Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=3)[N:11]=[CH:10][N:9]=2)=[N:3]1.F[C:20]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:21]=1[C:22]#[N:23].C(O[K])(C)(C)C.O>CN(C)C(=O)C>[CH3:28][C:27]1[C:20]([O:18][C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[N:11]=[CH:10][N:9]=[C:8]3[NH:7][C:4]2[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=2)=[C:21]([CH:24]=[CH:25][CH:26]=1)[C:22]#[N:23]
Reactant: Cc1cccc(C#N)c1F
Reactant: Cn1ccc(Nc2ncnc3ccc(O)cc23)n1
Agent: CC(C)(C)O[K]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cccc(C#N)c1Oc1ccc2ncnc(Nc3ccn(C)n3)c2c1
Temperature: 110 °C
Reaction time: 4 h
Yield: 23.3 %

Procedure:
4-[(1-Methyl-1H-pyrazol-3-yl)amino]quinazolin-6-ol (90 mg; 0.373 mmol) and 100 mg (0.741 mmol) of 2-fluoro-3-methylbenzonitrile were added to a solution of 105 mg (0.937 mmol) of tert-butoxy potassium in 5 ml of N,N-dimethylacetamide and the mixture was stirred at 110° C. for 4 hours. Water was added to the reaction solution and the mixture was extracted with chloroform. The organic layer was dried and concentrated and the resulting residue was purified by a silica gel chromatography (chloroform:methanol=12:1) to give 31 mg (yield: 23%) of the title compound as a colorless solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[C:7]1[N:11]=[C:10]([CH2:12][O:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH2:16][CH2:15]2)[O:9][N:8]=1.[NH:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[S:39](Cl)(=[O:41])=[O:40]>>[NH:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[S:39]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[C:7]1[N:11]=[C:10]([CH2:12][O:13][CH:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:21])[CH2:18][CH2:19]2)[O:9][N:8]=1)(=[O:40])=[O:41]
Reactant: O=S(=O)(Cl)c1nc2ccccc2[nH]1
Reactant: O=C(OCc1ccccc1)N1CCC(OCc2nc([C@@H]3CCCCN3)no2)CC1
Product: O=C(OCc1ccccc1)N1CCC(OCc2nc([C@@H]3CCCCN3S(=O)(=O)c3nc4ccccc4[nH]3)no2)CC1

Procedure:
The title compound was prepared by a similar method to Example 1 from benzyl 4-(3-[(2S)-2-piperidyl]-1,2,4-oxadiazol-5-ylmethoxy)-1-piperidinecarboxylate [see Preparation 95] and 1H-benzo[d]imidazol-2-sulfonyl chloride [see Preparation 8]. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 80:20 changing to 0:100, by volume, hexane:ethyl acetate, in 5% increments, to afford benzyl 4-(3-[(2S)-1-(1H-benzo[d]imidazol-2-ylsulfonyl)-2-piperidyl]-1,2,4-oxadiazol-5-ylmethoxy)-1-piperidinecarboxylate as a clear oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2[C:10]([N+:14]([O-:16])=[O:15])=[CH:11][CH:12]=[CH:13][C:6]=2[S:5]1(=[O:18])=[O:17].[CH2:19]([CH2:21][NH2:22])[OH:20]>C1COCC1>[OH:20][CH2:19][CH2:21][NH:22][C:8](=[O:9])[C:7]1[C:10]([N+:14]([O-:16])=[O:15])=[CH:11][CH:12]=[CH:13][C:6]=1[S:5]([NH:4][CH2:3][CH2:2][OH:1])(=[O:18])=[O:17]
Reactant: NCCO
Reactant: O=C1c2c([N+](=O)[O-])cccc2S(=O)(=O)N1CCO
Solvent: C1CCOC1
Product: O=C(NCCO)c1c([N+](=O)[O-])cccc1S(=O)(=O)NCCO
Reaction time: 72 h
Yield: 90.8 %

