Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:22]=[C:21]3[C:17]([N:18]([CH3:24])[C:19](=[O:23])[NH:20]3)=[C:16](I)[N:15]=2)=[N:6]1.[CH:30]([OH:33])([CH3:32])[CH3:31].C(=O)([O-])[O-].[Cs+].[Cs+].CC1C=NC2C(C=1C)=CC=C1C=2N=CC(C)=C1C>[Cu]I.CN1CCCC1=O>[F:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:22]=[C:21]3[C:17]([N:18]([CH3:24])[C:19](=[O:23])[NH:20]3)=[C:16]([O:33][CH:30]([CH3:32])[CH3:31])[N:15]=2)=[N:6]1
Reactant: Cn1c(=O)[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(I)c21
Reactant: CC(C)O
Agent: [Cu]I
Agent: Cc1cnc2c(ccc3c(C)c(C)cnc32)c1C
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Product: CC(C)Oc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2[nH]c(=O)n(C)c12
Temperature: 140 °C
Reaction time: 8 h

Procedure:
200 mg (0.399 mmol) of the compound obtained in example 107 were admixed in a microwavable flask with isopropanol (3 ml), 260 mg (0.798 mmol) of cesium carbonate, 8 mg (0.04 mmol) of copper(I) iodide and 19 mg (0.08 mmol) of 3,4,7,8-tetramethyl-1,10-phenanthroline. The flask was purged with argon while being treated with ultrasound for 5 min, and then closed with an appropriate septum. Then it was heated in a microwave at 140° C. for 2 h. Reaction monitoring showed low conversion. For that reason, N-methylpyrrolidone (1 ml) was added and the mixture was once again heated in a microwave at 140° C. for 2 h and then at 180° C. for 8 h. After cooling, the reaction mixture was filtered and concentrated, and the residue was purified by means of preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient). 21 mg of the title compound were obtained (12% of theory).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.Cl>O>[CH3:7][N:6]1[C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]=[C:2]1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: C1CNCCN1
Reactant: Cn1c(Cl)nc2ccccc21
Agent: Cl
Solvent: O
Product: Cn1c(N2CCNCC2)nc2ccccc21
Temperature: 150 °C

Procedure:
A mixture of 1 g (6.02 mmol) of 2-chloro-1-methyl-benzimidazole and 2.58 g (30 mmol) of piperazine is heated to 150° C. without a solvent. The cooled melt is combined successively with water and dilute hydrochloric acid and extracted with dichloromethane. Then the aqueous phase is made alkaline with dilute sodium hydroxide solution and extracted with dichloromethane. The organic phase is dried over sodium sulphate and concentrated by evaporation. The product is purified by column chromatography on silica gel (eluant: dichloromethane/ethanol/ammonia=5:1:0.1).
Reaction SMILES: [CH2:1]([N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][CH2:10][NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26](Cl)(=[O:29])[CH2:27][CH3:28]>C1COCC1>[C:13]1([CH2:12][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10][NH:11][C:26](=[O:29])[CH2:27][CH3:28])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCC(=O)Cl
Reactant: NCCN(Cc1ccccc1)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(=O)NCCN(Cc1ccccc1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a chilled solution of 5.0 g (21 mmol) N,N-dibenzylethylenediamine and 30mL (21 mmol) triethylamine in 20 mL THF is added 1.8 mL (21 mmol) propionylchloride, dropwise. The temperature of the reaction mixture is maintained below 0° C. during addition. The reaction mixture is stirred for 30minutes at 0° C. After this time, the reaction mixture is filtered and the solvents are evaporated to give the product which can be purified via column chromatography.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([C:9]#[N:10])[N:3]=1.CN(C=O)C.C(N(C(C)C)CC)(C)C.[CH3:25][NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CCOC(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([N:26]([CH3:25])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:5]=[C:4]([C:9]#[N:10])[N:3]=1
Reactant: N#Cc1nc(N)nc(Cl)n1
Reactant: CNc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(c1ccccc1)c1nc(N)nc(C#N)n1
Temperature: 25 °C

