Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[CH2:7]([O:9][C:10](=[O:19])[CH2:11][C:12]1[C:17](=[O:18])[CH2:16][CH2:15][CH2:14][CH:13]=1)[CH3:8].O>CS(C)=O>[CH2:7]([O:9][C:10](=[O:19])[CH2:11][C:12]12[CH2:2][CH:13]1[CH2:14][CH2:15][CH2:16][C:17]2=[O:18])[CH3:8]
Reactant: CCOC(=O)CC1=CCCCC1=O
Reactant: C[S+](C)(C)=O
Agent: [I-]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)CC12CC1CCCC2=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76.3 %

Procedure:
Sodium hydride (18.1 mmol, 543 mg of an 80% dispersion in mineral oil) was washed with 2×5 mL of petroleum ether under nitrogen, then it was dried and trimethylsulfoxonium iodide (3.99 g, 18.1 mmol) was added to the flask followed by 21.6 mL dimethylsulfoxide added dropwise. Next, a solution of 6-oxo-1-cyclohexeneacetic acid ethyl ester (2.90 g, 17.3 mmol) was added dropwise as a solution in 4.5 mL of dimethylsulfoxide as the reaction mixture was cooled with a water bath. After the addition, the reaction mixture was stirred at room temperature for 1.5 hours then poured into 80 mL of cold water and extracted with 4×60 mL of ether. The extracts were combined, washed with 80 mL of brine, dried over magnesium sulfate and concentrated affording 2.4 g (13.2 mmol, 73% yield) of the title compound as a yellow oil.
Reaction SMILES: [OH-].[Na+:2].[CH3:3][C:4]1[CH:5]=[N:6][C:7]([CH2:13][S+:14]([O-:26])[C:15]2[NH:16][C:17]3[CH:18]=[CH:19][C:20]([O:24][CH3:25])=[CH:21][C:22]=3[N:23]=2)=[C:8]([CH3:12])[C:9]=1[O:10][CH3:11]>CO>[CH3:3][C:4]1[CH:5]=[N:6][C:7]([CH2:13][S+:14]([O-:26])[C:15]2[N-:16][C:17]3[CH:18]=[CH:19][C:20]([O:24][CH3:25])=[CH:21][C:22]=3[N:23]=2)=[C:8]([CH3:12])[C:9]=1[O:10][CH3:11].[Na+:2]
Reactant: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2[n-]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Reaction time: 0.25 h
Yield: 96.3 %

Procedure:
8.7 g of sodium hydroxide and 175 ml of methanol were taken into a round bottom flask and stirred for 15 minutes. A solution of 50 g of esomeprazole dissolved in 175 ml of methanol was added to the above methanolic sodium hydroxide. The mixture was stirred at 29° C. for 3.5 hours. The mixture was then distilled atmospherically at 78° C. to remove 80% of the solvent. 250 ml of ethyl acetate was added to the residue and was co-distilled with 750 ml of ethyl acetate in three equal lots at 40° C. To the obtained residue, another 250 ml of ethyl acetate was added and stirred at 29° C. for 1 hour. The separated solid was filtered and washed with 100 ml of ethyl acetate. The wet compound was taken into another round bottom flask and 250 ml of ethyl acetate was added and stirred for 1 hour, 15 minutes. The separated solid was filtered and washed with 100 ml of ethyl acetate. The wet compound was dried at 62° C. for 6 hours to yield 51.2 g of the title compound.
Reaction SMILES: CO.[Na].Cl.[NH2:5][C:6]([NH2:8])=[NH:7].Cl[C:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C:21]2[C:22]3[CH:29]=[CH:28][N:27]([CH3:30])[C:23]=3[N:24]=[CH:25][N:26]=2)[CH:13]=1)=[O:11]>ClCCl>[CH3:30][N:27]1[C:23]2[N:24]=[CH:25][N:26]=[C:21]([N:14]3[C:15]4=[N:16][CH:17]=[CH:18][CH:19]=[C:20]4[C:12]([C:10]([NH:7][C:6]([NH2:8])=[NH:5])=[O:11])=[CH:13]3)[C:22]=2[CH:29]=[CH:28]1
Reactant: N=C(N)N
Reactant: Cn1ccc2c(-n3cc(C(=O)Cl)c4cccnc43)ncnc21
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: ClCCl
Product: Cn1ccc2c(-n3cc(C(=O)NC(=N)N)c4cccnc43)ncnc21
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 42.1 %

