Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([O:10]C)=[O:9])[C:5]([N:12]2[N:16]=[CH:15][CH:14]=[N:13]2)=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[C:5]([N:12]2[N:16]=[CH:15][CH:14]=[N:13]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1nc(C)ccc1-n1nccn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-n2nccn2)c(C(=O)O)n1

Procedure:
A solution of methyl 6-methyl-3-(2H-1,2,3-triazol-2-yl)-2-pyridinecarboxylate D39 (36 mg) and LiOH (5.93 mg, 0.247 mmol) in THF/water (2:1, 3 ml) was stirred overnight. The mixture was evaporated under reduced pressure; the residue was taken up in water (2 ml) and neutralised with 1 M HCl water solution and then loaded onto a pre-conditioned C18 5 g column (the column was eluted with water and then MeOH). The methanol fractions were evaporated under reduced pressure to give the title compound D40 (34 mg) as a white solid. UPLC (Basic QC_POS—50-800): rt=0.30 minutes. peak observed: 205 (M+1). C9H8N4O2 requires 204. 1H NMR (400 MHz, MeOD) δ (ppm) 8.24 (d, 1 H), 7.99 (s, 2 H), 7.61 (d, 1 H), 2.67 (s, 3 H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Br[CH2:9]/[CH:10]=[CH:11]/[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=2)=[O:21])=[CH:16][CH:15]=1.O>CN(C=O)C>[Br:28][C:25]1[CH:24]=[CH:23][C:22]([C:20]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:12]/[CH:11]=[CH:10]/[CH2:9][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)=[CH:15][CH:16]=2)=[O:21])=[CH:27][CH:26]=1
Reactant: O=C(c1ccc(Br)cc1)c1ccc(OC/C=C/CBr)cc1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc(Br)cc1)c1ccc(OC/C=C/Cn2ccnc2)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 35.3 %

Procedure:
A solution of 68 mg of imidazole in 4 ml of DMF is added dropwise to a suspension of 44 mg of 55% sodium hydride in 4 ml of DMF. After heating the mixture to 70° C. a solution of 441 mg of (E)-[4-(4-bromo-but-2-enyloxy)-phenyl]-(4-bromo-phenyl)-methanone in 12 ml of DMF is added dropwise. Then, the mixture is stirred at 70° C. for a further 1 h. and, after cooling, poured into 5 ml of water and concentrated. The residue is treated with water and extracted with methylene chloride. The organic phases are washed with saturated sodium chloride solution, dried and evaporated. The residue is purified on silica gel with toluene/acetone/triethylamine (70:29:1). The (E)-(4-bromo-phenyl)-[4-(4-imidazol-1-yl-but-2-enyloxy)-phenyl]-methanone (140 mg) is obtained as the beige solid base which is converted into the hydrochloride, MS: m/e 397 (M, 1Br).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:44]=[CH:43][C:16]([CH2:17][N:18]([CH2:30][C:31]3[CH:42]=[CH:41][C:34]([O:35][CH2:36][C:37]([O:39]C)=[O:38])=[CH:33][CH:32]=3)[C:19]([C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[NH:23][N:22]=3)=[O:20])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([O:35][CH2:36][C:37]([OH:39])=[O:38])=[CH:41][CH:42]=3)[C:19]([C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[NH:23][N:22]=3)=[O:20])=[CH:43][CH:44]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(OCC(=O)OC)cc3)C(=O)c3n[nH]c4ccccc34)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(OCC(=O)O)cc3)C(=O)c3n[nH]c4ccccc34)cc2)cc1