Procedure:
To 2-amino-4-chloro-6-cyano-[1,3,5]triazine (Intermediate 3, 243 mg, 1.6 mmol) was added anhydrous DMF (5 mL), diisopropylethylamine (0.54 mL, 3.1 mmol) and N-methyl-aniline (184 mg, 1.7 mmol). The mixture was heated at 90 C in a pressure tube for 18 h before allowing to cool to room temperature. The reaction mixture was diluted with EtOAc (20 mL), washed with water (2×10 mL) and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to furnish the desired product which was used directly without further purification (138 mg, 39%). Method C HPLC-MS: MH+ requires m/z=227. Found: m/z=227, Rt=1.20 min (93%).
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[CH2:3][CH2:4][CH:5]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:8][C:7](=[O:16])[NH:6]1.NC(CCC(C)C)C(C1C=CC=CC=1)O.Cl.Cl[CH2:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH3:1][CH:2]([CH3:17])[CH2:3][CH2:4][CH:5]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:8][C:7](=[O:16])[N:6]1[CH2:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: ClCCCN1CCCCC1
Reactant: CC(C)CCC1NC(=O)OC1c1ccccc1
Agent: CC(C)CCC(N)C(O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCC(C)=O
Product: CC(C)CCC1C(c2ccccc2)OC(=O)N1CCCN1CCCCC1
Reaction time: 24 h
Yield: 85 %

Procedure:
A mixture of (4RS, 5SR)-4-(3-methylbutyl)-5-phenyl-1,3-oxazolidin-2-one [mp: 111°-112 ° C.; prepared from (1RS,2SR)-2-amino-5-methyl-1-phenylhexan-1-ol by a known method {M. E. Dyen and D. Swern: Chem. Rev., 67, 197(1967)}] (1.17 g, 5 mmol), 1-(3-chloropropyl)piperidine hydrochloride (1.49 g, 7.5 mmol), anhydrous potassium carbonate powder (2.07 g, 15 mmol) in methyl ethyl ketone (15 ml) was refluxed with stirring for 24 hours. After cooling, insoluble material was removed by filtration and washed with methyl ethyl ketone. The washing and filtrate were combined together and concentrated under reduced pressure The residue was purified by silica gel column chromatography (silica gel:35 g ; eluent: chloroform/methanol) to obtain 1.52 g of the title compound as an oil (yield : 85%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]#[C:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:25][CH2:24][CH:23](O)[CH2:22][CH2:21]1)[C:11]([CH:13]1[CH2:18][CH2:17][CH:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[CH3:33][N:34]1[CH:38]=[N:37][N:36]=[C:35]1[SH:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C(N(CC)CC)C>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]#[C:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[CH:8][C:9]=1[N:10]([C:11]([CH:13]1[CH2:18][CH2:17][CH:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])[CH:20]1[CH2:25][CH2:24][CH:23]([S:39][C:35]2[N:34]([CH3:33])[CH:38]=[N:37][N:36]=2)[CH2:22][CH2:21]1)=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)C1CCC(C)CC1)C1CCC(O)CC1
Reactant: Cn1cnnc1S
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)C1CCC(C)CC1)C1CCC(Sc2nncn2C)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.6 %

Procedure:
5-(3,3-Dimethyl-but-1-ynyl)-3-[(4-hydroxy-cyclohexyl)-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (92 mg, 0.2 mmol, 1.0 eq.), 4-methyl-4H-[1,2,4]triazole-3-thiol (46 mg, 0.4 mmol, 2.0 eq.), triphenylphosphine (105 mg, 0.4 mmol, 2.0 eq.), DIAD (77 μL, 0.4 mmol, 2.0 eq.) and triethyl amine (42 μL, 0.3 mmol, 1.5 eq.) were weighed into a round-bottomed flask containing THF (2.0 mL). The solution was purged with N2 and stirred at room temperature for 12 h. The solution was concentrated to an oil and then purified by silica gel chromatography (0-100% EtOAc in hexanes) to afford 5-(3,3-dimethyl-but-1-ynyl)-3-{(4-methyl-cyclohexanecarbonyl)-[4-(4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-cyclohexyl]-amino}-thiophene-2-carboxylic acid methyl ester (63 mg, 57%).
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH3:24])[CH:19]=2)[CH:14]=1.C([O:29][B:30](OCCCC)[O:31]CCCC)CCC.Cl>O1CCCC1.O>[CH3:24][O:23][C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]([B:30]([OH:31])[OH:29])[CH:14]=2)[CH:19]=1
Reactant: COc1ccc2cc(Br)ccc2c1
Reactant: CCCCOB(OCCCC)OCCCC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2cc(B(O)O)ccc2c1
Reaction time: 1.17 h
Yield: 58.5 %