Procedure:
To 40 cm3 of methanol at about 20° C. under argon atmosphere, was added portionwise 0.36 g (16 mmol) of sodium. Then, after total consumption of the latter, 1.5 g (16 mmol) of guanidine hydrochloride were added. The reaction mixture was stirred at about 20° C. for 1.5 hours and filtered. The precipitate was washed with 5 cm3 of methanol and the combined filtrates were concentrated to dryness in vacuo (2.7 kPa). The residue was diluted in 30 cm3 of dichloromethane and concentrated to dryness in vacuo (2.7 kPa). The residue was diluted in 70 cm3 of tetrahydrofuran under argon atmosphere at about 20° C. and a suspension of 1.3 g (3.2 mmol) of 3-chlorocarbonyl-1-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine in 70 cm3 of dichloromethane was added. The reaction mixture was stirred at about 20° C. for 60 hours and then concentrated to dryness in vacuo (2.7 kPa). The residue was diluted in 100 cm3 of water and the off-white precipitate was filtered and washed twice with 10 cm3 of water. The solid was dried in vacuo at about 50° C. and then recrystallized from 30 cm3 of methanol. The precipitate was washed twice with 5 cm3 of methanol and once with 10 cm3 of diisopropylether respectively, and dried in vacuo at about 50° C. to yield 0.45 g of N-[1-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-guanidine as a gray cristalline powder: mp>260° C. IR spectrum (KBr): 3425; 3157; 1590; 1558; 1518; 1449; 1418; 1308; 1216; 1009; 805; 770; 723; 702 and 605 cm−1. Mass spectrum (EI): m/e 334 M+., m/e 276 (M−CH4N3)+. (base peak), m/e 145 (m/e=276−C7H5N3)+, m/e 132 (C7H6N3)+.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH:14]O.O>FC(F)(F)C(O)=O>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6](=[O:14])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: OO
Reactant: c1ccc2c(c1)sc1ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=S1c2ccccc2-c2ccccc21
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Dibenzothiophene (20.0 g) is suspended in 80.0 ml of trifluoroacetic acid at room temperature. Into the suspension is slowly dropped 12.4 ml of 30% aqueous hydrogen peroxide while cooling with ice so as to maintain the reaction temperature around 60° C. After completion of dropping, the reaction solution is stirred at room temperature for 30 minutes. After the reaction, the reaction solution is added to 1,000 ml of water to precipitate crystals. The crystals are recovered by filtration and washed with water. The obtained crystals are recrystallized with acetonitrile to obtain 19.2 g of dibenzothiophene-S-oxide.
Reaction SMILES: [C:1]1(=[O:12])[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][C:3](=[O:11])[CH2:2]1.C(N(CC)CC)C.C1(C)C=CC(S([N:29]=[N+:30]=[N-])(=O)=O)=CC=1>C(O)C>[N+:29](=[C:2]1[C:3](=[O:11])[CH2:4][CH:5]2[CH:10]([CH2:9][CH2:8][CH2:7][CH2:6]2)[C:1]1=[O:12])=[N-:30]
Reactant: O=C1CC(=O)C2CCCCC2C1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: [N-]=[N+]=C1C(=O)CC2CCCCC2C1=O
Temperature: -10 °C
Reaction time: 1 h
Yield: 35.4 %

Procedure:
A solution of 10.0 g (0.0768 mol) of decalin-1,3-dione in 50 ml of ethanol was magnetically stirred under nitrogen and cooled to -10° C. To the solution was added 7.77 g (0.0768 mol) of triethylamine followed by 15.14 g (0.0768 mol) of p-toluenesulfonylazide added all at once. The mixture was stirred for one hour at 0° C., and the solvent removed at reduced pressure at a temperature of less than 40° C. To the residue was added 200 ml of ether, and the ether removed to yield a yellow solid. This was recrystallized from ethanol to give 5.23 g of yellow crystals, mp 81°-83° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([C:17]4[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=4)[C:20]([OH:22])=O)=[CH:16][C:10]=3[C:9]=2[C:26](=[O:29])[NH:27][CH3:28])=[CH:4][CH:3]=1.Cl.[C:31]1([C:37]2([NH2:41])[CH2:40][CH2:39][CH2:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([C:17]4[CH:25]=[CH:24][CH:23]=[C:19]([C:20](=[O:22])[NH:41][C:37]5([C:31]6[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=6)[CH2:38][CH2:39][CH2:40]5)[CH:18]=4)=[CH:16][C:10]=3[C:9]=2[C:26]([NH:27][CH3:28])=[O:29])=[CH:6][CH:7]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)sc2ccc(-c3cccc(C(=O)O)c3)cc12
Reactant: NC1(c2ccccc2)CCC1
Agent: Cl
Product: CNC(=O)c1c(-c2ccc(F)cc2)sc2ccc(-c3cccc(C(=O)NC4(c5ccccc5)CCC4)c3)cc12

