Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][C@@H:12]([CH3:15])[C@H:11]([OH:16])[CH2:10]2)[C:5]([C:17]([NH2:19])=[O:18])=[CH:4][N:3]=1.[C:20]([NH2:24])([CH3:23])([CH3:22])[CH3:21]>CS(C)=O>[C:20]([NH:24][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][C@@H:12]([CH3:15])[C@H:11]([OH:16])[CH2:10]2)[C:5]([C:17]([NH2:19])=[O:18])=[CH:4][N:3]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: C[C@@H]1CC[C@@H](Nc2nc(Cl)ncc2C(N)=O)C[C@H]1O
Reactant: CC(C)(C)N
Solvent: CS(C)=O
Product: C[C@@H]1CC[C@@H](Nc2nc(NC(C)(C)C)ncc2C(N)=O)C[C@H]1O
Temperature: 68 °C
Reaction time: 80 h

Procedure:
To a reactor was charged 2-chloro-4-{[(1R,3R,4R)-3-hydroxy-4-methylcyclohexyl]amino}pyrimidine-5-carboxamide (41 kg), t-butylamine (105.3 kg) and DMSO (205 L). The batch was heated to 68° C. under 10 psig of nitrogen pressure, held for 80 h, and cooled to 25° C. The batch was filtered through a 0.45 μm in-line filter to a second reactor. The batch was heated to 60° C., and water (205 L) was charged through a 0.45 μm in-line filter. The batch was seeded with micronized Compound 1 (820 g) agitated at 60° C. for over an hour, and water (615 L) was charged to the batch through a 0.45 μm in-line filter in 3 h at 60° C. The batch was agitated for 1 h at 60° C., cooled to 25° C. over 6 h, filtered, and washed with water (410 mL), which was filtered through a 0.45 μm in-line filter. The solids were dried in a vacuum oven at 40° C. with nitrogen bleed for over 72 h to give 2-(tert-butylamino)-4-{[(1R,3R,4R)-3-hydroxy-4-methylcyclohexyl]amino}pyrimidine-5-carboxamide as Form A and a white solid (43.5 kg, 94% yield). 1H NMR (DMSO-d6) δ 0.95 (d, J=6.2 Hz, 3H), 0.97-1.28 (m, 4H), 1.37 (s, 9H), 1.60-1.75 (m, 1H), 1.83-2.00 (m, IH), 2.06-2.26 (m, 1H), 2.86-3.07 (m, 1H), 3.74-4.01 (m, 1H), 4.59 (d, J=5.7 Hz, 1H), 6.65 (br. s., 1H), 7.03 (br. s., 1H), 7.57 (br. s., 1H), 8.36 (s, 1H), 8.93 (br. s., 1H).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[CH2:10][OH:11].[Cl:19][CH2:20][C:21](Cl)=[O:22]>C1COCC1>[Cl:19][CH2:20][C:21]([NH:8][CH:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[CH2:10][OH:11])=[O:22]
Reactant: NC(CO)c1cccc(F)c1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCl)NC(CO)c1cccc(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In step 2-2, triethylamine (8.15 mL, 58.6 mmol) in a single portion was added to a solution of 2-amino-2-(3-fluorophenyl)ethanol (7.57 g, 48.8 mmol) in THF cooled to 0° C. and chloroacetyl chloride (5.08 mL, 58.6 mmol) was added drop-wise. The mixture was cooled to 0° C. and stirred for 1 hour. The reaction mixture was quenched with water and the organic phase was washed with 0.5 N HCl, saturated NaHCO3, brine, and dried over MgSO4. The organic phase was concentrated and purified with flash chromatography (50% EtOAc/hexanes) to yield 2-chloro-N-(1-(3-fluorophenyl)-2-hydroxyethyl)acetamide (2-2) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.O.O.[Sn](Cl)Cl>CCO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: Cc1ccc2nc(-c3ccc([N+](=O)[O-])cc3)cn2c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Cc1ccc2nc(-c3ccc(N)cc3)cn2c1
Yield: 57.9 %