Procedure:
A solution of 2-(2-hydroxyethyl)-4-nitro-2H-1,2-benzisothiazol-3-one 1,1-dioxide (100 mg, 0.37 mmol) and ethanolamine (24 mg, 0.39 mmol) in THF (5 ml) was allowed to stand at 20°-25° for 3 days. After removal of THF under reduced pressure, the residue was recrystallized from MeOH-EtOAc-hexane to give 112 mg (91%) of product, m.p. 176.5°-177.5°.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[C:5]([CH3:18])[CH:4]=1)#[N:2].[C:19](OC)(=[O:27])[C:20]1[C:21](=[CH:23][CH:24]=[CH:25][CH:26]=1)[SH:22].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:18][C:5]1[CH:4]=[C:3]([C:1]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19](=[O:27])[N:2]=2)[N:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH:6]=1
Reactant: COC(=O)c1ccccc1S
Reactant: Cc1cc(C#N)nc(CCC(=O)OC(C)(C)C)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cc(CCC(=O)OC(C)(C)C)nc(-c2nc(=O)c3ccccc3s2)c1
Yield: 55 %

Procedure:
tert-Butyl 3-(6-cyano-4-methyl-2-pyridyl)propanoate (0.72 g, 2.9 mmol) and methyl thiosalicylate (0.99 g, 5.9 mmol) were dissolved in toluene (4 ml), and triethylamine (2.0 ml, 14.3 mmol) was added thereto. The mixture was refluxed for 14 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (1:2, v/v) were collected, concentrated and recrystallized from ethyl acetate-hexane to give the titled compound (0.61 g, 54%) as white crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-])=O.[CH:11](=O)[CH2:12][CH3:13]>>[CH2:12]([CH:11]1[NH:6][C:5]2[C:4](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:1]2[CH:10]=[CH:4][CH:5]=[C:7]12)[CH3:13]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: CCC=O
Product: CCC1Nc2ccccc2-n2cccc21

Procedure:
The title compound was prepared from 2-nitro aniline according to the sequence of Example 1 and 2, and the resulting oil treated with proprionaldehyde according to the procedure of Example 3 to yield a light orange oil, which was used in the next step without further characterization.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:26])([CH3:25])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20](OC)=[CH:19][CH:18]=1)[C:12]([OH:14])=[O:13])(=[O:7])=[O:6].[CH:27]1([C:33]([O:35][CH:36](Cl)[CH3:37])=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:25])([CH3:26])[C@@H:11]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:12]([O:14][CH2:37][CH2:36][O:35][C:33]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:34])=[O:13])(=[O:6])=[O:7]
Reactant: COc1ccc(CO[C@@H](C(=O)O)C(C)(C)COS(=O)(=O)CCCCl)cc1
Reactant: CC(Cl)OC(=O)C1CCCCC1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(COS(=O)(=O)CCCCl)[C@@H](OCc1ccccc1)C(=O)OCCOC(=O)C1CCCCC1
Yield: 39.2 %

Procedure:
Following the general procedure for the preparation of acyloxyalkyl/alkoxycarbonyloxyalkyl carboxylic esters from carboxylic acids of Description 22, (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoic acid (11) (1.2 g, 3.3 mmol) dissolved in 10 mL of anhydrous toluene was reacted with 1.9 g (10.0 mmol) of chloroethyl cyclohexanecarboxylate (24) in the presence of 1.4 g (5.0 mmol) of silver carbonate (Ag2CO3). After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:9→EtOAc/Hxn=1:5) as eluent to provide 0.69 g (39% yield) of the title compound (44a) as a colorless oil. Rf=0.11 (EtOAc/Hxn=1:9). 1H NMR (400 MHz, CDCl3, both diastereomers): δ=1.06-1.08 (m, 6H), 1.23-1.36 (br. m, 3H), 1.44-1.50 (br. m, 2H), 1.53 (d, J=5.6 Hz, 3H), 1.58-1.68 (br. m, 1H), 1.74-1.80 (br. m, 2H), 1.86-1.97 (br. m, 2H), 2.25-2.39 (m, 3H), 3.21-3.26 (m, 2H), 3.63-3.66 (m, 2H), 3.82-3.84 (2s, 1H), 3.96 (d, J=9.2 Hz, 1H), 4.20-4.24 (m, 1H), 4.33-4.37 (2d, J=11.6, 11.6 Hz, 1H), 4.59-4.66 (2d, J=10.8, 11.2 Hz, 1H), 6.91-6.95 (m, 1H), 7.30-7.37 (m, 5H) ppm. MS (ESI) m/z 554.92 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[CH:23]1[C:24]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[CH:21][C:22]=1[O:1][CH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CO)C1
Reactant: Oc1ccc2ccccc2c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CC[C@H](COc2ccc3ccccc3c2)C1
Yield: 86 %

