Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=3)[C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc([N+](=O)[O-])cc23)cc1OC
Product: COc1ccc(CNc2nc(-n3cccn3)nc3sc([N+](=O)[O-])cc23)cc1OC

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-nitro-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-nitro-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:34]=[C:35]([O:37][CH:38]([CH3:40])[CH3:39])[CH:36]=1)[C:8]([NH:10][CH:11]([CH2:32][CH3:33])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH2:22][CH2:23][O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:14]=1)=O)([CH3:3])[CH3:2].O=P(Cl)(Cl)Cl>C(#N)C>[CH2:25]([O:24][CH2:23][CH2:22][O:21][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][C:16]=1[O:19][CH3:20])[C:8]([C:7]1[CH:6]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:36]=[C:35]([O:37][CH:38]([CH3:40])[CH3:39])[CH:34]=1)=[N:10][CH:11]([CH2:32][CH3:33])[CH2:12]2)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCC(Cc1ccc(OC)c(OCCOCc2ccccc2)c1)NC(=O)c1cc(OC(C)C)cc(OC(C)C)c1
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: CCC1Cc2cc(OCCOCc3ccccc3)c(OC)cc2C(c2cc(OC(C)C)cc(OC(C)C)c2)=N1

Procedure:
15.3 g of the product of step (v) and 12.4 g POCl3 in 250 ml acetonitrile are stirred for 5 hrs. under reflux. The reaction mixture is concentrated, the residue taken up in ethyl acetate and extracted with Na2CO3 solution and brine. The organic phase is dried over Na2SO4, filtered and evaporated and the residue purified chromatographically on silica gel (e 0.04-0.63 mm) to yield the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13]([C:15]3[S:16][C:17]([CH3:20])=[CH:18][CH:19]=3)=[O:14])[S:11][C:7]=2[C:6](I)=[CH:5][CH:4]=1.[CH3:22][C:23]1[CH:28]=[C:27]([Sn](C)(C)C)[CH:26]=[CH:25][N:24]=1>>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13]([C:15]3[S:16][C:17]([CH3:20])=[CH:18][CH:19]=3)=[O:14])[S:11][C:7]=2[C:6]([C:27]2[CH:26]=[CH:25][N:24]=[C:23]([CH3:22])[CH:28]=2)=[CH:5][CH:4]=1
Reactant: Cc1cc([Sn](C)(C)C)ccn1
Reactant: COc1ccc(I)c2sc(NC(=O)c3ccc(C)s3)nc12
Product: COc1ccc(-c2ccnc(C)c2)c2sc(NC(=O)c3ccc(C)s3)nc12
Yield: 50 %

Procedure:
5-Methyl-thiophene-2-carboxylic acid [4-methoxy-7-(2-methyl-pyridin-4-yl)-benzothiazol-2-yl]-amide is synthesized from 5-methyl-thiophene-2-carboxylic acid (4-methoxy-7-iodo-benzothiazol-2-yl)-amide (260 mg, 0.60 mmol) and 2-methyl-4-trimethylstannanyl-pyridine (384 mg, 0.90 mmol) using the general procedure B as a light yellow solid in 50% yield. MS: m/e=396 (M+H+).
Reaction SMILES: [CH2:1]([N:5]([CH3:22])[C:6]([CH:8]1[CH2:13][CH2:12][C:11]2[C:14]3[C:19](Cl)=[N:18][CH:17]=[N:16][C:15]=3[S:21][C:10]=2[CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].[NH2:23][C:24]1[C:33]([O:34][CH3:35])=[CH:32][C:27]2[NH:28][C:29](=[O:31])[S:30][C:26]=2[CH:25]=1>>[CH2:1]([N:5]([CH3:22])[C:6]([CH:8]1[CH2:13][CH2:12][C:11]2[C:14]3[C:19]([NH:23][C:24]4[C:33]([O:34][CH3:35])=[CH:32][C:27]5[NH:28][C:29](=[O:31])[S:30][C:26]=5[CH:25]=4)=[N:18][CH:17]=[N:16][C:15]=3[S:21][C:10]=2[CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: COc1cc2[nH]c(=O)sc2cc1N
Reactant: CCCCN(C)C(=O)C1CCc2c(sc3ncnc(Cl)c23)C1
Product: CCCCN(C)C(=O)C1CCc2c(sc3ncnc(Nc4cc5sc(=O)[nH]c5cc4OC)c23)C1