Procedure:
Prepared as described in the Nitro Reduction section using 6-methyl-2-(4-nitrophenyl)imidazo[1,2-a]pyridine (0.423 g, 1.67 mmol) and tin (II) chloride dihydrate (1.89 g, 8.36 mmol) in EtOH (45 ml) to give the title compound (0.216 g, 58%) as a pale orange solid, after work-up and flash chromatography (EtOAc).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:15])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][O:23][C:24]1[C:25]([CH3:31])=[CH:26][C:27]([NH2:30])=[CH:28][CH:29]=1>>[Cl:15][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:30][C:27]3[CH:28]=[CH:29][C:24]([O:23][CH2:22][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=4)=[C:25]([CH3:31])[CH:26]=3)=[N:3][CH:4]=[N:5]2)=[CH:10][C:9]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc2c(Cl)ncnc2cc1Cl
Reactant: Cc1cc(N)ccc1OCc1ccccn1
Product: Cc1cc(Nc2ncnc3cc(Cl)c([N+](=O)[O-])cc23)ccc1OCc1ccccn1
Yield: 81 %

Procedure:
Using an analogous procedure to that described in Example 1, 4,7-dichloro-6-nitroquinazoline was reacted with 5-amino-2-tolyl 2-pyridylmethyl ether to give 7-chloro-4-[3-methyl-4-(2-pyridylmethoxy)anilino]-6-nitroquinazoline in 81% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[C:6]=2[CH:7]=1.[F:22][C:23]1[CH:24]=[C:25]([S:30]([O-:32])=[O:31])[CH:26]=[C:27]([F:29])[CH:28]=1.[Na+]>>[F:29][C:27]1[CH:26]=[C:25]([S:30]([C:2]2[CH:3]=[CH:4][C:5]3[O:14][C:13]4[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=4[C:6]=3[CH:7]=2)(=[O:31])=[O:32])[CH:24]=[C:23]([F:22])[CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3ccc(Br)cc3c2C1
Reactant: O=S([O-])c1cc(F)cc(F)c1
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCc2oc3ccc(S(=O)(=O)c4cc(F)cc(F)c4)cc3c2C1
Yield: 50 %

Procedure:
The product of Example 29, step B and sodium 3,5-difluorobenzenesulfinate were coupled using the procedure of Example 29, step C. Purification by flash column chromatography (SiO2, 3:2 hexane/ethyl acetate) provided tert-butyl 8-(3,5-difluorophenylsulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (191 mg, 50%) as a pale yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.08 (s, 1H), 7.82 (dd, J=8.4, 1.8 Hz, 1H), 7.55 (d, J=8.7 Hz, 1H), 7.49-7.45 (m, 2H), 7.02-6.94 (m, 1H), 4.59 (s, 2H), 3.84 (t, J=5.4 Hz, 2H), 2.91-2.84 (m, 2H), 1.51 (s, 9H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH3:14])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([F:11])[C:5]=1[F:12].[C:15](OCC)(=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>>[CH3:14][O:13][CH:3]([O:2][CH3:1])[C:4]1[C:5]([F:12])=[C:6]([F:11])[C:7]([F:10])=[C:8]([C:15](=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:9]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: COC(OC)c1ccc(F)c(F)c1F
Product: CCOC(=O)C(=O)c1cc(C(OC)OC)c(F)c(F)c1F

Procedure:
Starting materials: 1-(dimethoxymethyl)-2,3,4-trifluorobenzene (Intermediate 39) and diethyl oxalate.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[O:7].Cl[CH2:33][CH2:34][O:35][CH2:36][CH2:37][OH:38].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:33][CH2:34][O:35][CH2:36][CH2:37][OH:38])[CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[O:7]
Reactant: Cc1ccc(C[C@@H]2CNCCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Reactant: OCCOCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(C[C@@H]2CN(CCOCCO)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Temperature: 70 °C
Reaction time: 1 h
Yield: 59.9 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine (500 mg), 2-(2-chloroethoxy)ethanol (168 mg), potassium carbonate (233 mg) and potassium iodide (56 mg) in N,N-dimethylformamide (2 ml) was heated with stirring at 50° C. for 17 hours, 60° C. for 13 hours and 70° C. for 1 hour. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine and dried over magnesium sulfate. After evaporation of the solvent, the resulting residue was purified by column chromatography on silica gel using dichloromethane-methanol (10:1) as eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[2-(2-hydroxyethoxy)ethyl]piperazine (359 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@H:6]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:5]2.[H-].[Na+].Br[CH2:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[C:24]#[N:25]>CN(C=O)C>[C:24]([C:23]1[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=1[CH2:21][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@H:6]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:5]2)#[N:25]
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(O)cc2C1
Reactant: N#Cc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(OCc3ccccc3C#N)cc2C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49 %

