Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[C:5]([Cl:10])=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[NH2:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][C@H:23]([C:27]([NH2:29])=[O:28])[CH2:22]1.C(OCC)(=O)C.CCCCCC>C(O)(C)C>[Cl:10][C:5]1[C:6]([S:8][CH3:9])=[N:7][C:2]([NH:20][C@@H:21]2[CH2:26][CH2:25][CH2:24][C@H:23]([C:27]([NH2:29])=[O:28])[CH2:22]2)=[N:3][CH:4]=1
Reactant: NC(=O)[C@H]1CCC[C@@H](N)C1
Reactant: CSc1nc(Cl)ncc1Cl
Solvent: CC(C)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CSc1nc(N[C@@H]2CCC[C@H](C(N)=O)C2)ncc1Cl
Temperature: 100 °C
Yield: 70.6 %

Procedure:
To a solution of Intermediate 1 (2 g, 10.36 mmol) in isopropyl alcohol (10 mL), was added DIPEA (4.01 g, 31.08 mmol) and Cis-3-aminocyclohexanecarboxamide (2.2 g, 15.45 mmol) at room temperature and heated to 100° C. for 48 h in a sealed tube. TLC showed completion of starting material and formation of a polar spot (TLC System: 10% ethyl acetate/hexane, (Rf): 0.1). After cooling down to room temperature, the mixture was concentrated, water (30 ml) was added, and the precipitated product was filtered, washed with pentane (20 ml) and dried to afford Cis-3-(5-chloro-4-(methylthio)pyrimidin-2-ylamino)cyclohexanecarboxamide as a white solid (2.2 g, 70.9%). MS m/z: 301.1 (ES+, M+H).
Reaction SMILES: [S:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].[F:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>>[F:13][C:14]1[CH:20]=[CH:19][C:17]([N:18]=[CH:9][C:8]2[CH:11]=[CH:12][C:5]([S:1](=[O:4])(=[O:3])[NH2:2])=[CH:6][CH:7]=2)=[CH:16][CH:15]=1
Reactant: NS(=O)(=O)c1ccc(C=O)cc1
Reactant: Nc1ccc(F)cc1
Product: NS(=O)(=O)c1ccc(C=Nc2ccc(F)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(i), but using 4-sulfamoylbenzaldehyde and 4-fluoroaniline as starting materials, the title compound was obtained as white prismatic crystals (yield 25%).
Reaction SMILES: C(O)C.Cl[C:5]1[CH:10]=[C:9]([CH:11]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[C:8]([Cl:30])=[CH:7][N:6]=1.O.[NH2:32][NH2:33]>CCCCCC>[Cl:30][C:8]1[C:9]([CH:11]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])=[CH:10][C:5]([NH:32][NH2:33])=[N:6][CH:7]=1
Reactant: NN
Reactant: O=S(=O)(c1ccc(Cl)cc1)C(c1cc(F)ccc1F)c1cc(Cl)ncc1Cl
Solvent: O
Solvent: CCCCCC
Solvent: CCO
Product: NNc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Temperature: 25 °C
Yield: 18 %

Procedure:
To an ethanol (10 ml) solution of the 2,5-dichloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridine (524 mg, 1.17 mmol) obtained in Example 57 was added hydrazine monohydrate (2 ml). The resulting mixture was heated under reflux for 3 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate (=1:1) eluate was concentrated under reduced pressure to afford a pale yellow oil. To the resulting oil was added hexane-ether and the solid thus precipitated was collected by filtration to give the title compound (95 mg, 0.214 mmol, 18%) as a white powder.
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([N:22]=[C:23]=[O:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C(O)C>[CH2:4]([NH:22][C:23](=[O:24])[NH:2][NH2:3])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCNC(=O)NN

