Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[C:13](=[O:14])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][C:11]2=[N:10][C:9]=1[CH:19]([N:23]([CH2:33][CH2:34][CH2:35][N:36]1C(=O)C2C(=CC=CC=2)C1=O)[C:24](=[O:32])[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)[CH:20]([CH3:22])[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NN.C(O)(C(F)(F)F)=O>C(O)C>[NH2:36][CH2:35][CH2:34][CH2:33][N:23]([CH:19]([C:9]1[N:10]=[C:11]2[CH2:18][CH2:17][CH2:16][CH2:15][N:12]2[C:13](=[O:14])[C:8]=1[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:20]([CH3:21])[CH3:22])[C:24](=[O:32])[C:25]1[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=1
Reactant: Cc1ccc(C(=O)N(CCCN2C(=O)c3ccccc3C2=O)C(c2nc3n(c(=O)c2Cc2ccccc2)CCCC3)C(C)C)cc1
Agent: NN
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: Cc1ccc(C(=O)N(CCCN)C(c2nc3n(c(=O)c2Cc2ccccc2)CCCC3)C(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product from Step 12 (22), 50 mg (0.08 mmol) was dissolved in 1 ml of anhydrous ethanol. Hydrazine 18 μl (0.57 mmol) was added and the reaction stirred at room temperature for 2 h. The precipitate was filtered through a PTFE filter and washed with ethyl acetate. The solvent was evaporated and the crude material was purified by reverse phase HPLC resulting to 11 mg (0.023 mmol) of N-(3-aminopropyl)-N-[1-(3-benzyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-2-yl)-2-methylpropyl]-4-methylbenzamide (2) as the TFA salt.
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].Cl.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C@@H:15]2[CH2:19][NH:18][C@H:17]([CH2:20][OH:21])[CH2:16]2)=[C:10]([N+:22]([O-:24])=[O:23])[CH:9]=1.[OH-].[Na+]>O1CCCC1.O>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C@@H:15]2[CH2:19][N:18]3[C@H:17]([CH2:20][O:21][CH2:2][C:3]3=[O:4])[CH2:16]2)=[C:10]([N+:22]([O-:24])=[O:23])[CH:9]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1N[C@@H]1CN[C@H](CO)C1
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C1COC[C@@H]2C[C@H](Nc3ccc(Br)cc3[N+](=O)[O-])CN12
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.8 %

Procedure:
Add chloroacetyl chloride (0.49 mol, 55.7 g) drop wise to a solution of (2S,4S)-[4-(4-bromo-2-nitro-phenylamino)-pyrrolidin-2-yl]-methanol, hydrochloride (0.22 mol, 79 g) in tetrahydrofuran/water (1:1) mixture (1180 mL) at room temperature. Maintain the reaction pH between 10-12 by continuous addition of 4 M sodium hydroxide solution. After complete addition of chloroacetyl chloride, stir the reaction mixture for 4 h at room temperature. Remove tetrahydrofuran under reduced pressure and extract the aqueous layer with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to obtain the title compound (50 g, 62%) as an orange solid. 1H NMR (400 MHz, CDCl3) δ 1.59-1.67 (m, 1H), 2.58-2.64 (m, 1H), 3.40 (t, 1H), 3.71 (dd, 1H), 3.91-4.01 (m, 2H), 4.09 (d, 1H), 4.20 (dd, 1H), 4.29-4.35 (m, 2H), 6.75 (d, 1H), 7.54 (dd, 1H), 8.05 (d, 1H), 8.32 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:15](=O)[C:14](=[CH:17]N(C)C)[CH2:13][C:7]2([O:11][CH:10](C)[CH2:9][O:8]2)[CH2:6]1)=[O:4].[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([NH:43][C:44]([NH2:46])=[NH:45])[CH:34]=[CH:35][C:36]=1[N:37]1[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38]1>>[CH2:10]1[CH2:9][O:8][C:7]2([CH2:6][CH:5]([C:3]([O:2][CH3:1])=[O:4])[C:15]3[N:46]=[C:44]([NH:43][C:33]4[CH:34]=[CH:35][C:36]([N:37]5[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38]5)=[C:31]([O:30][CH3:29])[CH:32]=4)[N:45]=[CH:17][C:14]=3[CH2:13]2)[O:11]1
Reactant: COC(=O)C1CC2(CC(=CN(C)C)C1=O)OCC(C)O2
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Solvent: O=[N+]([O-])O
Product: COC(=O)C1CC2(Cc3cnc(Nc4ccc(-n5cnc(C)c5)c(OC)c4)nc31)OCCO2