Procedure:
A mixture of (S)-N-(5-hydroxy-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide (0.098 mmol, 25 mg) and NaH (0.196 mmol, 4.70 mg) in DMF (1 mL) was stirred at room temp for 15 min. 2-(bromomethyl)benzonitrile (0.098 mmol, 19.20 mg) in DMF (1 mL) was added and the reaction mixture heated at 120° C. for 600 s in a Smith Synthesiser microwave. The reaction mixture was filtered through a Whatman filter and purified by preparative HPLC to give desired product (17.8 mg, 49.1%). MS (ESI): m/z [M−H]− 369.2
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[N:10][C:5]2=[N:4][CH:3]=1.C([Mg]Cl)(C)C.Cl[Sn:17]([CH3:20])([CH3:19])[CH3:18]>O1CCCC1>[CH3:18][Sn:17]([CH3:20])([CH3:19])[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[N:10][C:5]2=[N:4][CH:3]=1
Reactant: C[Sn](C)(C)Cl
Reactant: Brc1cnc2ncccn12
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: C[Sn](C)(C)c1cnc2ncccn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled (−78° C.) solution of 3-bromoimidazo[1,2-a]pyrimidine (1.0 g, 5.1 mmol) in anhydrous tetrahydrofuran (40 mL) under an atmosphere of nitrogen was added isopropylmagnesium chloride (2.0M solution in tetrahydrofuran, 2.8 mL, 5.6 mmol) dropwise over 10 minutes. The reaction was stirred for 2 h then a solution of chlorotrimethylstannane (1.1 g, 5.6 mmol) in tetrahydrofuran (10 mL) was added dropwise over 10 minutes. The reaction mixture was stirred for 30 minutes then allowed to warm to room temperature. The reaction was quenched with water (20 mL) and extracted with DCM (2×50 mL). The combined organic layer was dried over sodium sulfate, filtered, and evaporated in vacuo to afford the title compound as an orange oil which was used without any further purification.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=2)[C:5]2[CH:10]=[C:9]([CH3:11])[S:8][C:6]=2[N:7]=1.[NH:23]1[CH:27]=[CH:26][N:25]=[CH:24]1.C1(O)C=CC=CC=1>C(Cl)Cl>[N:23]1([C:2]2[N:3]=[C:4]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]4[O:20][CH2:21][O:22][C:16]=4[CH:15]=3)[C:5]3[CH:10]=[C:9]([CH3:11])[S:8][C:6]=3[N:7]=2)[CH:27]=[CH:26][N:25]=[CH:24]1
Reactant: Cc1cc2c(NCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Reactant: c1c[nH]cn1
Solvent: ClCCl
Solvent: Oc1ccccc1
Product: Cc1cc2c(NCc3ccc4c(c3)OCO4)nc(-n3ccnc3)nc2s1
Yield: 184.9 %

Procedure:
A solution of 2-chloro-6-methyl-4-(3,4-methylene dioxybenzylamino)-thieno-[2,3-d]-pyrimidine (1.67 g), imidazole (1.02 g) and phenol (2 g) are heated 5 hours at 150° C. After cooling, the residue is dissolved in CH2Cl2. The solvent is removed, and the usual workup yields 2-(imidazol-1-yl)-6-methyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine (3.38 g) Mp. 162° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:14][CH3:15])=[C:4]([CH2:12][OH:13])[CH:5]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:7]=1.N1C=CN=C1.[CH3:21][Si:22](Cl)([CH3:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(OCC)(=O)C>[C:8]([C:6]1[CH:5]=[C:4]([CH2:12][O:13][Si:22]([CH3:24])([CH3:23])[CH3:21])[C:3]([O:14][CH3:15])=[C:2]([NH2:1])[CH:7]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: C[Si](C)(C)Cl
Reactant: COc1c(N)cc(C(C)(C)C)cc1CO
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1c(N)cc(C(C)(C)C)cc1CO[Si](C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.03 g (3-amino-5-tert-butyl-2-methoxy-phenyl)-methanol and 2.4 g imidazole are dissolved in 20 ml of tetrahydrofuran and 2.75 ml trimethylsilyl chloride are added dropwise thereto. The mixture is stirred for 2 hours at ambient temperature, the solvents are eliminated in vacuo and the residue is divided between 10% aqueous potassium carbonate solution and ethyl acetate. The aqueous phase is extracted with ethyl acetate and the combined organic phases are washed with saturated sodium chloride solution. After drying with magnesium sulphate the solvents are eliminated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 95:5 to 50:50).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH:10]1([N:13]2[CH:17]=[C:16]([C:18]3[CH:19]=[C:20]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28](=[O:30])[CH3:29])[C@@H:23]([CH3:31])[CH2:22][NH:21]4)[CH:15]=[N:14]2)[CH2:12][CH2:11]1.[CH:32]1([C:35](Cl)=[O:36])[CH2:34][CH2:33]1>ClCCCl>[CH:32]1([C:35]([N:21]2[C:20]3[C:25](=[CH:26][CH:27]=[C:18]([C:16]4[CH:15]=[N:14][N:13]([CH:10]5[CH2:12][CH2:11]5)[CH:17]=4)[CH:19]=3)[N:24]([C:28](=[O:30])[CH3:29])[C@@H:23]([CH3:31])[CH2:22]2)=[O:36])[CH2:34][CH2:33]1
Reactant: CC(=O)N1c2ccc(-c3cnn(C4CC4)c3)cc2NC[C@@H]1C
Reactant: O=C(Cl)C1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(=O)N1c2ccc(-c3cnn(C4CC4)c3)cc2N(C(=O)C2CC2)C[C@@H]1C
Temperature: 50 °C
Reaction time: 16 h
Yield: 71.9 %

