1([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)[CH2:8][CH2:7][C:6](=[CH:9][C:10]([NH:12][CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)=[O:11])[CH2:5][CH2:4]1.[Cl:32][Si](C)(C)C>CC(CC)=O>[ClH:32].[CH3:31][N:2]([CH3:1])[C:3]1([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)[CH2:8][CH2:7][C:6](=[CH:9][C:10]([NH:12][CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)=[O:11])[CH2:5][CH2:4]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2cccc(F)c2)CCC(=CC(=O)NCCc2c[nH]c3ccccc23)CC1
Solvent: CCC(C)=O
Product: Cl
Reaction time: 1.5 h

Procedure:
2-[4-Dimethylamino-4-(3-fluorophenyl)cyclohexylidene]-N-[2-(1H-indol-3-yl)ethyl]acetamide (350 mg, 0.82 mmol) was dissolved in ethyl methyl ketone (25 ml), and chlorotrimethylsilane (0.164 ml, 1.3 mmol) was added. After 1.5 h it was possible to isolate the hydrochloride as a colourless solid in a yield of 89% (336 mg) with an m.p. of 196-200° C.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:13][CH2:12][C:11]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:14]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][CH:20]=[C:19]3[C:25]#[N:26])=[O:15])[CH2:10]1)=O)(C)(C)C>CO>[CH2:27]([C:11]1([C:14]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][CH:20]=[C:19]3[C:25]#[N:26])=[O:15])[CH2:12][CH2:13][NH:9][CH2:10]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccccc2)(C(=O)c2ccc3[nH]cc(C#N)c3c2)C1
Agent: Cl
Solvent: CO
Product: N#Cc1c[nH]c2ccc(C(=O)C3(Cc4ccccc4)CCNC3)cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 32.4 %

Procedure:
A solution of HCl (1.0 M in MeOH, 8 mL) was slowly added at 0° C. to a solution of 3-benzyl-3-(3-cyano-1H-indole-5-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (169 mg, 0.393 mmol) in MeOH (2 mL). The resulting pale yellow mixture was stirred at room temperature for 4 hours, then was quenched by addition of 0° C. aqueous NaOH (1.0 M). The resulting mixture was diluted with water and extracted with DCM. The combined organic extracts were dried over MgSO4, filtered and evaporated under reduced pressure. The crude was purified by flash chromatography (MeOH in DCM with 0.5% of NH4OH) to give 42 mg of 5-(3-Benzyl-pyrrolidine-3-carbonyl)-1H-indole-3-carbonitrile as a white foamy solid. This product was dissolved in DCM and a solution of HCl (1.0 M in Et20, 1 equivalent) was added. MeOH was added and the resulting mixture was evaporated under reduced pressure. The residue was triturated with Et2O and 32 mg of 5-(3-benzyl-pyrrolidine-3-carbonyl)-1H-indole-3-carbonitrile hydrochloride was collected as a white solid; MS=330 [M+H]+.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:6])=[CH:3]/[C:4]#[N:5].[C:7](OC1C(Cl)=CC(Cl)=CC=1Cl)(=[O:21])[CH2:8][C:9](OC1C(Cl)=CC(Cl)=CC=1Cl)=[O:10].CCOCC>COCCOCCOC>[OH:21][C:7]1[C:3]([C:4]#[N:5])=[C:2]([CH3:6])[NH:1][C:9](=[O:10])[CH:8]=1
Reactant: O=C(CC(=O)Oc1c(Cl)cc(Cl)cc1Cl)Oc1c(Cl)cc(Cl)cc1Cl
Reactant: C/C(N)=C\C#N
Solvent: COCCOCCOC
Solvent: CCOCC
Product: Cc1[nH]c(=O)cc(O)c1C#N
Temperature: 120 °C