Procedure:
The title compound was prepared from methyl 9-[1-dimethylamino-methylidene]-8-oxo-1,4-dioxa-spiro[4.5]decane-7-carboxylic acid methyl ester (80 mg, 0.3 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (83 mg, 0.22 mmol) using in analogous manner the procedure described in example 45b). Obtained as a pale-yellow solid (37 mg, 27%). MS ISP (m/e): 452.1 [(M+H)+]. mp 180-182° C.
Reaction SMILES: O.O.[Sn](Cl)Cl.[Cl:6][C:7]1[C:13]([N:14]2[CH2:18][CH2:17][CH2:16][CH:15]2[C:19](=[O:23])[N:20]([CH3:22])[CH3:21])=[CH:12][C:10]([NH2:11])=[C:9]([N+:24]([O-])=O)[CH:8]=1.C([O-])(O)=O.[Na+]>CCOC(C)=O>[CH3:21][N:20]([CH3:22])[C:19]([CH:15]1[CH2:16][CH2:17][CH2:18][N:14]1[C:13]1[CH:12]=[C:10]([NH2:11])[C:9]([NH2:24])=[CH:8][C:7]=1[Cl:6])=[O:23]
Reactant: CN(C)C(=O)C1CCCN1c1cc(N)c([N+](=O)[O-])cc1Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CN(C)C(=O)C1CCCN1c1cc(N)c(N)cc1Cl

Procedure:
Tin dichloride dihydrate (710 mg, 3.1 mmol) was added to 4-chloro-5-(2-dimethylcarbamoyl-pyrrolidin-1-yl)-2-nitroaniline (200 mg, 0.6 mmol) in EtOAc (5 mL). The reaction mixture was stirred at reflux for 3 h, cooled and poured into sat.aq. NaHCO3-solution. The mixture was filtered through a pad of celite. The organic layer was dried over Na2SO4 and concentrated to give the sub-title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][C@@H:14]([CH3:16])[CH2:13][C@H:12]1[C:17]1[NH:18][CH:19]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=2)[N:21]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[Cl:30]N1C(=O)CCC1=O>C(#N)C>[CH3:1][O:2][C:3](=[O:29])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][C@@H:14]([CH3:16])[CH2:13][C@H:12]1[C:17]1[NH:18][C:19]([Cl:30])=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=2)[N:21]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Solvent: CC#N
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc(-c2ccc(Br)cc2)c(Cl)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 110 %

Procedure:
A mixture of ((S)-1-{(2S,4S)-2-[4-(4-bromo-phenyl)-1H-imidazol-2-yl]-4-methyl-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (175 mg, 0.38 mmol) and N-chlorosuccinimide (202 mg, 1.51 mmol) in acetonitrile (4 mL) was stirred at RT overnight. The reaction mixture was concentrated by rotary evaporation and purified by silica gel chromatography (24 g silica, 0-100% hexanes/EtOAc) to provide the title intermediate (208 mg) as a brown solid. (m/z): [M+H]+ calcd for C21H2BrClN4O3 497.09, found 497.4.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Br:21]Br>C(#N)C>[Br:21][C:10]1[C:11]2[C:16](=[CH:15][C:14]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=2)[N:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[N:9]=1
Reactant: COC(=O)c1ccc2cnn(-c3ccc(C)cc3)c2c1
Reactant: BrBr
Solvent: CC#N
Product: COC(=O)c1ccc2c(Br)nn(-c3ccc(C)cc3)c2c1
Reaction time: 60 h
Yield: 74.2 %