Procedure:
N,N-Diisopropylethylamine (0.120 mL, 0.688 mmol) was added to a solution of (S)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)ethanone (0.068 g, 0.229 mmol) and cyclopropanecarbonyl chloride (0.031 mL, 0.344 mmol) in 1,2-dichloroethane (2.0 mL), and the mixture stirred at 50° C. for 16 h. The reaction mixture was concentrated to afford an orange oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 50-100% ethyl acetate-hexane) to afford (S)-1-(4-(cyclopropanecarbonyl)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)ethanone (0.060 g, 72%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.68-0.77 (m, 1 H), 0.83-1.02 (m, 5 H), 1.02-1.08 (m, 5 H), 1.87-2.04 (m, 1 H), 2.12 (s, 3 H), 3.33 (m, 1 H), 3.74 (tt, J=7.33, 3.81 Hz, 1 H), 4.61 (m, 1 H), 4.69-4.86 (m, 1 H), 7.37-7.57 (m, 2 H), 7.65 (s, 1 H), 7.85 (s, 1 H), 8.25 (s, 1 H). MS (ESI, pos. ion) m/z 365. [M+1]+.
Reaction SMILES: C([NH:8][C@H:9]1[CH2:13][CH2:12][C@@H:11]([CH2:14][N:15]2[N:19]=[CH:18][CH:17]=[N:16]2)[CH2:10]1)(OC(C)(C)C)=O.[C:20]([OH:26])([C:22]([F:25])([F:24])[F:23])=[O:21]>ClCCl>[F:23][C:22]([F:25])([F:24])[C:20]([OH:26])=[O:21].[N:16]1[N:15]([CH2:14][C@@H:11]2[CH2:12][CH2:13][C@H:9]([NH2:8])[CH2:10]2)[N:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](Cn2nccn2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CC[C@@H](Cn2nccn2)C1

Procedure:
Deprotection of N1-BOC-(1S,3R)-3-(2H-1,2,3-triazol-2-ylmethyl)cyclopentan-1-amine (500 mg, 1.87 mmol) using TFA (3 ml) in dry dichloromethane (3 ml) as described in Example 1, Step 2 gave 528 mg of the amine as its TFA salt, which was used as such for the coupling reaction.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@H:9]([NH:13][C:14]1[NH:22][C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]=2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][CH2:11][CH3:12].Br[CH2:27][CH2:28][CH2:29][CH2:30][Cl:31]>>[Cl:31][CH2:30][CH2:29][CH2:28][CH2:27][N:20]1[C:19]([O:23][CH3:24])=[N:18][C:17]2[C:21]1=[N:22][C:14]([NH:13][C@@H:9]([CH3:8])[CH2:10][CH2:11][CH3:12])=[N:15][C:16]=2[NH2:25]
Reactant: CCC[C@H](C)Nc1nc(N)c2nc(OC)nc-2[nH]1
Reactant: ClCCCCBr
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H](C)Nc1nc(N)c2nc(OC)n(CCCCCl)c2n1

Procedure:
Prepared similarly to Intermediate 44 from N2-[(1S)-1-methylbutyl]-8-(methyloxy)-3H-purine-2,6-diamine trifluoroacetate and 1-bromo-4-chlorobutane.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=3)[NH:16][C:15]=2[CH3:24])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[Cl:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([CH3:24])=[C:14]2[CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: Cc1[nH]c2ccc(Cl)cc2c1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1[nH]c2ccc(Cl)cc2c1C1CCNCC1
Yield: 23.1 %