Procedure:
20.0 Grams of hydrazine monohydrate and 200 ml of ethanol were charged in a flask equipped with a stirrer, a condenser and a calcium chloride drying tube and stirred with ice cooling. To the resulting solution was slowly added dropwise 14.8 g of octadecyl isocyanate. After completion of the addition, the temperature was returned to room temperature, followed by stirring for 1 hour, and the precipitated crystal was filtered off under reduced pressure and was recrystallized from ethanol to obtain 8.2 g of the desired product. m.p. 100° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([Cl:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([F:9])=[CH:7][CH:8]=1.[Cl:21][C:22]1[N:23]=[C:24]([CH3:30])[NH:25][C:26]=1[C:27](O)=[O:28].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:21][C:22]1[N:23]=[C:24]([CH3:30])[NH:25][C:26]=1[C:27]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([C:14]#[N:15])[CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:4]=1[Cl:20])=[O:28]
Reactant: N#Cc1cc(Cl)cc(Oc2c(F)ccc(CN)c2Cl)c1
Reactant: Cc1nc(Cl)c(C(=O)O)[nH]1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1nc(Cl)c(C(=O)NCc2ccc(F)c(Oc3cc(Cl)cc(C#N)c3)c2Cl)[nH]1
Yield: 68.3 %

Procedure:
The title compound was prepared as described herein using 3-{[3-(aminomethyl)-2-chloro-6-fluorophenyl]oxy}-5-chlorobenzonitrile (40 mg, 0.129 mmol), 4-chloro-2-methyl-1H-imidazole-5-carboxylic acid (20.64 mg, 0.129 mmol), EDC (27.4 mg, 0.143 mmol) and HOBT (27.3 mg, 0.178 mmol) in DMF (3.0 ml) to give the title compound as a white solid (40 mg, 69%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.42 (1H, br. s.) 7.46-7.54 (0H, m) 7.31-7.41 (2H, m) 7.16-7.23 (2H, m) 7.14 (1H, d, J=2.1 Hz) 7.00 (1H, s) 4.72 (2H, d, J=6.2 Hz) 2.41 (3H, s). LCMS: m/z 453 (M+1).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)=O.[C:21]1([CH3:29])[CH:26]=[CH:25][C:24]([NH:27]N)=[CH:23][CH:22]=1.Cl>>[C:14]1([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:27]([C:24]4[CH:25]=[CH:26][C:21]([CH3:29])=[CH:22][CH:23]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccccc2)ccc1=O
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Product: Cc1ccc(-n2nccc2-c2nn(-c3ccccc3)ccc2=O)cc1
Yield: 67 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-phenyl-1H-pyridazin-4-one (A-1) and p-tolylhydrazine×HCl according to the method described for Example 1 in 67% yield.
Reaction SMILES: [CH3:1][N:2]1CCN(C2C=CC3C(C=2)=CC=C2C=3OC(C(NC3C=CC(N4CCOCC4)=CC=3)=O)=CC2=O)CC1.C(O[C:41]1[CH:46]=[C:45]([N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)[C:44](OCC)=[CH:43][C:42]=1[NH:56][C:57]([C:59]1[O:60][C:61]2[C:66]([C:67](=[O:69])[CH:68]=1)=[CH:65][CH:64]=[CH:63][C:62]=2[N:70]1[CH2:75][CH2:74][N:73]([CH3:76])[CH2:72][CH2:71]1)=[O:58])C>>[C:1]([C:44]1[CH:43]=[C:42]([NH:56][C:57]([C:59]2[O:60][C:61]3[C:66]([C:67](=[O:69])[CH:68]=2)=[CH:65][CH:64]=[CH:63][C:62]=3[N:70]2[CH2:75][CH2:74][N:73]([CH3:76])[CH2:72][CH2:71]2)=[O:58])[CH:41]=[CH:46][C:45]=1[N:47]1[CH2:48][CH2:49][O:50][CH2:51][CH2:52]1)#[N:2]
Reactant: CCOc1cc(N2CCOCC2)c(OCC)cc1NC(=O)c1cc(=O)c2cccc(N3CCN(C)CC3)c2o1
Reactant: CN1CCN(c2ccc3c(ccc4c(=O)cc(C(=O)Nc5ccc(N6CCOCC6)cc5)oc43)c2)CC1
Product: CN1CCN(c2cccc3c(=O)cc(C(=O)Nc4ccc(N5CCOCC5)c(C#N)c4)oc23)CC1