Procedure:
Methyl 1-(4-methylphenyl)-1H-indazole-6-carboxylate (2.7075 g, 10.17 mmol) was dissolved in acetonitrile (102 ml) at 25° C. under Ar. Bromine (1.886 ml, 36.60 mmol) was added. The reaction mixture was allowed to stir for 60 h. The reaction was stopped, quenched by addition of saturated aqueous sodium bicarbonate (40 mL), and the mixture extracted with ethyl acetate (3×35 mL). The combined organic phases were washed with saturated aqueous sodium chloride (1×25 mL), dried (sodium sulfate), filtered, and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography (RediSep SiO2, 330 g column) on a CombiFlash Rf purification system eluting with ethyl acetate-hexanes (0-5%). The title compound (2.8006 g, 7.55 mmol, 74.2% yield) was recovered as a white solid. LC-MS [M+1]=346.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2([CH2:12][CH2:13][OH:14])[CH2:11][CH2:10][NH:9][CH2:8]2)=[CH:3][CH:2]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[C:20](Cl)=[O:21].C(=O)(O)[O-].[Na+]>>[CH3:29][O:28][C:24]1[CH:23]=[C:19]([CH:18]=[C:17]([O:16][CH3:15])[C:25]=1[O:26][CH3:27])[C:20]([N:9]1[CH2:10][CH2:11][C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)([CH2:12][CH2:13][OH:14])[CH2:8]1)=[O:21]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: OCCC1(c2ccncc2)CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cc(C(=O)N2CCC(CCO)(c3ccncc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 5.2.2 using 3-(pyrid-4-yl)-3-(2-hydroxyethyl)-pyrrolidine, 3,4,5-trimethoxybenzoyl chloride, and sodium bicarbonate to give the title compound: Rf=0.42 (silica gel, 8% methanol/dichloromethane).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19](Cl)=[O:20])=[CH:11]1>>[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]([O:9][CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:20])=[CH:11]1
Reactant: O=C(Cl)c1c[nH]c2ccccc12
Reactant: OCCN1CCCCC1
Product: O=C(OCCN1CCCCC1)c1c[nH]c2ccccc12

Procedure:
1-Piperidineethanol was reacted with 1H-indole-3-carboxylic acid chloride using the method described in Example 1 a to afford 2-(1-piperidyl)ethyl 1H-indole-3-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:21][CH:20]=3)[C:16]([C:17]#[N:18])=[C:12]2[NH:11][CH2:10][CH2:9]1.ClCCC(NC1C=C(C2N3N=C(C4C=CC(OC5C=CC=CC=5)=CC=4)C(C(N)=O)=C3NCC2)C=CC=1)=[O:37]>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:21][CH:20]=3)[C:16]([C:17]([NH2:18])=[O:37])=[C:12]2[NH:11][CH2:10][CH2:9]1
Reactant: N#Cc1c(-c2ccc(OCc3ccccc3)cc2)nn2c1NCCC2c1ccccc1N
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCCC2c1cccc(NC(=O)CCCl)c1
Product: NC(=O)c1c(-c2ccc(OCc3ccccc3)cc2)nn2c1NCCC2c1ccccc1N