Procedure:
4-(5-Chloro-2-methyl-1H-indol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (6.2 g, 107.8 mmol) was set stirring in 1:1 TFA/CH2Cl2. After 45 min the mixture was evaporated and the golden oil brought up in Et2O. A solid formed and was filtered, washed with Et2O and air dried to give 6.2 g (95%) of a white solid as a TFA salt. MS (electrospray): exact mass calculated for C14H17ClN2, 248.11; m/z found, 249.1 [M++H].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>O1CCCC1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Reactant: C1CNCCN1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(N2CCNCC2)nc1
Reaction time: 0.5 h

Procedure:
2-Bromo-5-nitropyridine (0.3 g, 1.48 mmol) was treated with piperazine (0.64 g, 7.89 mmol) in tetrahydrofuran (4 ml) and the reaction mixture was stirred for 30 minutes. Subsequently the reaction mixture was poured onto ice-cold water (25 ml) and extracted with ethyl acetate (25 ml). The organic layer was washed with brine and evaporated to furnish the product.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.BrBr.[C:15]1([C:23]([CH2:25][C:26]2[CH:33]=[CH:32][C:29]([O:30][CH3:31])=[CH:28][CH:27]=2)=[S:24])[CH:22]=[CH:21][C:18]([O:19][CH3:20])=[CH:17][CH:16]=1>ClC1C=CC=CC=1>[CH3:20][O:19][C:18]1[CH:17]=[CH:16][C:15]([C:23]2[S:24][C:33]3[CH:32]=[C:29]([O:30][CH3:31])[CH:28]=[CH:27][C:26]=3[CH:25]=2)=[CH:22][CH:21]=1
Reactant: COc1ccc(CC(=S)c2ccc(OC)cc2)cc1
Agent: BrBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Clc1ccccc1
Solvent: O
Product: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Temperature: 25 °C
Yield: 2.5 %

Procedure:
The p-toluene sulfonic acid mono hydrate (310 mg, 1.6 mmol) in 25 ml of chlorobenzene is placed in a 25 ml, 3-neck round bottom flask fitted with a thermometer, nitrogen gas inlet, 10 ml addition funnel, reflux condenser, Dean-Stark trap with drying tube, magnetic stirrer, and heating mantle. 10 ml of solvent is distilled off and bromine (0.08 ml, 1.55 mmol) is added followed by thiodesoxyanisoin (700 mg, 1.6 mmol) in 10 ml of chlorobenzene over 5 minutes. After stirring at reflux for 15 minutes the reaction is allowed to cool to room temperature. A precipitate forms and is filtered off. The filter cake is washed with 50 ml of chlorobenzene. The filtrate is washed with water (2×50 ml), 5% sodium bicarbonate, 50 ml water, and 50 ml of 10% aqueous sodium chloride. The organics are dried over sodium sulfate and concentrated. The crude product is purified by silica gel chromatography then triturated with chlorobenzene. The side product solid is filtered off and the filtrate concentrated. The residue is triturated with ethyl acetate and filtered to give 10.8 mg of pure product. (0.25%). 1H NMR.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8]N(CC)CC)=[CH:6][C:5]([CH3:14])=[CH:4][C:3]=1[N:15]1[N:19]=[C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]2=[N:16]1.[OH:24][C:25]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:26]=1[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:28].C[O-].[Na+].C1(C)C=CC=CC=1>CO>[N:16]1[N:15]([C:3]2[CH:4]=[C:5]([CH3:14])[CH:6]=[C:7]([CH2:8][C:38]3[C:37]([O:39][CH3:40])=[CH:36][CH:35]=[C:26]([C:27](=[O:28])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:25]=3[OH:24])[C:2]=2[OH:1])[N:19]=[C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=12
Reactant: CCN(CC)Cc1cc(C)cc(-n2nc3ccccc3n2)c1O
Reactant: COc1ccc(C(=O)c2ccccc2)c(O)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)c2ccccc2)c(O)c1Cc1cc(C)cc(-n2nc3ccccc3n2)c1O
Temperature: 130 °C
Reaction time: 20 h
Yield: 68.7 %