Procedure:
A mixture of (E)-3-aminobut-2-enenitrile (9.7 g, 118 mmol) and bis(2,4,6-trichlorophenyl) malonate (58.4 g, 126 mmol) in diglyme (120 ml) was heated to 120° C. for 2.5 hr. The mixture was cooled to RT and poured into Et2O and filtered to collect the precipitate. The precipitate was washed with Et20 to obtain 4-hydroxy-2-methyl-6-oxo-1,6-dihydropyridine-3-carbonitrile. MS ESI calc'd. for C7H7N2O2 [M+H]+ 151. found 151.
Reaction SMILES: Cl.Cl.C[O:4][C:5](=[O:23])[C:6]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([NH:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[N:8][CH:7]=1.C(O)(=O)C.C(N(C(C)C)C(C)C)C.[CH2:37]([O:39][C:40]1[CH:41]=[C:42]([CH:45]=[CH:46][C:47]=1[OH:48])[CH:43]=O)[CH3:38].C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)C>[CH2:37]([O:39][C:40]1[CH:41]=[C:42]([CH:45]=[CH:46][C:47]=1[OH:48])[CH2:43][N:20]1[CH2:19][CH2:18][CH:17]([NH:16][C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[C:6]([C:5]([OH:4])=[O:23])=[CH:7][N:8]=2)[CH2:22][CH2:21]1)[CH3:38]
Reactant: COC(=O)c1cnc(NC2CCNCC2)cc1C(F)(F)F
Reactant: CCOc1cc(C=O)ccc1O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: CCO
Product: CCOc1cc(CN2CCC(Nc3cc(C(F)(F)F)c(C(=O)O)cn3)CC2)ccc1O
Temperature: 55 °C
Reaction time: 1 h
Yield: 7 %

Procedure:
To a solution of 6-(piperidin-4-ylamino)-4-trifluoromethyl-nicotinic acid methyl ester dihydrochloride (56.42 mg, 0.15 mmol, 1.0 equiv; intermediate B7) in ethanol (2 mL), acetic acid (72.1 mg, 1.2 mmol, 8.0 equiv) and N-ethyl diisopropylamine (77.6 mg, 0.6 mmol, 4.0 equiv) was added 3-ethoxy-4-hydroxy-benzaldehyde (30.0 mg, 0.18 mmol, 1.2 equiv; commercially available) and the mixture stirred at 55° C. After 1 h, sodium cyanoborohydride (47.1 mg, 0.75 mmol, 5.0 equiv), dissolved in ethanol (0.5 mL), was added and the mixture stirred at 55° C. over night. A solution of 10 M NaOH (0.5 mL) was added and the reaction mixture heated by microwave irradiation to 100° C. for 15 min. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 4.3 mg (7%) of the title compound. MS (ISP): 440.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][CH2:15][C:16](Cl)=[O:17])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH:19]([C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)/[C:27](=[N:31]/O)/[CH2:26][CH2:25][CH2:24]2)=[CH2:20]>ClC1C=CC=CC=1Cl.CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][CH2:15][C:16]3[O:17][C:26]4[CH2:25][CH2:24][C:23]5[C:28](=[CH:29][CH:30]=[C:21]([CH:19]=[CH2:20])[CH:22]=5)[C:27]=4[N:31]=3)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCC1(c2ccc(F)cc2)CCCCC1
Reactant: C=Cc1ccc2c(c1)CCC/C2=N\O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: C=Cc1ccc2c(c1)CCc1oc(CCC3(c4ccc(F)cc4)CCCCC3)nc1-2
Yield: 14.7 %

Procedure:
To a solution of 3-(1-(4-fluorophenyl)cyclohexyl)propanoyl chloride (Preparation 42B, 215 mg, 0.799 mmol) and 6-vinyl-3,4-dihydronaphthalen-1(2H)-one oxime (Intermediate 1, 224 mg, 1.199 mmol) in 1,2-dichlorobenzene (2 mL) was added 4-(dimethylamino)pyridine (6.15 mg, 0.050 mmol), and the mixture was microwaved at 180° C. for 10 mins. The mixture of was purified by Combiflash (silica gel, 24 g) eluting with 5:95 followed by 2:8 ethyl acetate-hexane to give the desired 2-(2-(1-(4-fluorophenyl)cyclohexyl)ethyl)-7-vinyl-4,5-dihydronaphtho[1,2-d]oxazole (47 mg, 14.6% yield) as an oil. LC/MS M+1=402.26.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=3[Cl:23])=[C:10]([C:24]([O:26]CC)=[O:25])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[K+].CCO>>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[C:17]([C:19]([F:21])([F:22])[F:20])[CH:16]=[CH:15][C:14]=3[Cl:23])=[C:10]([C:24]([OH:26])=[O:25])[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cc(-c2ccnc(N)n2)[nH]c1-c1cc(C(F)(F)F)ccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Nc1nccc(-c2cc(C(=O)O)c(-c3cc(C(F)(F)F)ccc3Cl)[nH]2)n1
Temperature: 5 °C
Yield: 94.6 %