Procedure:
A solution of n-butyl lithium in hexane (1.5M; 8.9 ml, 13.4 mmol) was added dropwise to a solution of 2-bromo-6-methoxynaphthalene (3.0 g, 12.7 mmol) in tetrahydrofuran (45 ml) under argon atmosphere at −60° C. and the mixture was stirred at the same temperature for 70 min. To the mixture was added tri-n-butylborate (5.2 ml, 19.0 mmol) and the mixture was stirred at the same temperature for 1 hr. and then at 5° C. for 1.5 hrs. To the reaction mixture was added dropwise 20% hydrochloric acid (13 ml) at 5° C., and water was added thereto. The mixture was extracted with ethyl acetate. The organic layer was washed with water and brine in turn and dried. The solvent was distilled off under reduced pressure, and the residue was triturated with ethyl acetate and diethyl ether, filtered and dried to give (2-methoxy)-6-naphthalene boronic acid (1.50 g, 59%) as a colorless solid.
Reaction SMILES: [N:1]1([S:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=O)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:18]1([C:21]2[NH:25][N:24]=[C:23]([NH2:26])[CH:22]=2)[CH2:20][CH2:19]1>>[CH:18]1([C:21]2[CH:22]=[C:23]([NH:26][C:12](=[O:14])[C:11]3[CH:15]=[CH:16][CH:17]=[C:9]([S:6]([N:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)(=[O:7])=[O:8])[CH:10]=3)[NH:24][N:25]=2)[CH2:20][CH2:19]1
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCC2)c1
Product: O=C(Nc1cc(C2CC2)n[nH]1)c1cccc(S(=O)(=O)N2CCCC2)c1

Procedure:
The entitled compound was produced according to the method of Example 92 but using 3-(pyrrolidin-1-ylsulfonyl)benzoic acid and 5-cyclopropyl-1H-pyrazole-3-amine as the starting materials.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH3:30][Si:31]([C:34]#[C:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](O)=[O:41])=[CH:38][CH:37]=1)([CH3:33])[CH3:32]>C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:40]([C:39]2[CH:43]=[CH:44][C:36]([C:35]#[C:34][Si:31]([CH3:30])([CH3:33])[CH3:32])=[CH:37][CH:38]=2)=[O:41])[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: C[Si](C)(C)C#Cc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CN1CCN(C(=O)c2ccc(C#C[Si](C)(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.3 %

Procedure:
1-Methylpiperazine (0.66 mL, 6.0 mmol), HOBt (0.84 g, 6.2 mmol) and EDCl (1.15 g, 6.0 mmol) were added to a solution of 4-[(trimethylsilyl)ethynyl]benzoic acid (1.0 g, 4.6 mmol) in dry DCM (45 mL). The mixture was stirred at room temperature for 4 h, washed with saturated aqueous sodium bicarbonate (30 mL), brine, dried over sodium sulphate, and evaporated. The crude was purified by flash chromatography on silica gel (DCM/MeOH 96/4) to afford the title compound (1.29 g, 93%).
Reaction SMILES: C(C1N=C(N2CCOCC2)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.[C:28]([C:32]1[N:33]=[C:34](Cl)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29].[CH3:50][C@@H:51]1[CH2:55][CH2:54][C@@H:53]([CH3:56])[NH:52]1>>[C:28]([C:32]1[N:33]=[C:34]([N:52]2[C@H:53]([CH3:56])[CH2:54][CH2:55][C@H:51]2[CH3:50])[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: C[C@@H]1CC[C@@H](C)N1
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Product: C[C@@H]1CC[C@@H](C)N1c1nc(C(C)(C)C)nc2c1nnn2Cc1ccccc1Cl