Procedure:
The desired product was prepared from 7-(2-aminophenyl)-2-(4-(benzyloxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile using the procedure similar to step 2 for compound 2. 1H NMR (400 MHz, DMSO-d6) δ 7.47-7.33 (m, 7H), 7.06 (d, J=8.4 Hz, 2H), 6.96 (t, J=7.6 Hz, 1H), 6.75 (br s, 1H), 6.68 (d, J=7.6 Hz, 1H), 6.50 (t, J=7.6 Hz, 1H), 6.28 (d, J=7.6 Hz, 1H), 5.59-5.54 (m, 1H), 5.19 (br s, 2H), 5.12 (s, 2H), 3.30-3.20 (m, 1H), 3.02-2.92 (m, 1H), 2.25-2.14 (m, 1H) and 2.13-2.03 (m, 1H). MS (ESI) m/e [M+1]+ 439.9.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[C:7](=[O:12])[C:6](=[N:13]O)[CH2:5]2>C(O)(=O)C.[Pd]>[NH2:13][CH:6]1[CH2:5][C:4]2[C:8](=[CH:9][C:10]([F:11])=[C:2]([F:1])[CH:3]=2)[C:7]1=[O:12]
Reactant: O=C1C(=NO)Cc2cc(F)c(F)cc21
Agent: [Pd]
Solvent: CC(=O)O
Product: NC1Cc2cc(F)c(F)cc2C1=O
Reaction time: 72 h

Procedure:
5,6-Difluoroindan-1,2-dione 2-oxime (Preparation 77) (2.70 g, 13.7 mmol) was dissolved in acetic acid (70 mL) and 10% Palladium on carbon (717 mg) added. The reaction mixture was hydrogenated at 50 psi for 72 h, filtered through a pad of celite and washed with chloroform (100 mL). The resulting precipitate was collected by filtration and air dried to give the title compound: δH(DMSO-d6) 3.11 (1H, dd), 3.56 (1H, dd), 4.34 (1H, dd), 7.74-7.94 (2H, m), 8.75 (2H, bs).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][C@@H:7]2[C@@H:5]([CH2:6]2)[N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[CH:2]([C@@H:3]1[CH2:8][C@@H:7]2[C@@H:5]([CH2:6]2)[N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:1]
Reactant: CC(C)(C)OC(=O)N1[C@H](CO)C[C@H]2C[C@H]21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@H](C=O)C[C@H]2C[C@H]21
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.2 %

Procedure:
To a solution of (1R,3S,5R)-tert-butyl 3-(hydroxymethyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (4.85 g, 22.74 mmol) in DCM (125 mL) at 0° C. was added Dess-Martin periodinane (11.57 g, 27.3 mmol). The reaction was warmed up to RT and stirred for 3 h. The reaction was poured into a saturated aq solution of NaHCO3 then ca ˜20 g of Na2S2O3 was added and stirred for 1 h. The layers were separated and the aqueous layer was extracted several times with DCM. The combined organic extracts were dried over Na2SO4 and evaporated in vacuo. The residue was purified by flash column chromatography (BIOTAGE®), eluting with a gradient of 0 to 40% EtOAc/hexanes to afford (1R,3S,5R)-tert-butyl 3-formyl-2-azabicyclo[3.1.0]hexane-2-carboxylate (4.47 g, 21.2 mmol, 93% yield) as colorless oil. LC-MS retention time 0.813 min; m/z no ionization (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5u C18 4.6×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where Solvent A was 10% MeOH/90% H2O/0.1% TFA and Solvent B was 10% H2O/90% MeOH/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (400 MHz, chloroform-d) δ ppm 9.48 (br s, 1H), 3.67-3.97 (m, 1H), 3.33-3.59 (m, 1H), 2.10-2.31 (m, 2H), 1.56-1.67 (m, 1H), 1.47 (br s, 9H), 0.80 (br s, 1H), 0.55 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:9][CH3:10])[CH2:4][CH2:5][CH2:6][CH2:7]Br.C([O-])([O-])=O.[Na+].[Na+].[I-].[Na+].[N:19]1([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.[Al]>C(COC)OC>[CH3:1][O:2][CH:3]([O:9][CH3:10])[CH2:4][CH2:5][CH2:6][CH2:7][N:22]1[CH2:21][CH2:20][N:19]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23]1
Reactant: COC(CCCCBr)OC
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Al]
Agent: [I-]
Solvent: COCCOC
Product: COC(CCCCN1CCN(C(=O)OC(C)(C)C)CC1)OC
Temperature: 25 °C
Yield: 62.5 %