Procedure:
The procedure is the same as for Example 1 (Stage 1.2) starting from 2.00 g (9.94 mmol) of tert-butyl (S)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (commercial), 2.00 g (13.91 mmol) of naphth-2-ol, 3.90 g (14.91 mmol) of triphenylphosphine and 3.01 g (14.91 mmol) of diisopropyl azodicarboxylate. 2.80 g of product are obtained in the form of an oil after purification on a column of silica gel, elution being carried out with dichloromethane.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:32]=[CH:31][C:21]3[NH:22][C:23]([CH2:25][C:26]([O:28]CC)=O)=[N:24][C:20]=3[CH:19]=2)[CH2:14][CH2:13]1.[NH2:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][C:39]=1[C:40]#[N:41]>C1COCC1>[NH2:41][C:40]1[C:39]2[C:34](=[CH:35][N:36]=[CH:37][CH:38]=2)[NH:33][C:26](=[O:28])[C:25]=1[C:23]1[NH:22][C:21]2[CH:31]=[CH:32][C:18]([N:15]3[CH2:14][CH2:13][N:12]([CH3:11])[CH2:17][CH2:16]3)=[CH:19][C:20]=2[N:24]=1
Reactant: CCOC(=O)Cc1nc2cc(N3CCN(C)CC3)ccc2[nH]1
Reactant: N#Cc1ccncc1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCN(c2ccc3[nH]c(-c4c(N)c5ccncc5[nH]c4=O)nc3c2)CC1
Reaction time: 8 h

Procedure:
LiHMDS (3.6 eq) was added to ethyl [5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]acetate (1.0 eq) and 3-aminopyridine-4-carbonitrile (1.0 eq) in THF at 0° C. The reaction was stirred overnight. The resulting mixture was quenched with an aqueous saturated NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo to yield a green solid. The crude material was washed successively with CH2Cl2 and MeOH and then was purified by reverse phase HPLC to provide the desired product. LC/MS m/z 376.3 (MH+), Rt 1.70 minutes.
Reaction SMILES: [NH2:1][C:2]1[C:6]([NH2:7])=[CH:5][S:4][CH:3]=1.[C:8](OC)(OC)(OC)[CH2:9][CH2:10][CH2:11][CH3:12].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[CH2:9]([C:8]1[NH:1][C:2]2=[CH:3][S:4][CH:5]=[C:6]2[N:7]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCCCC(OC)(OC)OC
Reactant: Nc1cscc1N
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: CCCCc1nc2cscc2[nH]1

Procedure:
To a solution of 3,4-diaminothiophene (156 mg) in ethanol (10 ml) was added trimethyl orthovalerate (0.29 ml) and pyridinium p-toluenesulfonate (4 mg). The mixture was refluxed for one hour and concentrated in vacuo. The residue was purified by preparative thin layer chromatography on silica gel developed by ethyl acetate to give 2-butyl-1H-thieno[3,4-d]imidazole (155 mg) as crystals.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[NH:28]1[CH:32]([CH2:33][C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)[C:31](=[O:41])[NH:30][C:29]1=[O:42]>>[NH:28]1[CH:32]([CH2:33][C:34]2[CH:40]=[CH:39][C:37]([NH:38]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=4)/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:36][CH:35]=2)[C:31](=[O:41])[NH:30][C:29]1=[O:42]
Reactant: Nc1ccc(CC2NC(=O)NC2=O)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CC2NC(=O)NC2=O)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-((imidazolidin-2,4-dion-5-yl)-methyl)-aniline Rf value: 0.6 (silica gel, methylene chloride/methanol=5:1) C27H22N4O5
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:13]([O-])=O.[NH2:16][C:17](N)=[S:18].O>S1(CCCC1)(=O)=O>[NH2:16][C:17]1[S:18][C:2]2[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=2[N:13]=1
Reactant: CCS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NC(N)=S
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: CCS(=O)(=O)c1ccc2sc(N)nc2c1
Temperature: 120 °C
Yield: 85.3 %