Procedure:
100 mg (296 μmol) (RS)—N-butyl-4-chloro-N-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxamide (prepared according to intermediate example 89a) were transformed in analogy to example 1 using 6-amino-5-methoxy-1,3-benzothiazol-2(3H)-one to give after working up and purification 8.8 mg (6%) of the title compound.
Reaction SMILES: [C:1]([CH:4]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[C:5]#[N:6])(=O)[CH3:2].[CH3:14][NH:15][NH2:16]>C(O)C>[NH2:6][C:5]1[N:15]([CH3:14])[N:16]=[C:1]([CH3:2])[C:4]=1[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1
Reactant: CC(=O)C(C#N)c1ccc(F)cc1
Reactant: CNN
Solvent: CCO
Product: Cc1nn(C)c(N)c1-c1ccc(F)cc1
Temperature: 25 °C

Procedure:
α-Acetyl-4-fluorophenylacetonitrile (65.1 g) and methylhydrazine (30.9 mL) were dissolved in ethanol (320 mL), and the mixture was heated under reflux for 3 hrs. After the completion of the reaction, the reaction mixture was cooled to room temperature, and the solvent was evaporated. The obtained solid was collected by filtration and washed with hexane to give 5-amino-4-(4-fluorophenyl)-1,3-dimethylpyrazole (69.5 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11]N3CC4(CCN(C)CC4)C3)=[CH:8][C:6]=2[N:7]=1.[CH2:28]1[C:31]2([CH2:36][CH2:35][N:34]([C:37](=[O:39])[CH3:38])[CH2:33][CH2:32]2)[CH2:30][NH:29]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[C:5]2[S:10][C:9]([CH2:11][N:29]3[CH2:30][C:31]4([CH2:36][CH2:35][N:34]([C:37](=[O:39])[CH3:38])[CH2:33][CH2:32]4)[CH2:28]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CN1CCC2(CC1)CN(Cc1cc3nc(Cl)nc(N4CCOCC4)c3s1)C2
Reactant: CC(=O)N1CCC2(CC1)CNC2
Product: CC(=O)N1CCC2(CC1)CN(Cc1cc3nc(Cl)nc(N4CCOCC4)c3s1)C2

Procedure:
Prepared according to the method used in the preparation of 2-chloro-6-(7-methyl-2,7-diaza-spiro[3.5]non-2-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine using 1-(2,7-diaza-spiro[3.5]non-7-yl)-ethanone in place of 7-methyl-2,7-diaza-spiro[3.5]nonane. The title compound was obtained as a colourless solid (47 mg, 61%).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]([OH:10])[C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[C:13]1(C)C=CC(S(O)(=O)=O)=C[CH:14]=1.C([O-])(O)=O.[Na+]>C(O)C.O>[OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]([OH:10])[C:7]([O:9][CH2:13][CH3:14])=[O:8])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)C(O)c1ccc(O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(O)c1ccc(O)cc1
Temperature: 50 °C
Yield: 288 %