Procedure:
A mixture of 5-bromovaleraldehyde dimethyl acetal (27.5 g, 0.13 mol), Na2CO3 (20.7 g, 0.195 mol), sodium iodide (19.5 g, 0.13 mol) and tert-butyl 1-piperazinecarboxylate (25.5 g, 0.137 mol), in dimethoxyethane (250 ml), was heated at 100° C. for 3 h. Aluminium foil was wrapped around the vessel to exclude light. The mixture was cooled to room temperature and filtered. The filtrate was evaporated under reduced pressure and then EtOAc (50 ml) added and the mixture filtered again to remove inorganic salts. The solvent was removed under vacuum and the residue chromatographed on silica gel eluting with EtOAc to give the title-product (25.7 g, 63%). δ(250 MHz, CDCl3) 1.29-1.71 (6H, m, 3 of CH2); 1.46 (9H, s, OC(Me)3); 2.31-2.39 (6H, m, 3 of CH2); 3.32 (6H, s, CH(OMe)2); 3.41-3.45 (4H, m, 2 of CH2); 4.36 (1H, t, J=6 Hz, CH(OMe)2).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[N:3]=1.[H-].[Na+].[S:21]([NH2:25])([NH2:24])(=[O:23])=[O:22]>CN(C=O)C>[F:8][C:7]1[C:2]([NH:24][S:21]([NH2:25])(=[O:23])=[O:22])=[N:3][C:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[N:5][CH:6]=1
Reactant: NS(N)(=O)=O
Reactant: COc1cccc(COc2ncc(F)c(Cl)n2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(COc2ncc(F)c(NS(N)(=O)=O)n2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 7.2 %

Procedure:
To a magnetically stirred solution of 4-chloro-5-fluoro-2-(3-methoxybenzyloxy)pyrimidine* (1.3 g, 4.84 mmol) in dry DMF (5 mL) was added a pre-mixed suspension of 60% NaH (0.45 g, 10.65 mmol) and sulfamide (0.93 g, 9.68 mmol) in dry DMF (5 mL). The resulting off-white suspension was stirred at room temperature for 72 hrs. The orange suspension was then heated to 50° C. for 48 hours and cooled to room temperature. The reaction mixture was partitioned between ethyl acetate and brine solution. The organic extract was dried over Na2SO4, filtered, and evaporated. The crude material was purified by column chromatography on normal phase silica using a gradient of EtOAc/Hex and reverse phase using a gradient of H2O/ACN to yield [5-Fluoro-2-(3-methoxybenzyloxy)pyrimidin-4-yl]sulfamide (115 mg, 7.2% yield) as a white solid: mp 126-130° C.; 1H NMR (300 MHz, CD3OD) δ 8.01 (d, J=3.63 Hz, 1H), 7.25 (m, 1H), 7.01 (m, 2H), 6.88 (m, 1H), 5.37 (s, 2H), 3.78 (s, 3H); MS (ESI) m/z 326.9 (M−H)−. * The 4-chloro-5-fluoro-2-(3-methoxybenzyloxy)pyrimidine intermediate was prepared as described in the synthesis of 31.
Reaction SMILES: C[Al](C)C.[CH3:5][N:6]([CH3:12])[C:7](=[O:11])[CH2:8][NH:9][CH3:10].[C:13]([C:15]1[C:20]2[N:21]=[C:22]([C:24](OCC)=[O:25])[O:23][C:19]=2[C:18]([F:29])=[C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:16]=1[CH3:36])#[N:14].Cl>ClCCl>[C:13]([C:15]1[C:20]2[N:21]=[C:22]([C:24]([N:9]([CH2:8][C:7]([N:6]([CH3:12])[CH3:5])=[O:11])[CH3:10])=[O:25])[O:23][C:19]=2[C:18]([F:29])=[C:17]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:16]=1[CH3:36])#[N:14]
Reactant: CNCC(=O)N(C)C
Reactant: CCOC(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)c(F)c2oc(C(=O)N(C)CC(=O)N(C)C)nc2c1C#N
Reaction time: 0.58 h
Yield: 59.2 %