Procedure:
A suspension of 12.8 g of ethyl 4-chloro-3-nitrophenyl sulphone and 15.2 g of thiourea in 50 ml of sulpholane is heated to 120° C. and this temperature is maintained for 1.5 hours. The mixture is discharged into 600 ml of water, and the solid is filtered off with suction and washed with water. 10.6 g of colourless 2-amino-5-ethanesulphonylbenzothiazole are obtained.
Reaction SMILES: C([N:5]1[C:9]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](=[O:21])[N:13]([CH2:22][CH2:23][O:24][CH3:25])[N:12]=2)=[CH:8][C:7]([CH3:26])=[N:6]1)(C)(C)C>C(O)=O.O>[CH3:25][O:24][CH2:23][CH2:22][N:13]1[N:12]=[C:11]([NH:10][C:9]2[NH:5][N:6]=[C:7]([CH3:26])[CH:8]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=[O:21]
Reactant: COCCn1nc(Nc2cc(C)nn2C(C)(C)C)c2ccccc2c1=O
Solvent: O=CO
Solvent: O
Product: COCCn1nc(Nc2cc(C)n[nH]2)c2ccccc2c1=O
Yield: 93.5 %

Procedure:
4-(2-tert-Butyl-5-methyl-2H-pyrazol-3-ylamino)-2-(2-methoxy-ethyl)-2H-phthalazin-1-one (0.36 g, 1.0 mmol) was dissolved in formic acid (20 ml) and heated at reflux for 4 h. The resulting raw product was dissolved in H2O and dichloromethane, after evaporation of formic acid. Addition of NaHCO3 resulted in precipitation of a solid, which was collected by filtration. Subsequent washing with H2O, dichloromethane and diethyl ether and drying in vacuum at 40° C. yielded the desired product 2-(2-Methoxyethyl)-4-(5-methyl-2H-pyrazol-3-ylamino)-2H-phthalazin-1-one (example O-1) (0.28 g, 94%). 1H-NMR: (400 MHz, D6-DMSO) 9.21 (1H, s), 8.43 (1H, d), 8.29 (1H, d), 8.14 (1H, s), 7.84–7.94 (2H, m), 6.28 (1H, s), 4.23 (2H, t), 3.73 (2H, t), 3.33 (3H, s), 2.23 (3H, s); MS (ESI+)=300.3 (M+H)+
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9]([C:11]2[C:12]([NH:18][CH2:19][CH3:20])=[N:13][CH:14]=[C:15]([Br:17])[CH:16]=2)=[O:10])=[CH:6][CH:5]=[C:4]([Cl:21])[N:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].O1CCCC1>N1C=CC=CC=1>[Br:17][C:15]1[CH:14]=[N:13][C:12]2[N:18]([CH2:19][CH3:20])[C:2]3[N:3]=[C:4]([Cl:21])[CH:5]=[CH:6][C:7]=3[NH:8][C:9](=[O:10])[C:11]=2[CH:16]=1
Reactant: CCNc1ncc(Br)cc1C(=O)Nc1ccc(Cl)nc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCN1c2nc(Cl)ccc2NC(=O)c2cc(Br)cnc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 92.4 %