Procedure:
2-(4-fluorophenyl)-N-methyl-5-(3-(1-phenylcyclobutylcarbamoyl)phenyl)benzo[b]thiophene-3-carboxamide was prepared from 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzo[b]thiophen-5-yl)benzoic acid (0.075 g, 0.15 mmol) and 1-phenylcyclobutanamine hydrochloride (0.041 g, 0.22 mmol). 1H NMR (500 MHz, DMSO-D6) δ ppm 9.18 (s, 1H), 8.42 (d, J=4.58 Hz, 1H), 8.14-8.22 (m, 2H), 7.97 (s, 1H), 7.88 (dd, J=16.02, 7.48 Hz, 2H), 7.82 (d, J=8.54 Hz, 1H), 7.66 (dd, J=8.24, 5.80 Hz, 2H), 7.59 (t, J=7.63 Hz, 1H), 7.52 (d, J=7.63 Hz, 2H), 7.31-7.40 (m, 4H), 7.21 (t, J=7.32 Hz, 1H), 2.77 (d, J=4.58 Hz, 3H), 2.62-2.71 (m, 2H), 2.53-2.60 (m, 2H), 2.02-2.11 (m, 1H), 1.83-1.92 (m, 1H). LCMS: retention time: 3.370 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, 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 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3OH/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3OH/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 535 (MH+).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH:11]([OH:13])[C:10]2[CH:14]=[CH:15][S:16][C:9]=2[S:8]1(=[O:18])=[O:17])[CH3:2].[CH:19]([O:21][CH2:22][CH3:23])=[CH2:20].C(=O)(O)[O-].[Na+]>C1COCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:19]([O:21][CH:22]([O:13][CH:11]1[C:10]2[CH:14]=[CH:15][S:16][C:9]=2[S:8](=[O:17])(=[O:18])[N:7]([CH2:6][CH2:5][CH2:4][O:3][CH2:1][CH3:2])[CH2:12]1)[CH3:23])[CH3:20]
Reactant: CCOCCCN1CC(O)c2ccsc2S1(=O)=O
Reactant: C=COCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOCCCN1CC(OC(C)OCC)c2ccsc2S1(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.3 %

Procedure:
A solution of the product from Step B (13.0 g, 44.77 mmol) and p-toluenesulfonic acid (0.20 g) in THF (250 mL) was cooled in an ice bath and ethyl vinyl ether (4.7 mL, 49.24 mmol) was added slowly; this mixture was stirred at room temperature for 18 hr. Sodium bicarbonate (2.0 g) was added and the mixture stirred for 30 min, washed with water (3×75 mL), saturated aqueous sodium chloride (100 mL) and dried (MgSO4). The mixture was evaporated to a residue which was filtered through silica gel with 3:1 hexane/ethyl acetate to give a pale yellow oil (7.53 g, 46%) which was used in the next reaction.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:28](O)=[O:29])=[CH:11][C:12]3[N:16]([CH2:17][CH2:18][C:19](=[O:25])[N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)[CH:15]=[N:14][C:13]=3[C:26]=2[F:27])=[C:4]([Cl:31])[CH:3]=1.Cl.[CH:33]1([CH2:36][O:37][NH2:38])[CH2:35][CH2:34]1>>[CH:33]1([CH2:36][O:37][NH:38][C:28]([C:10]2[C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=3[Cl:31])=[C:26]([F:27])[C:13]3[N:14]=[CH:15][N:16]([CH2:17][CH2:18][C:19](=[O:25])[N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)[C:12]=3[CH:11]=2)=[O:29])[CH2:35][CH2:34]1
Reactant: O=C(O)c1cc2c(ncn2CCC(=O)N2CCCC2)c(F)c1Nc1ccc(Br)cc1Cl
Reactant: NOCC1CC1
Agent: Cl
Product: O=C(NOCC1CC1)c1cc2c(ncn2CCC(=O)N2CCCC2)c(F)c1Nc1ccc(Br)cc1Cl