Procedure:
Under nitrogen atmosphere, trimethylaluminium (1.03 M n-hexane solution, 1.19 ml, 1.23 mmol) was dropwise added at room temperature to a dichloromethane (2 ml) solution of N,N-dimethyl-2-methylaminoacetamide (143 mg, 1.23 mmol), and stirred for 35 minutes. Subsequently, a dichloromethane (2 ml) solution of ethyl 4-cyano-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-2-carboxylate (I-111) (200 mg, 617 μmol) was dropwise added and stirred for 66.5 hours. After the reaction, aqueous 1 N hydrochloric acid solution was added to the reaction liquid with cooling with ice, followed by stirring at room temperature, and the reaction liquid was extracted with chloroform. Next, the obtained organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and the eluate with ethyl acetate gave the entitled compound (144 mg, 59%) as an amorphous substance.
Reaction SMILES: Cl.C(OC([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([CH:20]2[C:22]([CH3:24])([CH3:23])[C:21]2([CH3:26])[CH3:25])=[O:19])=[CH:13][CH:12]=1)=O)(C)(C)C.C(Cl)Cl>O1CCOCC1>[CH3:25][C:21]1([CH3:26])[C:22]([CH3:23])([CH3:24])[CH:20]1[C:18]([NH:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][NH2:9])=[CH:16][CH:15]=1)=[O:19]
Reactant: CC(C)(C)OC(=O)NCc1ccc(NC(=O)C2C(C)(C)C2(C)C)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC1(C)C(C(=O)Nc2ccc(CN)cc2)C1(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 107.6 %

Procedure:
Add 4M hydrogen chloride in dioxane (6.1 mL) to a solution of N-(tert-butoxycarbonyl)-4-[(2,2,3,3-tetramethyl-cyclopropanecarbonyl)-amino]-benzylamine (0.678 g, 1.958 mmol) in anhydrous 1,4-dioxane (12.2 mL) at room temperature. After stirring at room temperature for 3 h, the reaction is a solid mass. Add more 1,4-dioxane (12.2 mL), DCM (24.4 mL) and more 4M hydrogen chloride in dioxane (6.1 mL), and stir overnight. Concentrate in vacuo and partition the residue between saturated aqueous NaHCO3 (200 mL) and DCM (500 mL). Dry the organic phase over Na2SO4, filter and concentrate in vacuo. The aqueous phase was extracted with DCM/iso-propanol (3:1, 4×200 mL). Dry the combined organic extracts over Na2SO4, filter, combine with the organic fraction isolated above and concentrate in vacuo. Purify by SCX chromatography eluting with DCM and DCM/2M ammonia in methanol (1:1) to obtain the title compound (0.519 g, 100%). MS (ES+) m/z: 247.2 (M+H)+.
Reaction SMILES: [CH3:1]/[C:2](=[CH:6]\[CH:7]=[CH:8]\[C:9](\[CH3:26])=[CH:10]\[CH2:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([O:19][C:20]([F:23])([F:22])[F:21])=[C:14]([CH3:24])[C:13]=1[CH3:25])/[CH:3]=[CH:4]/[OH:5]>[O-2].[O-2].[Mn+4].C(Cl)Cl>[CH3:1]/[C:2](/[CH:6]=[CH:7]/[CH:8]=[C:9](\[CH3:26])/[CH:10]=[CH:11]/[C:12]1[C:17]([CH3:18])=[CH:16][C:15]([O:19][C:20]([F:21])([F:23])[F:22])=[C:14]([CH3:24])[C:13]=1[CH3:25])=[CH:3]\[CH:4]=[O:5]
Reactant: CC(/C=C/O)=C\C=C\C(C)=C\Cc1c(C)cc(OC(F)(F)F)c(C)c1C
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(/C=C/C=C(C)/C=C/c1c(C)cc(OC(F)(F)F)c(C)c1C)=C\C=O