Procedure:
To a solution of N-(2,6-dichloro-3-pyridinyl)-5-bromo-2-ethylamino-3-pyridinecarboxamide (5.9 g, 15 mmol) in 30 mL of pyridine at 50° C. under argon was added by syringe a 1.0M solution of sodium hexamethyldisilazide in tetrahydrofuran (31.5 mL, 31.5 mmol). After 10 min, the reaction mixture was diluted with ice water and allowed to stir for 2 hours. The resultant orange-yellow precipitate was collected by suction filtration and air-dried to give 4.9 g of the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]3[CH:21]=2)=[CH:8][CH:7]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[N:22]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:13]=[C:14]4[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]4[CH:21]=3)=[CH:8][CH:7]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: Cc1ccn2cc(-c3ccc(OCCCCl)cc3)nc2c1
Reactant: C1CCNCC1
Product: Cc1ccn2cc(-c3ccc(OCCCN4CCCCC4)cc3)nc2c1
Temperature: 25 °C

Procedure:
The product of Step C (0.2 g) and piperidine (2.0 mL) were heated at reflux temperature for 5 hours. The reaction was cooled to ambient temperature and partitioned between ethyl acetate (10 mL) and saturated sodium bicarbonate solution (10 mL). The aqueous portion was extracted with additional ethyl acetate (10 mL) and the organic portions combined. The organic portions were dried over magnesium sulfate, filtered and evaporated. The residue was purified via silica gel chromatography (dichloromethane/methanol) to give the title compound (0.21 g). This compound can also be named as 7-(methyl-2-[4-(3-piperidin-1-yl-propoxy)-phenyl]-imidazo[1,2-a]pyridine. Treatment with 2M HCl in ether afforded the dihydrochloride. 1H NMR (CD3OD) δ 8.67 (d, J=7.5 Hz, 1H), 8.41 (s, 1H), 7.84 (m, 2H), 7.71 (s, 1H), 7.36 (dd, J=6.9 Hz, J=1.4 Hz, 1H), 7.16 (m, 2H), 4.22 (t, J=5.8 Hz, 2H), 3.64 (d, J=12.5 Hz, 2H), 3.35 (m, 2H), 3.04 (m, 2H), 2.62 (s, 3H), 2.34 (m, 2H), 1.99 (m, 2H), 1.86 (m, 3H), 1.59 (m, 1H); 13C NMR (CD3OD) δ 161.0, 147.1, 141.1, 136.2, 128.5, 128.2, 120.3, 119.3, 115.8, 110.6, 109.9, 65.8, 55.0, 53.8, 24.5, 23.6, 22.1, 21.2, MS (M+H)=350.2 Analysis: Calc'd for C22H27N3O·2HCl·(2H2O)C, 57.64; H, 7.26; N, 9.17. Found: C, 57.68; H, 7.13; N, 9.16.
Reaction SMILES: Cl[C:2]1[C:3]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:9][N:10]=2)[N:7]=1.[CH3:22][N:23]1[CH:27]=[N:26][C:25]([CH2:28][OH:29])=[N:24]1.[H-].[Na+]>CN(C=O)C.O>[CH2:18]([N:17]([CH2:20][CH3:21])[C:3]1[C:2]([O:29][CH2:28][C:25]2[N:26]=[CH:27][N:23]([CH3:22])[N:24]=2)=[N:7][N:6]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:9][N:10]=[C:5]2[CH:4]=1)[CH3:19]
Reactant: Cn1cnc(CO)n1
Reactant: CCN(CC)c1cc2nnc(-c3ccccc3)n2nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)c1cc2nnc(-c3ccccc3)n2nc1OCc1ncn(C)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.9 %