Procedure:
The title compound is prepared from 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-(3-oxo-3-pyrrolidin-1-yl-propyl)-3H-benzoimidazole-5-carboxylic acid and O-cyclopropylmethyl-hydroxylamine hydrochloride by the standard coupling procedure described in Step A: MS APCI (+) m/z 578, 580 (M+, Br pattern) detected; 1H NMR (400 MHz, DMSO-d6) δ 11.66 (s, 1H), 8.42 (s, 1H), 8.01 (s, 1H), 7.76 (s, 1H), 7.62 (s, 1H), 7.28 (d, 1H), 6.39 (890 m, 1H), 4.52 (t, 2H), 3.66 (d, 2H), 3.33 (t, 2H), 3.28 (t, 2H), 2.89 (t, 2H), 1.83 (m, 2H), 1.76 (m, 2H), 1.06 (m, 1H), 0.49 (m, 1H), 0.22 (m, 2H); 19F NMR (376 MHz, DMSO-d6)−132.94 (s, 1F).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[CH3:26][N:27]1[CH2:32][CH2:31][CH:30]([C:33](O)=[O:34])[CH2:29][CH2:28]1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:33]([CH:30]5[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]5)=[O:34])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: CN1CCC(C(=O)O)CC1
Agent: Cl
Product: CN1CCC(C(=O)N[C@H]2CC[C@H](CCN3CCC(c4cccc5c4OCO5)CC3)CC2)CC1

Procedure:
The title compound, white solid (26.9 mg, 69.5%), MS (ISP) m/z=456.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (31.2 mg, 0.085 mmol) and 1-methylpiperidine-4-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:12][CH:11]([CH2:13]OS(C)(=O)=O)[O:10][N:9]=2)=[N:6][CH:7]=1.[N-:19]=[N+:20]=[N-:21].[Na+].[Cl-].[Na+]>CN(C)C=O>[N:19]([CH2:13][CH:11]1[O:10][N:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[CH2:12]1)=[N+:20]=[N-:21]
Reactant: CS(=O)(=O)OCC1CC(c2ccc(Br)cn2)=NO1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC1CC(c2ccc(Br)cn2)=NO1
Temperature: 75 °C
Yield: 58.6 %

Procedure:
Methanesulfonic acid 3-(5-bromo-pyridin-2-yl)-4,5-dihydro-isoxazol-5-ylmethyl ester (30.5 g, 90.77 mmol) was added to dimethyl formamide (50 ml) followed by addition of sodium azide (11.8 g, 181.5 mmol). The mixture was heated to 75° C. for five hours and then added to aqueous sodium chloride (100 ml) followed by extraction with ethyl acetate (3×200 ml). The organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to yield the desired product (15 g).
Reaction SMILES: [N:1]1([C:7]([NH:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([C:27]4[C:32]([NH:33][CH:34]([CH3:36])[CH3:35])=[CH:31][CH:30]=[CH:29][N:28]=4)[CH2:23][CH2:22]2)=[O:20])=[CH:13]3)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C([BH3-])#N.[Na+].[CH3:41][C:42]([CH3:44])=O.[OH-].[Na+]>CO.C(O)(=O)C>[CH3:41][CH:42]([N:4]1[CH2:3][CH2:2][N:1]([C:7]([NH:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([C:27]4[C:32]([NH:33][CH:34]([CH3:36])[CH3:35])=[CH:31][CH:30]=[CH:29][N:28]=4)[CH2:25][CH2:26]2)=[O:20])=[CH:13]3)=[O:8])[CH2:6][CH2:5]1)[CH3:44]
Reactant: CC(C)=O
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2cc3cc(NC(=O)N4CCNCC4)ccc3[nH]2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2cc3cc(NC(=O)N4CCN(C(C)C)CC4)ccc3[nH]2)CC1