Procedure:
The titled compound was prepared following the procedure F using methyl (4-{[{4-[(4-butylphenyl)ethynyl]benzyl}(1H-indazol-3-ylcarbonyl)amino]methyl}phenoxy)acetate and NaOH 1N in the presence of MeOH/THF, as a yellow oil (75%). 1H NMR (MeOD, 300 MHz) δ 8.09 (m, 1H), 7.17-7.64 (m, 13H), 6.90 (m, 2H), 5.07 (s, 1H), 5.02 (s, 1H), 4.67 (m, 4H), 2.62 (t, J=7.6 Hz, 2H), 1.61 (m, 2H), 1.35 (m, 2H), 0.95 (t, J=7.3 Hz, 3H). M− (ESI): 570.3; M+ (ESI): 572.3. HPLC, Rt: 5.16 min (Purity: 94.1%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([C:14]([O:16]CC)=O)=[CH:12][N:11]=[C:10]([S:19][CH3:20])[N:9]=1.[OH-].[Na+].C(Cl)(=O)C(Cl)=O.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:39]=[CH:40][CH:41]=1)[CH2:34][NH:35][CH:36]([CH3:38])[CH3:37].C(N(C(C)C)CC)(C)C>C(O)C.O.C(Cl)Cl.CN(C=O)C>[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:39]=[CH:40][CH:41]=1)[CH2:34][N:35]([CH:36]([CH3:38])[CH3:37])[C:14]([C:13]1[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[N:9][C:10]([S:19][CH3:20])=[N:11][CH:12]=1)=[O:16]
Reactant: COc1cccc(CNC(C)C)c1
Reactant: CCOC(=O)c1cnc(SC)nc1-c1ccccc1F
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(CN(C(=O)c2cnc(SC)nc2-c2ccccc2F)C(C)C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 23.5 %

Procedure:
A mixture of ethyl 4-(2-fluorophenyl)-2-(methylthio)pyrimidine-5-carboxylate (3.3 g, 10.96 mmol), solid NaOH (3.2 g) in ethanol (30 mL) and water (6 mL) was refluxed for 1 h. and cooled to room temperature. The solvent was removed under reduced pressure, and the residue was acidified with 6N HCl. The product was extracted with EtOAC (3×50 mL), and the organic extracts were dried and concentrated to give crude acids (1.6 g). A solution of 2 M oxalyl chloride in CH2Cl2 (3.00 mL, 6 mmol) was added to a stirred solution of the crude acids (1.6 g) in CH2Cl2 (25 mL) and DMF (1 mL) at room temperature, and stirring continued for 15 min. A solution of N-(3-methoxybenzyl)propan-2-amine, (1.07 g, 6.00 mmol) in CH2Cl2 (2 mL) and diisopropylethylamine (2 mL, 12 mmol) was added and stirred for 1 hr. The solvent was removed under reduced pressure and the residue was purified by Biotage SP1 on packed silica gel column (10%-80% EtOAc/Hexanes gradient) to give N-(3-methoxybenzyl)-4-(2-fluorophenyl)-N-isopropyl-2(methylthio)pyrimidine-5-carboxamide (0.6 g, 13%). Mass Spec. FIA MS 426 (M+1).
Reaction SMILES: [CH3:1][CH2:2][NH:3][C:4]([C@H:6]1[N:10]([C:11]([C@@H:13]([NH:21][C:22]([C@@H:24]([NH:29][C:30]([C@H:32]([NH:37][C:38]([C@@H:40]([NH:49][C:50]([C@@H:52]([NH:55][C:56]([C@@H:58]([NH:69][C:70]([C@@H:72]([NH:79][C:80]([C@H:82]2[NH:87][C:85](=[O:86])[CH2:84][CH2:83]2)=[O:81])[CH2:73][C:74]2[N:78]=[CH:77][NH:76][CH:75]=2)=[O:71])[CH2:59][C:60]2[C:64]3[CH:65]=[CH:66][CH:67]=[CH:68][C:63]=3[NH:62][CH:61]=2)=[O:57])[CH2:53][OH:54])=[O:51])[CH2:41][C:42]2[CH:43]=[CH:44][C:45]([OH:48])=[CH:46][CH:47]=2)=[O:39])[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:31])[CH2:25][CH:26]([CH3:28])[CH3:27])=[O:23])[CH2:14][CH2:15][CH2:16][NH:17][C:18]([NH2:20])=[NH:19])=[O:12])[CH2:9][CH2:8][CH2:7]1)=[O:5].CC(O)=O.O.[C:93]([OH:112])(=[O:111])[CH2:94][CH2:95][CH2:96][CH2:97][CH2:98][CH2:99][CH2:100]/[CH:101]=[CH:102]\[CH2:103][CH2:104][CH2:105][CH2:106][CH2:107][CH2:108][CH2:109][CH3:110]>>[CH3:1][CH2:2][NH:3][C:4]([C@H:6]1[N:10]([C:11]([C@@H:13]([NH:21][C:22]([C@@H:24]([NH:29][C:30]([C@H:32]([NH:37][C:38]([C@@H:40]([NH:49][C:50]([C@@H:52]([NH:55][C:56]([C@@H:58]([NH:69][C:70]([C@@H:72]([NH:79][C:80]([C@H:82]2[NH:87][C:85](=[O:86])[CH2:84][CH2:83]2)=[O:81])[CH2:73][C:74]2[N:78]=[CH:77][NH:76][CH:75]=2)=[O:71])[CH2:59][C:60]2[C:64]3[CH:65]=[CH:66][CH:67]=[CH:68][C:63]=3[NH:62][CH:61]=2)=[O:57])[CH2:53][OH:54])=[O:51])[CH2:41][C:42]2[CH:47]=[CH:46][C:45]([OH:48])=[CH:44][CH:43]=2)=[O:39])[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:31])[CH2:25][CH:26]([CH3:28])[CH3:27])=[O:23])[CH2:14][CH2:15][CH2:16][NH:17][C:18]([NH2:20])=[NH:19])=[O:12])[CH2:9][CH2:8][CH2:7]1)=[O:5].[C:93]([O-:112])(=[O:111])[CH2:94][CH2:95][CH2:96][CH2:97][CH2:98][CH2:99][CH2:100]/[CH:101]=[CH:102]\[CH2:103][CH2:104][CH2:105][CH2:106][CH2:107][CH2:108][CH2:109][CH3:110]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1CCC(=O)N1
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)[O-]