Procedure:
Ethyl 5-(2-aminopyrimidin-4-yl)-2-[2-chloro-5-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate (1.0 g, 2.43 mmol) was treated with a 1.5 M solution of potassium hydroxide in 95% EtOH (32.4 mL, 20 eq) under reflux for 20 h. After cooling, the residue was concentrated, dissolved in water and washed with DCM. To the aqueous phase cooled to 5° C., a solution of HCl 2 N was added, under agitation. The resulting precipitate was collected by filtration to give the title compound (0.88 g, 95%).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.[O:26]1[C:31]2([CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]2)[CH2:30][NH:29][CH2:28][CH2:27]1.[S:44]1[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=2[N:46]=[C:45]1[C:53](O)=[O:54].C(N(CC)CC)C>CN(C=O)C>[S:44]1[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=2[N:46]=[C:45]1[C:53]([N:29]1[CH2:30][C:31]2([CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]2)[O:26][CH2:27][CH2:28]1)=[O:54]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCCO2
Reactant: O=C(O)c1nc2ccccc2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(C(=O)c1nc3ccccc3s1)CCO2
Reaction time: 16 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.45 g) was added to a solution of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (WuXi PharmaTech) (0.8 g), 1,3-benzothiazol-2-carboxylic acid (0.588 g) and triethylamine (1.51 mL) in DMF (15 mL) and the resulting mixture stirred for 16 h. The volume of DMF was reduced in vacuo and the reaction mixture was partitioned between water (30 mL) and ethyl acetate (30 mL). The organic layer was washed with water (30 mL) and brine (30 mL), dried over magnesium sulphate, filtered and evaporated in vacuo. Purification was by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give the subtitled compound as a yellow oil. Yield 0.83 g.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:34]=[CH:33][CH:32]=[CH:31][C:12]=3[C:13]=2[C:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:18][CH:17]=2)=[O:15])=[CH:5][CH:4]=1>CO>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:34]=[CH:33][CH:32]=[CH:31][C:12]=3[C:13]=2[CH:14]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][N:25]3[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]3)=[CH:20][CH:21]=2)[OH:15])=[CH:5][CH:4]=1
Reactant: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc(O)cc2)oc2ccccc12
Agent: Cl
Solvent: CO
Product: Oc1ccc(-c2oc3ccccc3c2C(O)c2ccc(OCCN3CCCCC3)cc2)cc1
Yield: 84.7 %

Procedure:
2.0 g (4.23 mmol) of [2-(4-hydroxyphenyl)-benzofuran-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl] methanone hydrochloride was reduced to the carbinol using the method described in Example 1. This yielded 1.59 g of the title compound as an amorphous powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:11]([O-])=O)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2>[Pd]>[Cl:1][C:2]1[C:3]([NH2:11])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2
Reactant: O=[N+]([O-])c1c(Cl)ccc2[nH]ncc12
Agent: [Pd]
Product: Nc1c(Cl)ccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution that consists of 5-chloro-4-nitro-1H-indazole (872 mg, 4.41 mmol) is mixed with 150 mg of palladium on carbon (10%) and stirred under hydrogen atmosphere at room temperature. After 45 minutes, the catalyst is suctioned off on one frit and washed with methanol. The filtrate is concentrated by evaporation, and the residue is taken up in 200 ml of ethyl acetate and heated. After renewed suctioning-off and concentration by evaporation of the filtrate, the purification on silica gel is carried out with hexane/ethyl acetate (100-33% hexane). 296 mg (40% of theory) of the product is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)=O.[Cl:24][CH2:25][C:26](=O)[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].S(=O)(=O)(O)O>C(O)(=O)C>[Cl:24][CH2:25][C:26]1[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:4]([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=2)[C:3]2[C:2](=[CH:19][C:18]([O:20][CH3:21])=[C:17]([O:22][CH3:23])[CH:16]=2)[N:1]=1
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)cc2N)cc1OC
Reactant: CCOC(=O)CC(=O)CCl
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(CCl)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 53 %