Procedure:
To a solution of 1-[5-(1-piperazinylcarbonylamino)-indole-2-carbonyl]-4-[3-(1-methylethylamino)-2-pyridinyl]piperazine (EXAMPLE 46, 0.41 g) in methanol (50 ml) is added sodium cyanoborohydride (53 mg) and acetone (1 ml). Additional sodium cyanoborohydride (44.3 mg total) and excess acetone are added in portions until the reaction is complete as judged by TLC on silica gel. The mixture is acidified with acetic acid, neutralized with 50% aqueous sodium hydroxide and concentrated. The residue is dissolved in methylene chloride, washed with water, saturated potassium carbonate solution, and saline and dried over sodium sulfate followed by concentration. The resulting material is purified by chromatography on silica gel (100 ml) packed in methanol/chloroform (1/99) and eluted with a methanol/chloroform gradient (1→5%) to give the title compound, NMR (chloroform-d) 9.14, 7.71, 7.33, 7.17, 6.95, 6.86, 6.74, 4.06, 3.58, 3.20, 2.78, 2.60, 1.27, 1.08 δ.
Reaction SMILES: COC1C=CC=CC=1[C:9]1[CH:14]=[C:13]([N+]([O-])=O)[CH:12]=[CH:11][C:10]=1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][C:22]=1C1C=CC=CC=1OC)(=[O:20])=[O:19].[OH-].[Na+].[CH2:40]([OH:42])C>>[CH3:40][O:42][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:18]([C:21]1[CH:22]=[CH:23][C:24]([NH2:27])=[CH:25][CH:26]=1)(=[O:19])=[O:20]
Reactant: CCO
Reactant: COc1ccccc1-c1cc([N+](=O)[O-])ccc1S(=O)(=O)c1ccc([N+](=O)[O-])cc1-c1ccccc1OC
Agent: [Na+]
Agent: [OH-]
Product: COc1ccccc1S(=O)(=O)c1ccc(N)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
To a stirred slurry of 2-methoxyphenyl-4-nitrophenyl sulfone (12.36 g, 4.2 mmol) and 90 mL of absolute ethanol was added stannous chloride dihydrate (47.4 g, 21 mmol) in one portion. The mixture was heated to 50° C. where an exothermic reaction caused the solution to strongly reflux. The mixture was allowed to stir at ambient temperature for 30 min., poured onto ice-water and made strongly basic by the addition of 350 mL of 15% NaOH. The mixture was extracted with methylene chloride (3×275 mL), the extracts dried (MgSO4), filtered, and the solvent removed in vacuo to yield a white solid which was recrystallized from ethyl acetate-hexane. After cooling the solid was filtered to yield the title benzenamine (5.38 g, 49%) as a white solid; mp 206°-208° C. 1H-NMR (300 MHz, d6 -DMSO): 3.75 (s, 3H, OCH3), 6.10 (s, 2H, NH2), 6.56-6.61 (m, 2H, aromatic), 7.07-7.13 (m, 2H, aromatic), 7.49-7.61 (m, 3H, aromatic), 7.90 (dd, 1H, J =8.1 & 1.7 Hz, aromatic). MS (CI, CH4): 264 (M+1).
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH:27]1[CH2:31][CH2:30][CH2:29][O:28]1)[C:4]1[C:5]2[CH2:25][NH:24][CH2:23][CH2:22][C:6]=2[N:7]=[C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:13][CH:12]=2)[N:9]=1)[CH3:2].[C:32](O)(=O)C.C=O.C([BH3-])#N.[Na+]>CO>[CH2:1]([N:3]([CH2:26][CH:27]1[CH2:31][CH2:30][CH2:29][O:28]1)[C:4]1[C:5]2[CH2:25][N:24]([CH3:32])[CH2:23][CH2:22][C:6]=2[N:7]=[C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:15][CH:16]=2)[N:9]=1)[CH3:2]
Reactant: CCN(CC1CCCO1)c1nc(Nc2ccc(-c3cnco3)cc2)nc2c1CNCC2
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCN(CC1CCCO1)c1nc(Nc2ccc(-c3cnco3)cc2)nc2c1CN(C)CC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
N4-Ethyl-N2-(4-(oxazol-5-yl)phenyl)-N4-((tetrahydrofuran-2-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (125 mg, 0.30 mmol, example 81a) was dissolved in methanol (3 mL). Acetic acid (0.017 mL, 0.30 mmol) was added followed by formaldehyde (0.022 mL, 0.30 mmol). The reaction was stirred at room temperature for 15 minutes and sodium cyanoborohydride (18.7 mg, 0.30 mmol) (MP—CNBH3) was added. The reaction was stirred overnight at room temperature. The MP—CNBH3 was filtered, the solvent evaporated under reduced pressure, the crude dissolved in methanol and purified by preparative HPLC N4-ethyl-6-methyl-N2-(4-(oxazol-5-yl)phenyl)-N4-((tetrahydrofuran-2-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (29.8 mg, 21.04%) as acetate salt. MS (ES+) m/z 435.2 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH:12]([O:15][CH3:16])[O:13][CH3:14])[N:8]([C:17]([O:19]C1C=CC=CC=1)=O)[CH2:7][CH2:6][CH2:5]2.[NH2:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][N:28]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH:12]([O:13][CH3:14])[O:15][CH3:16])[N:8]([C:17]([NH:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][N:28]=1)=[O:19])[CH2:7][CH2:6][CH2:5]2
Reactant: COC(OC)c1nc2c(cc1Br)CCCN2C(=O)Oc1ccccc1
Reactant: N#Cc1ccc(N)nc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(OC)c1nc2c(cc1Br)CCCN2C(=O)Nc1ccc(C#N)cn1
Reaction time: 2 h