Procedure:
A mixture of 5 g of 4-hydroxymandelic acid and 1.28 g of p-toluenesulfonic acid in 200 ml of ethanol is heated at 50° C. for 4 hours. The mixture is poured into saturated aqueous NaHCO3 solution, and a white precipitate is formed. The mixture is diluted with water until the precipitate disintegrates, and then is extracted with diethyl ether. The organic phases are dried over sodium sulfate. Filtration and evaporation of the solvent give ethyl 4-hydroxymandelate (4.2 g, 82%) as a pale yellowish solid.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:2].[Na+].[Na+].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH:21]=[O:22])=[CH:16][CH:15]=1.C1(C)C=CC=CC=1>O>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:2])=[O:22])=[CH:16][CH:15]=1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: COc1ccc(CC=O)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(CC(=O)O)cc1
Temperature: 20 °C
Reaction time: 17 h
Yield: 9896.6 %

Procedure:
1.44 equivalents (7.7 g) of sodium periodate NaIO4, 0.6 mol % (0.045 g) of sodium dichromate Na2Cr2O72H2O and 3 g of 1N sulfuric acid H2SO4 (12 mol %) were dissolved in 50 ml of water. To this solution were added 25 mmol (3.75 g) of 4-methoxyphenylacetaldehyde and 25 ml of toluene, whereupon the reaction mixture was stirred for 17 h at 20° C. The phases were then separated and the aqueous phase was extracted with 2×10 ml of toluene. 30 ml of 1N NaOH were added to the combined toluene phases. The basic water phase was made acidic with 3 g of conc. H2SO4 and extracted with 2×25 ml of toluene. The combined organic phases were washed 3× with H2O, dried over Na2SO4 and evaporated to dryness. 17 mmol (2.82 g) of p-methoxyphenylacetic acid (yield 68% of theory) with a purity of 98% were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[N:6][CH:7]=1.N1C=CN=C1.C([Si](C)(C)Cl)(C)(C)C.CN(C)[CH:25]=[O:26]>>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH:3]=1)[C:8]([O:26][CH3:25])=[O:9]
Reactant: CN(C)C=O
Reactant: OCc1cncc(Br)c1
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Product: COC(=O)c1cncc(Br)c1

Procedure:
5-Bromo-3-hydroxymethylpyridine (3.41 g), imidazole (13.33 g), t-butyldimethylchlorosilane (13.57 g) and N,N-dimethylformamide (63 ml) were treated as reported in J. Am. Chem. Soc., 6190 (1972) to give the title compound (5.605 g) as a yellow oil (yield: quantitative).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9](Cl)=[O:10])[CH:4]=1.[CH3:12][N:13]([CH3:15])[NH2:14].C(N(CC)C(C)C)(C)C>C1COCC1.O.CCOC(C)=O>[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([NH:14][N:13]([CH3:15])[CH3:12])=[O:10])[CH:4]=1
Reactant: O=C(Cl)c1cc(Cl)ccn1
Reactant: CN(C)N
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CN(C)NC(=O)c1cc(Cl)ccn1
Reaction time: 0.25 h
Yield: 55.9 %