Procedure:
To a mixture of 2-amino-3',4,4',5-tetramethoxybenzophenone (6.6 g), ethyl 4-chloroacetoacetate (3.7 g) and acetic acid (60 ml) was added concentrated sulfuric acid (0.3 ml) and the mixture was stirred at 100° C. for 3 hours. The reaction mixture was then concentrated under reduced pressure and the residue was poured in water, made basic with 2N--NaOH, and extracted with chloroform. The chloroform layer was washed with water and dried (MgSO4) and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with chloroform-ethyl acetate (7:3, v/v) to give ethyl 2-chloromethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate (53%). Recrystallization from acetone-ether provided colorless prisms, m.p. 147°-148° C.
Reaction SMILES: [N:1]1([CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:7]#N)[CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1C=O.[C-]#N.[K+].Cl([O-])(=O)(=O)=O.[NH2+]1CCCC1.[H-].[Na+].CI.[BH4-].[Na+]>CS(C)=O.O1CCCC1.C(O)C.CCCCCC>[N:1]1([CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH3:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: N#CC(c1ccccn1)N1CCCC1
Agent: C1CC[NH2+]C1
Agent: O=Cc1ccccn1
Agent: [BH4-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCO
Product: CC(c1ccccn1)N1CCCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 87.9 %

Procedure:
To 25.0 g (0.134 mol) of 2-(1-pyrrolidinyl)-2-(2-pyridyl)acetonitrile, prepared by the reaction of pyridine-2-carboxaldehyde with potassium cyanide and pyrrolidinium perchlorate, in 75 ml dry dimethylsulfoxide and 200 ml tetrahydrofuran at -10° was added 7.75 g (0.161 mol) of 50% sodium hydride dispersion. After no further gas evolution was observed, a solution of 22.34 g (0.161 mol) of methyl iodide in 10 ml tetrahydrofuran was added over a 10 minute period. After addition had been completed, the reaction mixture was warmed to 40° for two minutes and cooled to 15°. The reaction mixture was filtered and the precipitate was washed with methylene chloride. The filtrates were combined, washed with saturated sodium chloride solution, and dried over sodium sulfate. Removal of the solvent gave 24.75 g (92%) of the crude product, 2-(1-pyrrolidinyl)-2-(2-pyridyl)propionitrile. The total crude product was dissolved in 500 ml 95% ethanol, cooled to 5° and treated with 9.3 g (0.245 mol) sodium borohydride. The reaction mixture was stirred at room temperature for 20 hours and then filtered. Removal of the solvent at reduced pressure gave a tan oil which was dissolved in hexane and dried over sodium sulfate. The hexane solution was then filtered and concentrated. The crude product was distilled (78°-80°/0.2 mm Hg) to give 20.77 g (88%) of 1-(1-pyrrolidinyl)-1-(2-pyridyl)ethane.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[N:7]([CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:8][CH2:9][F:10])([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:19]=[C:20]([CH3:26])[C:21]([CH:24]=O)=[N:22][CH:23]=1.C([O-])([O-])=O.[K+].[K+].[BH4-].[Na+].C([O-])(O)=O.[Na+]>CO>[C:1]([O:5][C:6](=[O:16])[N:7]([CH2:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:24][C:21]1[C:20]([CH3:26])=[CH:19][C:18]([Cl:17])=[CH:23][N:22]=1)[CH2:8][CH2:9][F:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCF)CCCCN
Reactant: Cc1cc(Cl)cnc1C=O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: CO
Product: Cc1cc(Cl)cnc1CNCCCCN(CCF)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 16 h
Yield: 65.2 %