Procedure:
This compound was prepared from 8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 1) and 5-amino-2-morpholin-4-yl-benzonitrile (Reference Example 15) as prepared in Example 12, yielding a yellow solid. (120 mg=82%), LCMS-m/z=474.5.
Reaction SMILES: [F:1][C@@H:2]1[CH2:6][N:5]([C:7](=[O:10])[CH2:8][OH:9])[C@H:4]([C:11]([NH2:13])=O)[CH2:3]1.CN(C)CCCN(C)C.[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(#N)C.O.C(N(CC)CC)C>[C:23]1([S:29]([O:9][CH2:8][C:7]([N:5]2[CH2:6][C@@H:2]([F:1])[CH2:3][C@H:4]2[C:11]#[N:13])=[O:10])(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NC(=O)[C@@H]1C[C@H](F)CN1C(=O)CO
Agent: CN(C)CCCN(C)C
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)COS(=O)(=O)c1ccccc1
Reaction time: 1 h
Yield: 91 %

Procedure:
(2S,4S)-4-fluoro-1-(2-hydroxyacetyl)pyrrolidine-2-carboxa mide (381 mg) was suspended in acetonitrile and N,N,N′,N′-tetramethyl-1,3-propanediamine (34.0 μL) and triethylamine (0.98 mL) were added to the suspension. While this mixture was cooled in a salt-ice bath, benzenesulfonyl chloride (0.28 mL) was added dropwise. The mixture was stirred at the same temperature for 1 hour and trifluoroacetic anhydride (0.34 mL) was added dropwise, followed by stirring for another 1 hour. Subsequently, water (10 mL) was added to the reaction mixture and acetonitrile was evaporated under reduced pressure. The resulting crystal was collected by filtration, washed successively with water and diethyl ether, and dried under reduced pressure to give (2S,4S)-1-[2-(benzenesulfonyloxy)acetyl]-4-fluoropyrrolidine-2-carbonitrile as a white crystal (567 mg, 91% yield). This compound was identical to the compound obtained in Example 3.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([C:19]2[S:23][C:22]([C:24]([OH:30])([CH3:29])[C:25]([F:28])([F:27])[F:26])=[N:21][CH:20]=2)[CH:15]=[C:16]([CH3:18])[CH:17]=1.C(O)(=O)C>O1CCOCC1>[CH3:18][C:16]1[CH:17]=[C:12]([NH:11][C:2]2[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]=2)[CH:13]=[C:14]([C:19]2[S:23][C:22]([C:24]([OH:30])([CH3:29])[C:25]([F:28])([F:27])[F:26])=[N:21][CH:20]=2)[CH:15]=1
Reactant: O=C(O)c1ccnc(Cl)n1
Reactant: Cc1cc(N)cc(-c2cnc(C(C)(O)C(F)(F)F)s2)c1
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Cc1cc(Nc2nccc(C(=O)O)n2)cc(-c2cnc(C(C)(O)C(F)(F)F)s2)c1
Temperature: 100 °C