Procedure:
To a suspension of 4-chloropicolinoyl chloride hydrochloride (352 mg, 2.0 mmol, 1.0 eq) in 10 mL of THF were added N,N-dimethylhydrazine (120 mg, 2.0 mmol, 1.0 eq) and N,N-diisopropylethylamine (383 μL, 2.2 mmol, 1.1 eq) at room temperature. The reaction mixture was stirred for 15 min and diluted with water (25 mL) and EtOAc (50 mL). The separated organic layer was washed with brine (25 mL), saturated sodium bicarbonate solution (25 mL) and dried over sodium sulfate. Concentration under reduced pressure gave the title compound as colorless solid (223 mg, 56%), which was used without further purification. MH+=200, Rt=1.42 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:32](COCC[Si](C)(C)C)[C:31]([O:41][C@H:42]3[C@H:46]4[O:47][CH2:48][C@@H:49]([OH:50])[C@H:45]4[O:44][CH2:43]3)=[N:30][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH:24]=[C:23]([CH2:25][C:26]([OH:29])([CH3:28])[CH3:27])[CH:22]=[N:21]3)=[CH:16][N:15]=2)=[CH:10][CH:9]=1.C(O)=O.OS([O-])(=O)=O.[K+].[OH-].[Na+]>CS(C)=O.CO.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:32][C:31]([O:41][C@H:42]3[C@H:46]4[O:47][CH2:48][C@@H:49]([OH:50])[C@H:45]4[O:44][CH2:43]3)=[N:30][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH:24]=[C:23]([CH2:25][C:26]([OH:29])([CH3:28])[CH3:27])[CH:22]=[N:21]3)=[CH:16][N:15]=2)=[CH:10][CH:9]=1
Reactant: CC(C)(O)Cc1cnn(-c2ccc(-c3ccc(-c4nc5nc(O[C@@H]6CO[C@H]7[C@@H]6OC[C@H]7O)n(COCC[Si](C)(C)C)c5cc4Cl)cc3)nc2)c1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=CO
Solvent: CS(C)=O
Product: CC(C)(O)Cc1cnn(-c2ccc(-c3ccc(-c4nc5nc(O[C@@H]6CO[C@H]7[C@@H]6OC[C@H]7O)[nH]c5cc4Cl)cc3)nc2)c1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
A mixture of (3R,3aR,6R,6aR)-6-[6-chloro-5-[4-[5-[4-(2-hydroxy-2-methyl-propyl)pyrazol-1-yl]-2-pyridyl]phenyl]-1-(2-trimethylsilylethoxy-methyl)imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol (10.1 mg, 0.014 mmol), formic acid (1.0 mL, 26.1 mmol), and saturated aqueous KHSO4 (0.05 mL) was heated to 40° C. with stirring. After 16 hours, the reaction mixture was cooled to room temperature before being cooled to 0° C. in an ice bath. The pH of the reaction mixture was adjusted to pH 14 through the addition of 5 N NaOH (5.8 mL, 29.0 mmol). THF (2 mL) was added to the reaction mixture, and the reaction was removed from the ice bath and allowed to warm to room temperature. After 30 minutes, the pH of the reaction mixture was adjusted to pH 7 through the addition of 2 N HCl. The reaction mixture was partitioned between EtOAc (30 mL) and water (20 mL). The aqueous layer was extracted with EtOAc (2×20 mL). The organic layers were combined, washed with brine (1× mL), dried over MgSO4, filtered, and evaporated under reduced pressure to give a white residue. This material was dissolved in DMSO/MeOH, and purified by HPLC reverse phase (C-18), using a 30×150 mm Sunfire™ column and eluting with a 20%-100% acetonitrile/water+0.05% TFA gradient followed by a 100% acetonitrile+0.05% TFA flush. The desired fractions were combined, evaporated under reduced pressure, and lyophilized from ethanol and benzene to afford the title compound as a pale yellow solid. LC-MS: calculated for C30H29ClN6O5 589.19 observed m/e: 589.28 (M+H)+ (Rt 1.10/2 min); 1H NMR δ (ppm) (CD3OD): 9.15 (d, J=2.5 Hz, 1H), 8.46 (dd, J=2.7 Hz, 8.9 Hz, 1H), 8.26 (s, 1H), 8.19 (d, J=8.7 Hz, 1H), 8.14 (d, J=8.4 Hz, 2H), 7.97 (s, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.73 (s, 1H), 5.58 (qt, J=5.2 Hz, 1H), 4.98 (t, J=5.2 Hz, 11H), 4.47 (t, J=5.0 Hz, 1H), 4.27-4.31 (m, 1H), 4.17 (dd, J=5.4 Hz, 10.2 Hz, 1H), 4.14 (dd, J=4.7 Hz, 10.2 Hz, 1H), 3.91 (m, 1H), 3.60 (t, J=8.6 Hz, 1H), 2.73 (s, 2H), 1.25 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:18][C:19](=[O:27])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([OH:17])=O)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[Cl:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[C:19]([NH:18][C:4]1[C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15](=[O:17])[N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)=[O:27]
Reactant: C1CCNCC1
Reactant: O=C(O)CN1CCN(c2ncc(Cl)cc2NC(=O)c2cccc(Cl)c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Cl)cnc1N1CCN(CC(=O)N2CCCCC2)CC1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 46.6 %