Procedure:
2-(2-Hydroxy-3-diethylaminomethyl-5-methylphenyl)-2H-benzotriazole (20.0 g, 0.064 tool), 2-hydroxy-4-methoxybenzophenone (14.7 g, 0,064 mol), and sodium methoxide (1.0 g, 25% in methanol) are charged to a reaction flask. The mixture is heated to 130° C. and held at this temperature for 20 hours with agitation under a nitrogen flow. At that time, the product is identified using thin layer chromatography, with toluene as the mobile phase. To the brown-yellow solid is added hot methanol. The yellow solids are vacuum filtered and triturated twice using methanol, yielding 20.6 g product. To remove the yellow color, the solids are dissolved in hot toluene, and silica gel is introduced. The silica gel is gravity filtered hot. The toluene is removed by vacuum distillation, yielding 12.1 g of the title compound as a pale yellow solid, m.p. 206°-209° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:22]=[C:21]([C:23]#[C:24][CH2:25][NH:26][C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:12][C@@H:11]1[OH:33])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(O)(=O)C.C(OC(=O)C)(=O)C.[CH3:45][S:46]([CH3:48])=O>>[Si:1]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:22]=[C:21]([C:23]#[C:24][CH2:25][NH:26][C:27](=[O:32])[C:28]([F:30])([F:31])[F:29])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:12][C@@H:11]1[O:33][CH2:45][S:46][CH3:48])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(C#CCNC(=O)C(F)(F)F)c(=O)[nH]c2=O)C[C@@H]1O
Reactant: CS(C)=O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CSCO[C@H]1C[C@H](n2cc(C#CCNC(=O)C(F)(F)F)c(=O)[nH]c2=O)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 89 %

Procedure:
To a solution of (2) (1.84 g, 3.7 mmol) in dry DMSO (7 ml) was added acetic acid (3.2 ml) and acetic anhydride (10.2 ml). The mixture was stirred for 2 days at room temperature, before it was quenched with sat. aq. NaHCO3. EtOAc (50 ml) was added and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with sat. aq. NaHCO3 solution and dried (MgSO4). After removing the solvent under reduced pressure, the product (3) was purified by chromatography on silica (EtOAc:petroleum ether 8:2) yielding a clear sticky oil (1.83 g, 89%). 1H NMR (d6 DMSO): δ 0.00 (s, 6H, CH3), 0.79 (s, 9H, tBu), 1.96-2.06 (m, 1H, H-2′), 1.99 (s, 3H, SCH3), 2.20-2.26 (m, 1H, H-2′), 3.63-3.74 (m, 2H, H-5′), 3.92-3.95 (m, 1H, H-4′), 4.11-4.13 (m, 2H, CH2), 4.28-4.30 (m, 1H, H-3′), 4.59 (br s, 2H, CH2), 5.97 (t, J=6.9 Hz, 1H, H-1′), 7.85 (s, 1H, H-6), 9.95 (t, J=5.3 Hz, 1H, NH), 11.64 (s, 1H, NH). Mass (−ve electrospray) calcd for C22H32F3N3O6SSi 551.17. found 550.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH:9]=[CH:10]N(C)C)[CH:5]=[CH:4][N:3]=1.[OH-].[Na+].FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[Cl:31][C:32]1[CH:37]=[C:36]([NH:38][C:39]([NH2:41])=[NH:40])[CH:35]=[CH:34][N:33]=1>CC(O)C>[Cl:31][C:32]1[CH:37]=[C:36]([NH:38][C:39]2[N:41]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=3)[CH:9]=[CH:10][N:40]=2)[CH:35]=[CH:34][N:33]=1
Reactant: CN(C)C=CC(=O)c1ccnc(Cl)c1
Reactant: N=C(N)Nc1ccnc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: Clc1cc(Nc2nccc(-c3ccnc(Cl)c3)n2)ccn1
Reaction time: 20 h
Yield: 49.1 %

Procedure:
To a solution of 6.32 g of 1-(2-chloropyridin-4-yl)-3-(dimethylamino)prop-2-en-1-one (30 mmol) in 60 ml of 2-Propanol was added 2.52 g of sodium hydroxide (63 mmol) and 11.96 g of 1-(2-chloropyridin-4-yl)guanidine bis(trifluoroacetate) (30 mmol). The reaction mixture was heated to reflux under stirring for 20 h. After filtration, the precipitate was washed with 100 ml of n-butanol and 120 ml of iPr2O and then air-dried to yield 4.69 g of N,4-bis(2-chloropyridin-4-yl)pyrimidin-2-amine (yield=37%).