Procedure:
To 2-chloropyrimidine-4-carboxylic acid (175 mg, 1.104 mmol) in dioxane (2.201 mL) was added 2-[5-(3-amino-5-methylphenyl)-1,3-thiazol-2-yl]-1,1,1-trifluoropropan-2-ol (INTERMEDIATE 17, (334 mg, 1.104 mmol) and acetic acid (69.5 μL, 1.214 mmol). The reaction was heated to 100° C. overnight and was complete by LCMS analysis. The reaction was cooled to room temperature and the solvent was removed under reduced pressure. Remaining acetic acid was azeotroped with toluene (2×5 mL) to yield 2-({3-methyl-5-[2-(1,1,1-trifluoro-2-hydroxypropan-2-yl)-1,3-thiazol-5-yl]phenyl}amino)pyrimidine-4-carboxylic acid as a tan powder. MS ESI: [M+H]+ m/z 425.1. 1H NMR (500 MHz, dmso) δ 13.79-13.63 (m, 10.05 (s, 1H), 8.73 (d, J=5.0, 1H), 8.22-8.14 (m, 1H), 8.10 (s, 1H), 7.65 (s, 1H), 7.56 (s, 1H), 7.32 (d, J=5.0, 1H), 7.12 (s, 1H), 2.31 (s, 3H), 1.76 (s, 3H). rhSYK activity=+
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9](/[CH:12]=[CH:13]/[CH2:14][O:15][C:16]2[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].CC(C)=[O:26].OS(O)(=O)=O.O=[Cr](=O)=O.O>CC(C)=O>[CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9](/[CH:12]=[CH:13]/[CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([OH:26])=[O:21])=[CH:22][CH:23]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC[C@H]1CC[C@H](/C=C/COc2ccc(C=O)cc2)CC1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCC[C@H]1CC[C@H](/C=C/COc2ccc(C(=O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4 g of 4-[(E)-3-(trans-4-pentylcyclohexyl)allyloxy]benzaldehyde (Prepared according to Example 3) in 100 ml of acetone was treated dropwise with 10 ml of Jones' reagent. The mixture was stirred at room temperature for 1 hour and then poured into 100 ml of water. The preciPitate which thereby resulted was filtered off, washed portionwise with water and dried in a vacuum. The crude product was recrystallized from ethanol and gave 2,5 g of pure 4-[(E)-3-(trans-4-pentylcyclohexyl)allyloxy]benzoic acid; m.p. 214-215° C..
Reaction SMILES: ClC1C=CC([C:8]2C3C(NC)=NC=CC=3C3C(C)=NOC=3C[N:14]=2)=CC=1.Cl[C:26]1[CH:27]=[CH:28][C:29]2[C:30]3[C:46]([CH3:47])=[N:45][O:44][C:31]=3[CH2:32][N:33]=[C:34]([C:37]3[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=3)[C:35]=2[N:36]=1.ClC1C=CC(C2C3C(F)=NC=CC=3C3C(C)=NOC=3CN=2)=CC=1>>[Cl:43][C:40]1[CH:41]=[CH:42][C:37]([C:34]2[C:35]3[N:36]=[C:26]([NH:14][CH3:8])[CH:27]=[CH:28][C:29]=3[C:30]3[C:46]([CH3:47])=[N:45][O:44][C:31]=3[CH2:32][N:33]=2)=[CH:38][CH:39]=1
Reactant: Cc1noc2c1-c1ccc(Cl)nc1C(c1ccc(Cl)cc1)=NC2
Reactant: CNc1nccc2c1C(c1ccc(Cl)cc1)=NCc1onc(C)c1-2
Agent: Cc1noc2c1-c1ccnc(F)c1C(c1ccc(Cl)cc1)=NC2
Product: CNc1ccc2c(n1)C(c1ccc(Cl)cc1)=NCc1onc(C)c1-2

Procedure:
A procedure similar to 6-(4-chlorophenyl)-N,1-dimethyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepin-7-amine (Compound 173) was followed, except that 8-chloro-6-(4-chlorophenyl)-1-methyl-4H-isoxazolo[5,4-c]pyrido[3,2-e]azepine (Compound 240) was used as starting material instead of 6-(4-chlorophenyl)-7-fluoro-1-methyl-4H-isoxazolo[4,5-e]pyrido[3,4-c]azepine. LC/MS m/z 339 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 7.83 (d, J=8.72 Hz, 1H), 7.41 (td, J=2.10, 8.50 Hz, 2H), 7.36 (td, J=2.10, 8.50 Hz, 2H), 6.96 (q, J=4.50 Hz, 1H), 6.77 (d, J=8.93 Hz, 1H), 4.61 (br. s, 2H), 2.62 (d, J=4.78 Hz, 3H), 2.46 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14](C(OC(C)(C)C)=O)[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]3[CH2:27][O:26]C(C)(C)O3)=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(OC(N1CCC(N(C(OC(C)(C)C)=O)C2C=CC(O)=CN=2)CC1)=O)(C)(C)C.BrCCCOC1CCCCO1.C(=O)([O-])[O-].[K+].[K+].Cl.ClC1C=CC(CN2CCC(NC3C=CC(C#N)=CC=3)CC2)=CC=1OCC>CN(C=O)C.O1CCOCC1.C(O)C>[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][CH2:27][OH:26])=[CH:19][CH:20]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(N(C(=O)OC(C)(C)C)c2ccc(OCC3COC(C)(C)O3)cn2)CC1
Agent: BrCCCOC1CCCCO1
Agent: CC(C)(C)OC(=O)N1CCC(N(C(=O)OC(C)(C)C)c2ccc(O)cn2)CC1
Agent: CCOc1cc(CN2CCC(Nc3ccc(C#N)cc3)CC2)ccc1Cl
Solvent: C1COCCO1
Solvent: CCO
Solvent: CN(C)C=O
Product: OCCCOc1ccc(NC2CCNCC2)nc1