Procedure:
A solution of phenyl 6-bromo-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (intermediate 11, 640 mg, 1.57 mmol) and 6-aminonicotinonitrile (206 mg, 1.73 mmol) in THF (10 ml) at −10° C. was treated with LHMDS (1M in THF, 1.89 ml, 1.89 mmol) and stirred for 2 h. The reaction mixture was quenched with saturated aqueous NH4Cl. The org. layer was washed with water (2×) and brine, dried over Na2SO4, filtered and concentrated under vacuum. The crude material was dissolved in a small quantity of DCM and then, MeOH was added to precipitate the product. The white solid was collected by filtration and washed with MeOH to obtain the title compound as a white solid. (UPLC-MS 1) tR 1.18 min; ESI-MS 432.0, 434.0 [M+H]+.
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:18])[N:14]=2)=[CH:6][C:5]=1[OH:26].[CH2:28](I)[CH3:29]>>[F:27][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:18])[N:14]=2)=[CH:6][C:5]=1[O:26][CH2:28][CH3:29]
Reactant: Cc1cccnc1C(=O)CCc1coc(-c2ccc(OC(F)F)c(O)c2)n1
Reactant: CCI
Product: CCOc1cc(-c2nc(CCC(=O)c3ncccc3C)co2)ccc1OC(F)F

Procedure:
Using the compound obtained in Example 327 and ethyl iodide, white powdery 3-[2-(4-difluoromethoxy-3-ethoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one was obtained following the procedure of Example 330.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:24]3[CH2:29][CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12.[ClH:37]>O1CCOCC1.C(OCC)C>[ClH:37].[O:17]([C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[N:8]([C@@H:24]3[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]3)[N:9]=2)=[CH:16][CH:15]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2[C@@H]1CCCNC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
Compound 35 (700 mg, 1.48 mmol, 1 equiv) was dissolved in dioxane (8 mL). A solution of hydrogen chloride in dioxane (4 mL of a 4 N solution in dioxane, 16 mmol, 10.7 equiv) was added and the reaction was stirred at room temperature overnight. The reaction was diluted with diethyl ether (20 mL) and the resulting solids were collected by filtration under a stream of nitrogen. The product was further dried in a vacuum oven to yield 36 (550 mg, 88% yield) as an off-white solid.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.Br.BrCC1[C:51]([Cl:52])=[C:50]([Cl:53])[CH:49]=[CH:48][N:47]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[C:51]([Cl:52])=[C:50]([Cl:53])[CH:49]=[CH:48][N:47]=3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: Clc1ccnc(CBr)c1Cl
Agent: Br
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3nccc(Cl)c3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(bromomethyl)-3,4-dichloropyridine hydrobromide and isolated as light yellow gum. MS (m/e): 442.3 (MH+).