Procedure:
77.4 mg of leuprolide acetate (MW 1209.4, 84.2%) was dissolved in 1 mL of Dl water (0.0539 mmol). 31.38 mg of oleic acid (#A0241935, MW 282.46, 97%) was added to obtain a 1:2 molar ratio of LA:OL. A white precipitate formed upon mixing the solution. The complex was separated by centrifugation, and the resulting precipitate was washed with water and then dried under vacuum.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.C(N(CC)C(C)C)(C)C.[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:38]=[C:39]([CH:41]=[CH:42][CH:43]=2)[NH2:40])[CH2:33][CH2:32]1>COCCO>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:6]2[C:7]([CH:8]=[N:9][C:4]([NH:40][C:39]3[CH:41]=[CH:42][CH:43]=[C:37]([N:34]4[CH2:33][CH2:32][N:31]([CH3:30])[CH2:36][CH2:35]4)[CH:38]=3)=[N:5]2)=[CH:10][CH:11]=1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Reactant: CN1CCN(c2cccc(N)c2)CC1
Solvent: COCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1ccc2cnc(Nc3cccc(N4CCN(C)CC4)c3)nn12
Temperature: 180 °C
Yield: 7.9 %

Procedure:
2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (75.0 mg, 0.000261 mol), N,N-Diisopropylethylamine (0.0682 mL, 0.000392 mol) and 3-(4-Methylpiperazin-1-yl)aniline (99.8 mg, 0.000522 mol) were dissolved in 2-Methoxyethanol (1.83 mL) and the reaction was heated under 300 W microwave conditions at 180° C. until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 8.59 mg of [7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine as lyophilated powder. (M+H)=415.18. 1H NMR (400 MHz, CDCl3) δ 10.42 (s, 1H), 8.55 (s, 1H), 7.87 (d, 1H, J=6.57 Hz), 7.52 (s, 1H), 7.30 (m, 3H), 7.18 (m, 2H), 7.09 (m, 2H), 6.57 (s, 1H), 3.84 (s, 3H), 3.55 (d, 2H, J=11.12 Hz), 3.45 (d, 2H, J=13.64 Hz), 3.18 (m, 2H), 2.90 (m, 2H), 2.86 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[OH-].[K+].[I:13]I>CN(C=O)C.C(=O)(O)[O-].[Na+]>[I:13][C:6]1[C:5]2[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[NH:8][CH:7]=1
Reactant: II
Reactant: Fc1ccc2cc[nH]c2c1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc2c(I)c[nH]c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.4 %