Procedure:
The title compound was prepared in analogy to the procedure described for rac-4-{tert-butoxycarbonyl-[5-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-pyridin-2-yl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (intermediate B19/step 1) from 4-[tert-butoxycarbonyl-(5-hydroxy-pyridin-2-yl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (intermediate B18 step 5) by reaction with rac-2-(3-bromopropoxy)-tetrahydro-2H-pyran (commercially available) and potassium carbonate in DMF at rt, followed by BOC and THP cleavage with 4 M HCl in dioxane and ethanol at 70° C. in analogy to the synthesis of (5-methanesulfonyl-pyridin-2-yl)-piperidin-4-yl-amine (intermediate B16/step 2). MS (ISP): 252.1 [M+H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]=O)=[CH:4][CH:3]=1.[H-].[Na+].[Cl:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH3:23])=C(Cl)[N:15]=1.O>CN(C)C=O>[Cl:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH3:23])=[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:15]=1
Reactant: Cn1cnc2c(Cl)nc(Cl)nc21
Reactant: O=CNc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cnc2c(Nc3ccc(Cl)cc3)nc(Cl)nc21
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
N-(4-Chloro-phenyl)-formamide (766 mg, 4.93 mmol) was dissolved in N,N-dimethylformamide (10 mL). Sodium hydride (60% in mineral oil, 240 mg, 5.91 mmol) was added and the mixture was stirred for 30 min. 2,6-Dichloro-9-methyl-9H-purine (1.0 g, 4.93 mmol) was added and the reaction mixture was heated at 80° C. for 2 hours, cooled to room temperature and poured into water. The resulting precipitate was collected by filtration, washed with water and dried to give (2-chloro-9-methyl-9H-purin-6-yl)-(4-chloro-phenyl)-amine (1.2 g, 4.08 mmol, 83%).
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([CH3:35])=[C:15]([NH:18][C:19]3[N:27]4[C:22]([CH2:23][O:24][CH2:25][C@H:26]4[C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)=[N:21][N:20]=3)[CH:16]=2)[CH:11]=[N:10]1)(C)(C)C.Cl>CO>[F:34][C:31]1[CH:32]=[CH:33][C:28]([C@@H:26]2[CH2:25][O:24][CH2:23][C:22]3=[N:21][N:20]=[C:19]([NH:18][C:15]4[CH:16]=[C:17]5[C:12]([CH:11]=[N:10][N:9]5[CH2:8][CH2:7][OH:6])=[CH:13][C:14]=4[CH3:35])[N:27]23)=[CH:29][CH:30]=1
Reactant: Cc1cc2cnn(CCO[Si](C)(C)C(C)(C)C)c2cc1Nc1nnc2n1[C@H](c1ccc(F)cc1)COC2
Agent: Cl
Solvent: CO
Product: Cc1cc2cnn(CCO)c2cc1Nc1nnc2n1[C@H](c1ccc(F)cc1)COC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.6 %