Procedure:
To a solution of N-(6-chloro-3-phenyl-1,2,4-triazolo[4,3-b]pyridazin-7-yl)-N,N-diethylamine (180 mg, 0.33 mmol) and (1-methyl-1 H-1,2,4-triazol-3-yl)methanol (68 mg) in dry DMF (5 ml) was added sodium hydride (60% dispersion in oil, 34 mg, 0.36 mmol). The mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water (50 ml) and extracted with dichloromethane (3×25 ml). The combined extracts were washed with brine, dried over magnesium sulphate, filtered and evaporated. The solid was recrystallised from ethyl acetate, and collected by filtration to afford the title pyridazine (81 mg, 36%). 1H NMR (500 MHz, DMSO-d6) δ1.08 (6 H, t, J=8.5 Hz), 3.31 (4 H, q, J=8.5 Hz), 3.87 (3 H, s), 5.50 (2 H, s), 7.22 (1 H, s), 7.47-7.59 (3 H, m), 8.37 (2 H, d, J=8.5 Hz), 8.51 (1 H, s). MS (ES+) 379 [MH]+.
Reaction SMILES: [F:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([NH:9][CH:10]2[CH2:15][CH:14]([CH3:16])[CH2:13][CH:12]([NH:17][C:18]3[C:23]([F:24])=[CH:22][N:21]=[C:20]([C:25]4[C:33]5[C:28](=[N:29][CH:30]=[C:31]([F:34])[CH:32]=5)[N:27](S(C5C=CC(C)=CC=5)(=O)=O)[CH:26]=4)[N:19]=3)[CH2:11]2)=[O:8])[CH2:3]1.C[O-].[Na+]>CO>[F:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([NH:9][C@@H:10]2[CH2:15][C@H:14]([CH3:16])[CH2:13][C@H:12]([NH:17][C:18]3[C:23]([F:24])=[CH:22][N:21]=[C:20]([C:25]4[C:33]5[C:28](=[N:29][CH:30]=[C:31]([F:34])[CH:32]=5)[NH:27][CH:26]=4)[N:19]=3)[CH2:11]2)=[O:8])[CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC4CC(C)CC(NC(=O)N5CC[C@H](F)C5)C4)n3)c3cc(F)cnc32)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C[C@H]1C[C@@H](NC(=O)N2CC[C@H](F)C2)C[C@@H](Nc2nc(-c3c[nH]c4ncc(F)cc34)ncc2F)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (3S)-3-fluoro-N-(3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-5-methylcyclohexyl)pyrrolidine-1-carboxamide, 76d, (0.090 g, 0.143 mmol) in MeOH (2.5 ml) was added 25% sodium methoxide in methanol (2 ml). The reaction was stirred at room temperature for 30 minutes and quenched with aqueous saturated NH4Cl. The methanol was removed in-vacuo and the residue was extracted with EtOAc and water. The organics were dried over sodium sulfate and concentrated to dryness. The resulting crude racemate was purified by SFC separation on a chiral column. The second peak was concentrated in vacuo to afford 32 mg of enantiomerically pure (S)-3-fluoro-N-((1R,3S,5R)-3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-5-methylcyclohexyl)pyrrolidine-1-carboxamide as a white solid: LCMS RT=1.89 (M+1) 474.2, (M−1) 472.4; SFC RT=3.2 min., 15% MeOH @ 5 mL/min on an ODH (4.6* 100), 100 bar, 35 C, 220 nm; 1H NMR (300 MHz, DMSO) δ 12.26 (s, 1H), 8.41 (dd, J=9.9, 2.8 Hz, 1H), 8.32-8.18 (m, 2H), 8.14 (d, J=4.0 Hz, 1H), 7.53 (d, J=7.6 Hz, 1H), 6.02 (d, J=7.9 Hz, 1H), 5.28 (d, J=53.6 Hz, 1H), 4.35-4.00 (m, 1H), 3.81-3.09 (m, 12H), 2.24-1.77 (m, J=41.2, 26.1, 10.6 Hz, 4H), 1.74-1.51 (m, 1H), 1.51-1.22 (m, 1H), 1.14-0.70 (m, 4H).
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]([F:21])([F:20])[C:8]([C:11]1[NH:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1)([OH:10])[CH3:9].[N+:22]([O-])([OH:24])=[O:23]>C(OCC)C>[F:21][C:7]([F:6])([F:20])[C:8]([C:11]1[NH:15][C:14]2[CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:19][C:13]=2[N:12]=1)([OH:10])[CH3:9]
Reactant: CC(O)(c1nc2ccccc2[nH]1)C(F)(F)F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CC(O)(c1nc2ccc([N+](=O)[O-])cc2[nH]1)C(F)(F)F
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To stirred concentrated sulfuric acid (11 mL) was added 1,1,1-trifluoro-2-benzimidazol-2-ylpropan-2-ol (3.00 g) under a nitrogen atmosphere while maintaining the temperature at 5° C. The reaction mixture was treated with a nitrating reagent (3.5 mL) containing concentrated nitric acid and concentrated sulfuric acid (1.5 mL), while maintaining the reaction temperature below 35° C., and was then stirred for 1 hour at ice bath temperature. The reaction mixture was then poured onto ice, neutralized to pH 7-8, extracted with diethyl ether, and dried. The solvent was evaporated to leave a gold oil. Trituration of the oil with diethyl ether provided the title compound as a white solid (0.80 g); mp 73°-75° C., resolidified mp 173°-174° C.; NMR (250 MHz): 1.68 (s,3), 7.62 (s,1), 7.78 (broad d,1), 8.19 (dd,1), 8.52 (s,1), 13.4 (s,1); MS: m/z=276 (M+1). Analysis for C10H8F3N3O: Calculated C, 43.65; H, 2.93; N, 15.27; Found: C, 43.32; H, 3.02; N, 15.03.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([O:13]C)=O.O.[NH2:16][NH2:17]>C(O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:16][NH2:17])=[O:13]
Reactant: NN
Reactant: COC(=O)c1ccc2ccccc2n1
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccc2ccccc2n1
Temperature: 25 °C