Procedure:
A mixture of 0.011 g (0.027 mmol) of {4-[5-chloro-3-(3-chloro-benzoylamino)-pyridin-2-yl]-piperazin-1-yl}-acetic acid in N,N-dimethylformamide (1 mL), 0.011 g (0.13 mmol) of piperdine, 0.011 g (0.10 mmol) of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, and 0.011 mL (0.081 mmol) of triethylamine is stirred at room temperature for 4 hours. The mixture is concentrated under reduced pressure and the residue is diluted with water causing a solid to precipitate from solution. The material is collected by filtration, washed with water and dried on the filter pad to provide 0.0060 g (47%) of the title compound (282) as a colorless solid. [M+H]+=476.2.
Reaction SMILES: [Na].[CH2:2]([N:6]1[C:14]2[N:13]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[CH:18][CH:17]=3)[NH:11][C:10]=2[C:9](=[O:26])[N:8]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][Si](C(C)(C)C)(C)C)[C:7]1=[O:42])[CH2:3][CH2:4][CH3:5].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH2:2]([N:6]1[C:14]2[N:13]=[C:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[CH:20][CH:21]=3)[NH:11][C:10]=2[C:9](=[O:26])[N:8]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[OH:34])[C:7]1=[O:42])[CH2:3][CH2:4][CH3:5]
Reactant: CCCCn1c(=O)n(Cc2ccccc2O[Si](C)(C)C(C)(C)C)c(=O)c2[nH]c(Cc3ccc(NC(C)=O)cc3)nc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCn1c(=O)n(Cc2ccccc2O)c(=O)c2[nH]c(Cc3ccc(NC(C)=O)cc3)nc21
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 20.6 %

Procedure:
A suspension of N-(4-{3-butyl-1-[2-(tert-butyl-dimethyl-silanyloxy)-benzyl]-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl}-phenyl)-acetamide sodium salt (75 mg, 0.12 mmol) in tetrahydrofuran cooled to 0° C. was treated with tetrabutylammonium fluoride. The reaction was stirred at 0° C. for 1.5 h. At this time, the reaction mixture was treated with a saturated aqueous ammonium chloride solution (1.0 mL) and then diluted with ethyl acetate (50 mL). This solution was washed with water and brine. The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting residue was diluted with acetonitrile. The insolubles were collected, washed with acetonitrile, and dried in vacuo for 24 hrs to afford N-{4-[3-butyl-1-(2-hydroxy-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-acetamide (11.4 mg, 19%) as a white solid: EI-HRMS m/e calcd for C25H27N5O4 (M+) 461.2063, found 461.2073.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:28])[C:7](=[O:27])[C:8]3[CH:18]=[C:17]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=4)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[C-:29]#[N:30].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:29]([C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:28])[C:7](=[O:27])[C:8]3[CH:18]=[C:17]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=4)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1)#[N:30]
Reactant: [C-]#N
Reactant: CCN1c2ncc(CCc3ccncc3)cc2C(=O)N(C)c2ccc(Cl)nc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCN1c2ncc(CCc3ccncc3)cc2C(=O)N(C)c2ccc(C#N)nc21
Yield: 15 %