Procedure:
To a stirring room temperature solution of {1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-1H-indazol-6-yl}-[(R)-5-(4-fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl]-amine (110 mg, 0.21 mmol) in MeOH (5 mL) was added 6N aqueous HCl (0.5 mL). The mixture was stirred at room temperature for 15 minutes and then concentrated under reduced pressure. The residue was recrystallized from MeOH/EtOAc/diethyl ether to give 70 mg of 2-{6-[(R)-5-(4-fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-5-methyl-indazol-1-yl}-ethanol, MP=215-217° C., MS (M+H)=409.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([Br:30])=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:29][CH2:28][C:23]2(OCC[O:24]2)[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].Cl>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([Br:30])=[CH:8][C:9]=1[N:10]([C:11]([C@H:13]1[CH2:14][CH2:15][C@H:16]([CH3:19])[CH2:17][CH2:18]1)=[O:12])[CH:20]1[CH2:29][CH2:28][C:23](=[O:24])[CH2:22][CH2:21]1)=[O:4]
Reactant: COC(=O)c1sc(Br)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)c1sc(Br)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC(=O)CC1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
The 5-bromo-3-[(1,4-dioxa-spiro[4.5]dec-8-yl)-(trans-4-methylcyclohexane-carbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (8.6 g, 17 mmol) was dissolved in tetrahydrofuran (100 ml) and treated with 3N HCl solution (50 ml). The reaction was stirred at 40° C. for 3 hours. The reaction mixture was evaporated under reduced pressure. The residue was dissolved in EtOAc and wash with aq. sat. NaHCO3 solution. The organic layer was separated, dried on Na2SO4, filtered and concentrated to give 5-Bromo-3-[(trans-4-methyl-cyclohexanecarbonyl)-(4-oxo-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester as a solid (7.4 g, 95%).
Reaction SMILES: [N+:1]([C:4]1[N:5]([CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].C(C1NC=CN=1)(C1NC=CN=1)=O.Cl.[CH3:26][C:27]([CH3:31])=[CH:28][CH2:29][NH2:30].C([O-])(O)=O.[Na+]>CN(C=O)C.CO.ClCCl>[CH3:26][C:27]([CH3:31])=[CH:28][CH2:29][NH:30][C:10](=[O:12])[CH2:9][N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[N+:1]([O-:3])=[O:2]
Reactant: O=C(O)Cn1ccnc1[N+](=O)[O-]
Reactant: CC(C)=CCN
Agent: Cl
Agent: O=C([O-])O
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)=CCNC(=O)Cn1ccnc1[N+](=O)[O-]
Reaction time: 0.25 h

Procedure:
2-(2-Nitro-1H-imidazol-1-yl)acetic acid (8.6 g, 50 mmol) was dissolved in DMF (50 mL). Carbonyl diimidazole [CDI] (8.7 g, 60 mmol) was added to the solution in small portions. The reaction mixture was stirred under N2 for 15 min. 3,3-Dimethylallylamine hydrochloride was suspended in DMF (50 mL) and stirred with NaHCO3 (4.2 g, 50 mmol). This suspension was added to the CDI and 2-(2-nitro-1H-imidazol-1-yl)acetic acid in DMF solution. The mixture was stirred under N2 atmosphere at room temperature overnight. TLC (silica gel, 10% methanol-dichloromethane) showed one spot with Rf =0.5, indicating completion of the reaction. DMF was evaporated on a rotary evaporator and the residue was triturated with ice-water (125 mL) and filtered. The solid was washed with cold water (3×50 mL) and dried in vacuum to give a white solid. Yield: 7.2 g (61%). mp: 174°-176° C. MS: 254 (M+NH4)+, 238 (M+H)+. 1H NMR (DMSO-d6) δ1.62 and 1.68 [s, 6H, =C(CH3)2 ], 3.68 (t, 2H, CH2CH=), 5.08 (s, 2H, COCH2 -imidazolyl), 5.14 (t, 1H, CH2CH=), 7.19 and 7.62 (s, 2H, 2-nitroimidazolyl-H), 8.37 (t, 1H, HNCO). Anal. Calcd. for C20H32N10O7 : Calcd: C, 50.41; H, 5.92; N, 23.52. Found: C, 50.67; H, 5.97; N 23.38.
Reaction SMILES: [CH3:1][C:2]([S:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[Br:8][C:9]1[CH:10]=[C:11]([CH:15]=O)[CH:12]=[N:13][CH:14]=1.O>ClCCl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Br:8][C:9]1[CH:10]=[C:11]([CH:15]=[N:7][S:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])[CH:12]=[N:13][CH:14]=1
Reactant: O=Cc1cncc(Br)c1
Reactant: CC(C)(C)S(N)=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)S(=O)N=Cc1cncc(Br)c1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 101.4 %