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (2R,5R)-2,5-dimethylpyrrolidine and isolated as colorless gum (11.2 mg, 60%). MS(m/e): 399.4 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:15]([Sn](C)(C)C)=[N:14][N:13]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:10]3=[CH:11][N:12]=2)[CH:2]=1.[Br:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31](Br)[N:30]=1>>[Br:28][C:29]1[N:30]=[C:31]([C:15]2[C:9]3[C:10](=[CH:11][N:12]=[C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH:8]=3)[N:13]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:14]=2)[CH:32]=[CH:33][CH:34]=1
Reactant: C[Si](C)(C)CCOCn1nc([Sn](C)(C)C)c2cc(-c3cccnc3)ncc21
Reactant: Brc1cccc(Br)n1
Product: C[Si](C)(C)CCOCn1nc(-c2cccc(Br)n2)c2cc(-c3cccnc3)ncc21
Yield: 67 %

Procedure:
Following the Stille coupling procedure of Example 299, 5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(trimethylstannyl)-1H-pyrazolo[3,4-c]pyridine and 2,6-dibromopyridine were reacted. The mixture was purified via silica gel chromatography using a gradient of ethyl acetate in heptane to afford 81 mg (67%) of 3-(6-Bromopyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine. ESI MS m/z 482.2 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=O)[CH2:4][CH2:3]1.B.C1COCC1.Cl.C([O-])(O)=O.[Na+]>>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][CH:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:7]1
Reactant: CN1CCN(C(=O)C2CCN(c3ccc([N+](=O)[O-])cc3)CC2)CC1
Agent: B
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: CN1CCN(CC2CCN(c3ccc([N+](=O)[O-])cc3)CC2)CC1

Procedure:
1-Methyl-4-[1-(4-nitro-phenyl)-piperidin-4-ylmethyl]-piperazine was prepared by warming (4-Methyl-piperazin-1-yl)-[1-(4-nitro-phenyl)-piperidin-4-yl]-methanone of Example 444a with borane.THF (10 equivalents) at 60° C. for 16 hours, followed by a standard aqueous HCl workup. The resulting aqueous phase was neutralized with NaHCO3 and extracted with EtOAc (2×). The organics were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to give 1-Methyl-4-[1-(4-nitro-phenyl)-piperidin-4-ylmethyl]-piperazine as an orange solid, which was used for subsequent step without further manipulation. LC/MS (E/I+) 319.15 (M+H).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[C:12]([O:16][CH:17]1[CH:24]2[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:26][CH:18]1[CH2:19]3)[CH2:23]2)(=[O:15])C=C>>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:1]/[CH:2]=[CH:3]/[C:12]([O:16][CH:17]2[CH:18]3[CH2:26][CH:22]4[CH2:21][CH:20]([CH2:25][CH:24]2[CH2:23]4)[CH2:19]3)=[O:15])=[CH:5][CH:6]=1
Reactant: C=CCc1ccc(OC)cc1
Reactant: C=CC(=O)OC1C2CC3CC(C2)CC1C3
Product: COc1ccc(C/C=C/C(=O)OC2C3CC4CC(C3)CC2C4)cc1
Yield: 82.1 %

Procedure:
The representative procedure was followed using 4-allylanisole (74 mg, 0.50 mmol), 2-adamantyl acrylate (206 mg, 1.00 mmol) and Grubbs-2 catalyst (8.5 mg, 0.01 mmol). Column chromatography on silica gel (eluting with 5% EtOAc/hexanes) afforded the product as a colorless oil (134 mg, 82%).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C.CS(Cl)(=O)=O.[CH:26]([NH2:29])([CH3:28])[CH3:27].C(=O)([O-])O.[Na+]>ClCCl>[CH:26]([NH:29][CH2:2][CH2:3][CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:28])[CH3:27]
Reactant: CN(CCCO)C(=O)OC(C)(C)C
Reactant: CC(C)N
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)NCCCN(C)C(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 69.2 %