Procedure:
A solution of 2-chloro-5,11-dihydro-11-ethyl-8-[2-(4-pyridyl)ethyl]-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (78 mg, 0.2 mmol), Sodium cyanide impregnated alumina (2 g/4 g, 0.44 g, 4.5 mmol), and tetrakis(triphenylphosphine)palladium(0) (45 mg, 0.04 mmol) in 5 mL of toluene was heated at 100° C. under argon for 8 hours. The reaction mixture was filtered, and the collected solid was washed with ethyl acetate. The filtrate was concentrated to give a yellow oil, which was purified by flash chromatography (elution with isopropannol-hexanes) and recrystallization (ethyl acetate-hexanes) to afford 11.5 mg (15%) of the title compound, m.p. 149°-150° C.
Reaction SMILES: C([O:8][C:9]1[CH:33]=[CH:32][C:12]([O:13][CH2:14][C@@H:15]([OH:31])[CH2:16][NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27]([F:30])([F:29])[F:28])[CH2:21][CH2:20]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[OH:31][C@@H:15]([CH2:16][NH:17][CH2:18][CH:19]1[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][C:27]([F:30])([F:28])[F:29])[CH2:23][CH2:24]1)[CH2:14][O:13][C:12]1[CH:32]=[CH:33][C:9]([OH:8])=[CH:10][CH:11]=1
Reactant: O[C@@H](CNCC1CCN(CCC(F)(F)F)CC1)COc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Oc1ccc(OC[C@@H](O)CNCC2CCN(CCC(F)(F)F)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.7 %

Procedure:
A mixture of (2S)-1-(4-Benzyloxy-phenoxy)-3-{[1-(3,3,3-trifluoro-propyl)-piperidin-4-ylmethyl]-amino}-propan-2-ol (0.20 g, 0.43 mmol) and ammonium formate (0.135 g, 2.15 mmol) in 10 mL of methanol over 0.20 g of 10% palladium on carbon was stirred at ambient temperature for 2 hours. The catalyst was filtered (solka floc) and the filtrate concentrated in vacuo. Crystallization of the crude oil form EtOAc-hexane provided 0.040 g of the title compound as a white solid.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[N:11]=[CH:12][C:13]2[CH:18]=[CH:17][NH:16][C:14]=2[N:15]=1.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(#N)C>[Cl:9][C:10]1[N:11]=[CH:12][C:13]2[C:18]([I:1])=[CH:17][NH:16][C:14]=2[N:15]=1
Reactant: Clc1ncc2cc[nH]c2n1
Reactant: O=C1CCC(=O)N1I
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CC#N
Product: Clc1ncc2c(I)c[nH]c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
N-Iodosuccinimide (742 g, 3.30 mol) was added to 2-chloro-7H-pyrrolo[2,3-d]pyrimidine (482.5 g, 3.14 mol) in acetonitrile (2500 mL) at 12° C. The mixture was stirred at room temperature for 1 hour then sodium metabisulphite (650 g in 4500 mL of water) was added. The mixture was stirred for 1 hour then filtered to afford the title compound as a orange solid in 82% yield, 716.2 g.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl.[NH:9]1[CH2:12][CH:11]([C:13]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([CH3:22])=[CH:21][C:15]=3[N:14]=2)[CH2:10]1.[Cl:23][C:24]1[C:29](Cl)=[N:28][CH:27]=[CH:26][N:25]=1>CN1C(=O)CCC1>[Cl:23][C:24]1[C:29]([N:9]2[CH2:12][CH:11]([C:13]3[NH:17][C:16]4[CH:18]=[CH:19][C:20]([CH3:22])=[CH:21][C:15]=4[N:14]=3)[CH2:10]2)=[N:28][CH:27]=[CH:26][N:25]=1
Reactant: Clc1nccnc1Cl
Reactant: Cc1ccc2[nH]c(C3CNC3)nc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: Cc1ccc2[nH]c(C3CN(c4nccnc4Cl)C3)nc2c1
Temperature: 100 °C
Yield: 44.1 %