Procedure:
To a solution of 2-methyl-propane-2-sulfinamide (11 g, 91 mmol) and 5-bromo-3-pyridine-carboxaldehyde (14 g, 75 mmol) in dichloromethane (500 mL) is added titanium isopropoxide (43 g, 150 mmol). The reaction is then heated at reflux (bath temperature=60° C.) for 4 hours. The resultant mixture is cooled to room temperature and poured into a stirred mixture of diatomaceous earth (50 g) and water (150 mL). The slurry is stirred for 10 min and then filtered. The organic layer from the filtrate is washed with brine and dried over sodium sulfate. Filtration and concentration in vacuo affords 2-methyl-propane-2-sulfinic acid 1-(5-bromo-pyridin-3-yl)-methylideneamide as a yellow solid (22 g, 99%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:15]([OH:18])([CH3:17])[CH3:16])=[N:8][N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=12)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[OH:3][CH2:4][C:6]1[C:7]([C:15]([OH:18])([CH3:16])[CH3:17])=[N:8][N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=12
Reactant: CCOC(=O)c1c(C(C)(C)O)nn2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O)c1nn2ccccc2c1CO
Temperature: 25 °C
Reaction time: 16 h
Yield: 117.3 %

Procedure:
To a solution of 2-(1-hydroxy-1-methyl-ethyl)-pyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester (1.54 g, 6.20 mmol) in tetrahydrofuran (25 mL) at 0° C. was added lithium aluminum hydride (0.27 g, 6.88 mmol). The mixture was allowed to warm to room temperature and stirred for 16 h. The reaction was cooled in an ice bath and 0.27 mL of water, 0.27 mL of 15% aqueous sodium hydroxide and 0.81 mL of water were sequentially added. The mixture was filtered through a plug of Celite, which was washed with methanol. The filtrate and washes were combined and concentrated in vacuo to give 1.5 g of the title compound as a yellow oil that was used directly in the next step.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[C:8]([CH3:11])[CH:9]=2)[NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>C(#N)C>[I:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[C:8]([CH3:11])[CH:9]=2)[N:4]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[N:3]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1cc2c(I)n[nH]c2cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc2c(I)nn(CC(=O)OC(C)(C)C)c2cn1
Temperature: 25 °C

Procedure:
To a suspension of 3-iodo-5-methyl-1H-pyrazolo[3,4-c]pyridine (1.00 g, 3.86 mmol), and potassium carbonate (1.28 g, 9.26 mmol) in acetonitrile (40 mL) was added tert-butyl bromoacetate (0.685 mL, 4.63 mmol) dropwise at RT and the resulting mixture was heated to reflux for 16 h. The mixture was cooled to RT and filtered, the solid was washed with acetonitrile and the filtrate was concentrated under vacuum. The residual oil was used directly in the next step without further purification. MS (LC/MS): 374.0 [M+H]+; tR (HPLC conditions k): 2.96 min.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH3:11][C:12](=[CH2:14])[CH3:13].OS(O)(=O)=O>ClCCl>[C:12]([O:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1)([CH3:14])([CH3:13])[CH3:11]
Reactant: CC(=O)c1cccc(O)c1
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(=O)c1cccc(OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 3'-hydroxyacetophenone (22.64 g), isobutylene (300 mL) and concentrated H2SO4 (1 mL) in dry dichloromethane (310 mL) was stirred in a sealed pressure vessel at room temperature for 3 days. After the reaction vessel was vented, the organic phase was washed (10% NaOH, water and brine), dried and evaporated to an oil (25.95 g) which was purified by chromatography, eluting with dichloromethane:ethyl acetate, to give 3'-tert-butoxyacetophenone (22.62 g); TLC: Rf =0.55, ethyl acetate:dichloromethane (3:97); MS: m/z=193(M+1).