Procedure:
tert-Butyl (3-hydroxypropyl)methylcarbamate (430 mg, 2.27 mmol) was dissolved in dichloromethane (5 mL), triethylamine (0.633 mL, 4.55 mmol) and methanesulfonyl chloride (0.262 mL, 3.41 mmol) were added under ice cooling, and the mixture was stirred at the same temperature for 10 minutes. Isopropylamine (1.3 g, 23 mmol) was further added, and then the mixture was stirred overnight at room temperature. After the reaction was completed, a saturated aqueous sodium hydrogencarbonate solution was added, the mixture was extracted with methylene chloride (×3), and the resulting organic layer was dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (elution solvents, n-hexane:ethyl acetate=9:1→1:1, v/v) to give the title compound (362 mg; yield, 73%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:30][N:31]([CH3:37])[C:32](=[O:36])[C:33](O)=[O:34]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:33]([C:32]([N:31]([CH3:37])[CH3:30])=[O:36])=[O:34])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: CN(C)C(=O)C(=O)O
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)C(=O)N(C)C)c1

Procedure:
Prepared as described in Example 76 using (1R,2S)-1-[1-(4-fluorophenyl)-indazol-5-yl]oxy-1-(3-methoxyphenyl)-propan-2-amine (51 mg, 0.13 mmol) and 2-(dimethylamino)-2-oxoacetic acid (13 mg, 0.13 mmol). Yield 44 mg (69%).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([C:10]2[N:14]=[CH:13][N:12]([C:15]3[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=3)[N:11]=2)=[O:9])[CH2:3]1.[CH3:22][O:23][C:24]1[N:29]=[C:28]([C:30](O)=[O:31])[CH:27]=[CH:26][CH:25]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:22][O:23][C:24]1[N:29]=[C:28]([C:30]([N:7]2[CH2:6][CH2:5][N:4]([C:8]([C:10]3[N:14]=[CH:13][N:12]([C:15]4[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=4)[N:11]=3)=[O:9])[CH2:3][C@H:2]2[CH3:1])=[O:31])[CH:27]=[CH:26][CH:25]=1
Reactant: Cc1cccc(-n2cnc(C(=O)N3CCN[C@H](C)C3)n2)c1
Reactant: COc1cccc(C(=O)O)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc(C(=O)N2CCN(C(=O)c3ncn(-c4cccc(C)c4)n3)C[C@H]2C)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 86 mg (0.30 mmol) ((R)-3-methyl-piperazin-1-yl)-(1-m-tolyl-1H-[1,2,4]-triazol-3-yl)-methanone, 46 mg (0.30 mmol) 6-methoxy-pyridine-2-carboxylic acid, 0.11 g (0.33 mmol) TBTU and 80 μL (0.45 mmol) DIPEA in 5.0 mL DMF was stirred at RT for 12 h. The reaction mixture was poured into ice water and extracted with EtOAc. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo.
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[Br:11][C:12]1[S:16][C:15]2=[CH:17][N:18]=[CH:19][N:14]2[CH:13]=1.[OH-].[Na+]>C(Cl)Cl.O>[Br:11][C:12]1[S:16][C:15]2=[C:17]([CH:3]=[O:4])[N:18]=[CH:19][N:14]2[CH:13]=1
Reactant: CN(C)C=O
Reactant: Brc1cn2cncc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=Cc1ncn2cc(Br)sc12
Temperature: 80 °C
Reaction time: 6 h

Procedure:
Dimethylformamide (0.13 ml) and 0.15 ml of phosphorus oxychloride were added in that order to a solution of 300 mg of 2-bromoimidazo[5,1-b]thiazole in 3 ml of methylene chloride under an argon atmosphere, and the mixture was stirred at 80° C. for 6 hr. Water was added to the reaction mixture to stop the reaction, and the reaction mixture was adjusted to pH 10 by the addition of a 1 N aqueous sodium hydroxide solution. The reaction mixture was then extracted with ethyl acetate, and the organic layer was then washed with saturated brine and was dried over magnesium sulfate. The solvent was removed by evaporation, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:10) to give 223 mg of 2-bromo-7-formylimidazo[5,1-b]thiazole.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]([S:14][CH3:15])[N:3]=1.[F:16][C:17]([F:26])([F:25])[C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21]>>[CH3:13][C:6]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:2]([NH:21][C:20]2[CH:22]=[CH:23][CH:24]=[C:18]([C:17]([F:16])([F:25])[F:26])[CH:19]=2)[N:3]=[C:4]([S:14][CH3:15])[N:5]=1
Reactant: CCOC(=O)c1c(C)nc(SC)nc1Cl
Reactant: Nc1cccc(C(F)(F)F)c1
Product: CCOC(=O)c1c(C)nc(SC)nc1Nc1cccc(C(F)(F)F)c1
Yield: 97.5 %