Procedure:
To a mixture of cesium carbonate (4.44 g, 13.6 mmol) and 2-(azetidin-3-yl)-5-methyl-1H-benzo[d]imidazole dihydrochloride (1.05 g, 4.04 mmol) was added NMP (6 mL) and 2,3-dichloropyrazine (1.0 mL, 9.6 mmol). The reaction mixture was degassed and heated to 100° C. for 30 min. The reaction was diluted with EtOAc. The organic phase was washed with water (2×), brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (50% to 100% EtOAc in hexanes) gave 2-(1-(3-chloropyrazin-2-yl)azetidin-3-yl)-5-methyl-1H-benzo[d]imidazole (0.532 g, 1.78 mmol, 44% yield) as an orange solid.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]([CH3:32])[C:24]([CH:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)(C)(C)C.Cl>O1CCOCC1>[NH2:7][CH:8]1[CH2:9][CH2:10][N:11]([S:14]([C:17]2[CH:18]=[CH:19][C:20]([N:23]([CH3:32])[C:24]([CH:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])=[CH:21][CH:22]=2)(=[O:15])=[O:16])[CH2:12][CH2:13]1
Reactant: CN(C(=O)C1CCOCC1)c1ccc(S(=O)(=O)N2CCC(NC(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CN(C(=O)C1CCOCC1)c1ccc(S(=O)(=O)N2CCC(N)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 111.4 %

Procedure:
[(1-{4-[Methyl-(tetrahydro-pyran-4-carbonyl)-amino]-benzenesulfonyl}-piperidin-4-yl)-carbamic acid tert-butyl ester (0.17 g, 0.4 mmol) was suspended in a 4M solution of HCl in Dioxane (5 ml). The resulting suspension was stirred at room temperature for 3 hours. After this time the solution was concentrated under vacuum, then azeotroped with methanol and suspended in diethyl ether. The resulting solid precipitate was then collected by filtration, washed with diethyl ether and dried under vacuum to afford the title compound (0.17 g, Quantitative yield) as a white solid. Tr=1.20 min, m/z (ES+) (M+H)+ 382.
Reaction SMILES: C(O)(C(F)(F)F)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C:18]([C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[CH2:28][N:27]([C:30]1[S:31][C:32]([CH2:38][CH2:39][CH2:40][O:41][C:42]3[CH:47]=[CH:46][C:45](C4C(C#N)=CSC=4)=[CH:44][CH:43]=3)=[C:33]([C:35]([OH:37])=[O:36])[N:34]=1)[CH2:26][CH2:25]2)=[O:19].[CH3:55][N:56]1[CH2:61][CH2:60][N:59]([CH2:62]C2C=CC(O)=CC=2)[CH2:58][CH2:57]1>>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C:18]([C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[CH2:28][N:27]([C:30]1[S:31][C:32]([CH2:38][CH2:39][CH2:40][O:41][C:42]3[CH:43]=[CH:44][C:45]([CH2:55][N:56]4[CH2:61][CH2:60][N:59]([CH3:62])[CH2:58][CH2:57]4)=[CH:46][CH:47]=3)=[C:33]([C:35]([OH:37])=[O:36])[N:34]=1)[CH2:26][CH2:25]2)=[O:19]
Reactant: CN1CCN(Cc2ccc(O)cc2)CC1
Reactant: N#Cc1cscc1-c1ccc(OCCCc2sc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)cc1
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(Cc2ccc(OCCCc3sc(N4CCc5cccc(C(=O)Nc6nc7ccccc7s6)c5C4)nc3C(=O)O)cc2)CC1

Procedure:
The title compound 89 was prepared as a TFA salt in a similar manner to the synthesis of compound 51 by substituting compound 51A with compound 89A: 1H NMR (DMSO-d6): δ 8.03 (d, J=7.67 Hz, 1H), 7.79 (d, J=7.98 Hz, 1H), 7.67 (d, J=7.06 Hz, 1H), 7.34-7.50 (m, 4H), 7.28 (d, J=8.59 Hz, 2H), 6.93 (d, J=8.59 Hz, 2H), 4.83 (s, 2H), 3.98 (d, J=6.29 Hz, 2H), 3.16-3.19 (m, 4H), 3.03 (t, J=5.83 Hz, 2H), 2.76 (s, 3H), 1.97-2.03 (m, 2H). ESI (+)/MS: 683 (M+H)+.