Procedure:
A mixture of (4-amino-butyl)-(2-fluoro-ethyl)-carbamic acid tert-butyl ester (0.190 g, 0.882 mmol), 5-chloro-3-methyl-pyridine-2-carbaldehyde (0.129 g, 0.882 mmol) and K2CO3 (0.122 g, 0.82) in MeOH (5 mL) was stirred for 16 h. The mixture was filtered through a celite cake and the filtrate was cooled at 0° C. NaBH4 (0.038 g, 1.0 mmol) was added to the filtrate, and the mixture was stirred at for 30 min. Saturated aqueous NaHCO3 (20 mL) was added and MeOH was removed. The aqueous residue was extracted with CH2Cl2 (3×30 mL). The organic extracts were combined and dried over anhydrous Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified by flash chromatography on a silica gel column (200:10:1 CH2Cl2/MeOH/NH4OH), affording {4-[(5-chloro-3-methyl-pyridin-2-ylmethyl)-amino]-butyl}-(2-fluoro-ethyl)-carbamic acid tert-butyl ester as a pale yellow oil (0.215 g, 72%). 1H NMR (CDCl3) δ 1.45 (s, 9H), 1.53-1.66 (m, 4H), 2.30 (s, 3H), 2.71 (t, 2H, J=6.6 Hz), 3.24-3.30 (m, 2H), 3.42-3.52 (m, 2H), 3.84 (s, 2H), 4.40-4.48 (m, 1H), 4.56-4.64 (m, 1H), 7.43 (s, 1H), 8.34 (s, 1H).
Reaction SMILES: [OH:1][C:2]([C:5]1[C:6]2[N:7]([C:11]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH:21]4[CH2:26][CH2:25][CH:24]([C:27](O)=[O:28])[CH2:23][CH2:22]4)[N:15]=3)=[CH:12][N:13]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[NH:66]1[CH2:71][CH2:70][CH:69]([OH:72])[CH2:68][CH2:67]1>CN(C=O)C>[OH:1][C:2]([C:5]1[C:6]2[N:7]([C:11]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH:21]4[CH2:26][CH2:25][CH:24]([C:27]([N:66]5[CH2:71][CH2:70][CH:69]([OH:72])[CH2:68][CH2:67]5)=[O:28])[CH2:23][CH2:22]4)[N:15]=3)=[CH:12][N:13]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:4]
Reactant: CC(C)(O)c1cccn2c(-c3ccnc(NC4CCC(C(=O)O)CC4)n3)cnc12
Reactant: OC1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)c1cccn2c(-c3ccnc(NC4CCC(C(=O)N5CCC(O)CC5)CC4)n3)cnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
A mixture of 4-{4-[8-(1-hydroxy-1-methyl-ethyl)-imidazo[1,2-a]pyridin-3-yl]-pyrimidin-2-ylamino}-cyclohexanecarboxylic acid (0.175 g), BOP (0.39 g), DIEA (0.23 mL), and piperidin-4-ol (67 mg) in DMF (5 mL) was stirred at RT overnight. The resulting solid was filtered and dried, purified by ISCO using 100% DCM to 20% MeOH/DCM. The fractions were collected and concentrated, then titurated with EtOAc, and the resulting solid filtered and dried at 50° C. overnight to provide (4-{4-[8-(1-hydroxy-1-methyl-ethyl)-imidazo[1,2-a]pyridin-3-yl]-pyrimidin-2-ylamino}-cyclohexyl)-(4-hydroxy-piperidin-1-yl)-methanone (Compound 2, 140.4 mg). Mp=188.0-190.0° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].[C:10]([N:13]1[C:17]([NH2:18])=[N:16][C:15]([S:19](Cl)(=[O:21])=[O:20])=[N:14]1)(=[O:12])[CH3:11]>N1C=CC=CC=1>[C:10]([N:13]1[C:17]([NH2:18])=[N:16][C:15]([S:19]([NH:4][C:3]2[C:2]([Cl:1])=[CH:8][CH:7]=[CH:6][C:5]=2[Cl:9])(=[O:20])=[O:21])=[N:14]1)(=[O:12])[CH3:11]
Reactant: CC(=O)n1nc(S(=O)(=O)Cl)nc1N
Reactant: Nc1c(Cl)cccc1Cl
Solvent: c1ccncc1
Product: CC(=O)n1nc(S(=O)(=O)Nc2c(Cl)cccc2Cl)nc1N
Temperature: 60 °C
Reaction time: 12 h

Procedure:
42.63 g (0.26 mol) 2,6-dichloroaniline in 350 ml pyridine was treated with 54 g (0.24 mol) of 1-acetyl-5-amino-1,2,4-triazole-3-sulphonyl chloride and stirred at 60° C. for 12 hours. After cooling, the crystals were separated, washed with a small amount of pyridine and ether and dried in vacuo.