Procedure:
The title compound; (MS m/z: 372.2 (M+H)+) was prepared as described in example 1d by starting from ethyl 4-chloro-6-methyl-2-(methyl thio)pyrimidine-5-carboxylate (1.2 g, 4.86 mmol) and 3-(trifluoromethyl)aniline (611 uL, 4.86 mmol) and continuing until the reaction yielded dark brown solids (ethyl 4-methyl-2-(methylthio)-6-(3-(trifluoromethyl)phenylamino)pyrimidine-5-carboxylate (1.76 g, 97.4%)).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[Li+].[Cl-].C([Cu])#N.[F:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1>C1COCC1>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][C:7]=1[C:19]([C:18]1[CH:22]=[CH:23][C:15]([F:14])=[CH:16][CH:17]=1)=[O:20]
Reactant: Clc1ccc(Cl)nn1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: N#C[Cu]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(c1ccc(F)cc1)c1cc(Cl)nnc1Cl
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
3,6-Dichloropyridazine (3) (149 mg, 1.0 mmol) in THF (2 mL) was added to a solution of TMPZnCl.LiCl (2) (1.3 M in THF, 0.85 mL, 1.1 mmol) at 25° C. and the reaction mixture was then stirred at this temperature for 30 min according to TP 2. After cooling down to −20° C., CuCN.2LiCl (1.0 M in THF, 1.1 mmol, 1.1 equiv) was added and the resulting mixture was stirred for 30 min at this temperature. 4-Fluorobenzoyl chloride (317 mg, 2.0 mmol) was then slowly added and the resulting mixture was allowed to warm up slowly to 10° C. The reaction mixture was quenched with a sat. aq. NH4Cl solution (20 mL), extracted with diethyl ether (3×50 mL) and dried over anhydrous Na2SO4. After filtration, the solvent was evaporated in vacuo. Purification by flash-chromatography (CH2Cl2/n-pentane, 1:1) furnished compound 5b (259 mg, 96%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][NH2:12].[Cl:13][C:14]1[C:19]2[C:20](=[O:24])[O:21][CH:22](O)[C:18]=2[C:17]([F:25])=[C:16]([Cl:26])[N:15]=1>CO>[Cl:13][C:14]1[N:15]=[C:16]([Cl:26])[C:17]([F:25])=[C:18](/[CH:22]=[N:12]/[CH2:11][C:4]2[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=2[O:2][CH3:1])[C:19]=1[C:20]([OH:24])=[O:21]
Reactant: O=C1OC(O)c2c(F)c(Cl)nc(Cl)c21
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CO
Product: COc1ccc(C/N=C/c2c(F)c(Cl)nc(Cl)c2C(=O)O)c(OC)c1
Reaction time: 0.5 h
Yield: 81.6 %

Procedure:
To a solution of (2,4-dimethoxyphenyl)methanamine (40.5 g, 242.0 mmol) in MeOH (250 mL) was added 4,6-dichloro-7-fluoro-1-hydroxyfuro[3,4-c]pyridin-3(1H)-one (55.0 g, 231.0 mmol). The mixture was stirred for 0.5 h, filtered, and washed with petroleum ether to give the title compound as a white solid (73.0 g, 82%). 1H NMR (CDCl3, 400 MHz) δ ppm 3.75 (s, 3H), 3.79 (s, 3H), 3.93 (s, 2H), 6.30 (s, 1H), 6.40-6.42 (m, 2H), 7.12 (d, J=8.4 Hz, 1H). [M+H] calc'd for C16H13Cl2FN2O4, 387. found, 387.