Procedure:
(2E,4E,6E,8E)-3,7-dimethyl-9-[2,3,6-trimethyl-4-(trifluoromethoxy)phenyl]-nonatetraen-1-ol (0.6 mmol) could be dissolved in 20 ml. of methylene chloride and added to a suspension of 1.1 g. of activated manganese dioxide in 40 ml. of methylene chloride. After filtration, the filtrate is concentrated to afford (2E,4E,6E,8E)-3,7-dimethyl-9-[2,3,6-trimethyl-4-(trifluoromethoxy)phenyl]-nonatetraen-1-al which is purified by crystallization or chromatography in a conventional manner.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]3[N:13]([CH2:16][C@H:17]4[O:22][CH2:21][CH2:20][N:19]([C:23]5[N:28]=[CH:27][C:26](B6OC(C)(C)C(C)(C)O6)=[CH:25][N:24]=5)[CH2:18]4)[N:14]=[N:15][C:10]3=[N:9][CH:8]=2)[CH:4]=[N:3]1.[OH2:38]>C1COCC1>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]3[N:13]([CH2:16][C@@H:17]4[CH2:18][N:19]([C:23]5[N:24]=[CH:25][C:26]([OH:38])=[CH:27][N:28]=5)[CH2:20][CH2:21][O:22]4)[N:14]=[N:15][C:10]3=[N:9][CH:8]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(B6OC(C)(C)C(C)(C)O6)cn5)CCO4)c3n2)cn1
Reactant: O
Solvent: C1CCOC1
Product: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(O)cn5)CCO4)c3n2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
(S)-2-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)pyrimidin-2-yl)morpholine 109 mg (0.22 mmol) was dissolved in THF 3 ml and distilled water 3 ml, and NaBO3 65 mg (0.651 mmol) was added. The mixture was stirred at room temperature for 1 hour. When the reaction was completed, the reaction mixture was extracted with MC and water, and the organic layer was dried over Na2SO4. Prep LC with 4% MeOH/MC gave a product 54 mg (63%).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24](OC)=[O:25])=[C:21]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]([F:39])([F:38])[F:37])[CH:20]=3)[C:12]=2[CH:11]=1)(C(C)(C)C)(C)C.[NH3:40]>CO>[OH:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([NH2:40])=[O:25])=[C:21]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]([F:38])([F:37])[F:39])[CH:20]=3)[C:12]=2[CH:11]=1
Reactant: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1OCc1ccccc1C(F)(F)F
Reactant: N
Solvent: CO
Product: NC(=O)c1sc(-n2cnc3cnc(CO)cc32)cc1OCc1ccccc1C(F)(F)F
Temperature: 120 °C
Reaction time: 3 h

Procedure:
A mixture of 3.15 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxylate (compound B2b) and 218 ml of a saturated solution of ammonia in methanol was stirred in an autoclave at 120° C. for 3 h. The mixture was allowed to cool down to room temperature and concentrated to dryness to give the crude corresponding acid amide that was immediately used for the next step without further purification. The residue was dissolved in 180 ml tetrahydrofuran and to this solution is added 2.0 ml of tetra-n-butylammonium fluoride solution (˜75% in H2O) at 0° C. The reaction mixture was stirred at 0° C. for 12 h. The solvent was evaporated and the residue was treated with 250 ml dichloromethane and 60 ml saturated aqueous NaHCO3 solution. The resulting precipitate was dissolved by addition of propan-2-ol, the organic layer was separated, washed with 60 ml saturated aqueous NaHCO3 solution, dried with MgSO4 and concentrated under vacuum. The residue was suspended in 40 ml dichloromethane and stirred for one hour. The suspension was filtered, the filter cake washed with 20 ml dichloromethane and dried under vacuum to yield the title compound.