Procedure:
To a solution of 6-fluoroindole (1.14 g, 8.44 mmol) in DMF (20 mL) was added potassium hydroxide (0.521 g, 9.28 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 10 minutes before the addition of iodine (2.57 g, 10.1 mmol). After stirring at room temperature with protection from light for 18 hours, the reaction was diluted with saturated sodium bicarbonate. The aqueous mixture was extracted three times with EtOAc. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography (5% MeOH in DCM) to give 3-iodo-6-fluoroindole as a red solid (1.44 g, 65.4%).
Reaction SMILES: [CH2:1]([N:5]1[C:13]([N:14]2[CH2:19][CH2:18][NH:17][C@@H:16]([CH3:20])[CH2:15]2)=[N:12][C:11]2[C:6]1=[N:7][C:8]([C:27]1[CH:28]=[N:29][C:30]([NH2:33])=[N:31][CH:32]=1)=[N:9][C:10]=2[N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)[CH:2]([CH3:4])[CH3:3].[O:34]1CCC[CH2:35]1.CN(CCS(O)(=O)=O)C.[OH-].[Na+]>C(Cl)Cl>[NH2:33][C:30]1[N:31]=[CH:32][C:27]([C:8]2[N:7]=[C:6]3[C:11]([N:12]=[C:13]([N:14]4[CH2:19][CH2:18][N:17]([CH:35]=[O:34])[C@@H:16]([CH3:20])[CH2:15]4)[N:5]3[CH2:1][CH:2]([CH3:4])[CH3:3])=[C:10]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:9]=2)=[CH:28][N:29]=1
Reactant: C1CCOC1
Reactant: CC(C)Cn1c(N2CCN[C@@H](C)C2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Agent: CN(C)CCS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)Cn1c(N2CCN(C=O)[C@@H](C)C2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Reaction time: 0.58 h
Yield: 75 %

Procedure:
5-{9-Isobutyl-8-[(3S)-3-methylpiperazin-1-yl]-6-morpholin-4-yl-9H-purin-2-yl}pyrimidin-2-amine (123.4 mg, 0.27 mmol) was added to a tetrahydrofuran solution (7.0 ml) of 1H-benzotriazole-1-carboxyaldehyde (44.6 mg, 0.27 mmol) at room temperature and the resulting mixture was stirred for 35 minutes. Methylene chloride was added to the reaction mixture and then the resulting mixture was poured into a 2 N aqueous sodium hydroxide solution and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, the mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative thin layer silica gel chromatography (methylene chloride:methanol=10:1) to give the title compound (98.3 mg, 75%) as a pale yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:16]=[CH:17][C:18]3[S:22][C:21]([C:23]([OH:25])=O)=[C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:19]=3[CH:32]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:33][CH:34]([CH3:37])[CH2:35][OH:36]>>[OH:36][CH2:35][CH:34]([NH:33][C:23]([C:21]1[S:22][C:18]2[CH:17]=[CH:16][C:15]([NH:14][S:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=3)(=[O:12])=[O:13])=[CH:32][C:19]=2[C:20]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25])[CH3:37]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc3sc(C(=O)O)c(-c4ccccc4)c3c2)cc1
Reactant: CC(N)CO
Product: CC(CO)NC(=O)c1sc2ccc(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)cc2c1-c1ccccc1
Yield: 29 %