Procedure:
Methyl quinoline-2-carboxylate 3.2 (10.1 g, 0.054 mol) was dissolved in 50 mL of ethanol and hydrazine hydrate (8.1 g, 0.16 mol) was added. The mixture was heated to reflux for 1 h and cooled down to RT at which point a precipitate formed. The mixture was concentrated to approximately ⅓ of the volume and the precipitate was filtered off, washed with small volumes of ethanol to afford intermediate 2a solvated by ½ equivalent of ethanol. Yield 10 g (99%). 1HNMR (DMSO-d6): δ: 9.95 ppm (s, 1H), 8.55 (d, 1H), 8.1 ppm (d, 2H), 8.05 ppm (d, 1H), 8.85 ppm (t, 1H), 7.65 ppm (t, 1H), 4.6 ppm (s, 2H), 4.3 ppm (t, 0.5H), 4.4 ppm (q, 1H), 1.05 ppm (q, 1.5H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11]C2C=C(Cl)C=CC=2Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.O>C1COCC1>[C:5]1([S:8]([NH2:11])(=[O:10])=[O:9])[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: O=S(=O)(Nc1cc(Cl)ccc1Cl)c1ccc(Cl)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccccc1
Reaction time: 12 h
Yield: 52 %

Procedure:
To a solution of 4-chloro-N-[5-chloro-2-chlorophenyl]benzenesulfonamide (1.00 g, 2.97 mmol), triphenylphosphine (1.64 g, 6.24 mmol) and 5S-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-2-pentanol (1.30 g, 5.94 mmol) in THF (12 mL) was added diisopropylazodicarboxylate (1.23 mL, 6.24 mol) dropwise at 0° C. under nitrogen. The resulting mixture was allowed to warm to 22 DC with stirring. Stirring was continued for a period of 12 h followed by the addition of 25 mL of H2O. The mixture was extracted with ether (3×25 mL). The combined organic extracts were washed with 1M NaHCO3 and sat. brine. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. Silica gel chromatography (1:5 ethyl acetate:hexanes) of the concentrate afforded 830 mg of 4-chloro-N-[5-chloro-2-chlorophenyl]-N-[(R)-1-methyl-4-[(1,1-dimethylethyl)-dimethylsilyl]oxy)butyl]benzenesulfonamide as a yellow oil in 52% yield.