Procedure:
According to Step 1, after reaction of 5-(4-tert-Butylbenzenesulfonylamino)-3-phenyl-1-benzothiophene-2-carboxylic acid (155 mg, 0.33 mmol) with 2-amino-1-propanol (0.027 mL, 0.35 mmol) followed by chromatographic purification (silica gel, dichloromethane/methanol (0-10% methanol)) and recrystallization from ethyl acetate/hexane, the desired compound is obtained at 29% yield (51 mg).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([O:9]C)=O.O.[NH2:12][NH2:13]>CC(O)C>[OH:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([NH:12][NH2:13])=[O:9]
Reactant: COC(=O)[C@@H]1CCC[C@H]1O
Reactant: NN
Solvent: O
Solvent: CC(C)O
Product: NNC(=O)[C@@H]1CCC[C@H]1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
To a 200-mL four-necked flask were added 18.47 g (128.1 mmol) of methyl (R,R)-2-hydroxycyclopentanecarboxylate and 75 mL of 2-propanol and stirring was started. Hydrazine monohydrate (12.83 g; 256.2 mmol) was dropped thereinto at 20° C. taking 1 hour and 30 minutes. After the dropping, the mixture was stirred at 85° C. for 15 hours. After the reaction, heating was stopped and the mixture was cooled to room temperature to precipitate the crystals. The crystals were filtered and washed with small amount of 2-propanol. The resulting crystals were dried to give 10.89 g of the title compound. The yield was 59%. Ratio of anti-form to syn-form of the compound was measured by a high-performance liquid chromatography (column: Inertsil ODS-3V) and found that the anti/syn ratio was more than 99/1.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[N:10]=[C:11]=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][N:19]1[C:27]2[C:26]([CH3:28])=[C:25]([CH3:29])[N:24]=[C:23]([NH2:30])[C:22]=2[N:21]=[C:20]1[CH3:31]>>[NH2:30][C:23]1[C:22]2[N:21]=[C:20]([CH3:31])[N:19]([CH2:18][CH2:17][O:16][CH2:15][CH2:14][NH:13][C:11]([NH:10][C@@H:8]3[CH2:9][C@H:7]3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:12])[C:27]=2[C:26]([CH3:28])=[C:25]([CH3:29])[N:24]=1
Reactant: O=C=N[C@@H]1C[C@H]1c1ccccc1
Reactant: Cc1nc(N)c2nc(C)n(CCOCCN)c2c1C
Product: Cc1nc(N)c2nc(C)n(CCOCCNC(=O)N[C@@H]3C[C@H]3c3ccccc3)c2c1C

Procedure:
Using the method of Examples 54-68, trans-2-phenylcyclopropyl isocyanate was reacted with 1-[2-(2-aminoethoxy)ethyl]-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The product was purified using Method A. The observed accurate mass was 423.2508.
Reaction SMILES: [Li]C(CC)C.C1CCCCC1.[CH2:12]([N:14]([CH2:24][CH3:25])[C:15](=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22])[CH3:13].CN(CCN(C)C)C.[CH3:34][Sn:35](Cl)([CH3:37])[CH3:36]>C1COCC1.CCOCC>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([Sn:35]([CH3:37])([CH3:36])[CH3:34])[C:16]=1[C:15]([N:14]([CH2:12][CH3:13])[CH2:24][CH3:25])=[O:23]
Reactant: C[Sn](C)(C)Cl
Reactant: CCN(CC)C(=O)c1ccccc1Cl
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1c(Cl)cccc1[Sn](C)(C)C
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 77.8 %

Procedure:
1.3M s-BuLi in cyclohexane (4.8 mL, 6.2 mmol) was added dropwise to a -78° C. cooled solution of the compound of Example e (1.0 g, 4.7 mmol) and TMEDA (930 μL, 6.2 mmol) in THF (15 mL). The resulting yellow mixture was stirred at -78° C. for 45 min, then was quenched by the dropwise addition of trimethyltin chloride (1.41 g, 7.1 mmol) in THF (5 mL), maintaining the internal reaction temperature ≤-65° C. The resulting green solution was warmed to RT to afford a yellow solution which was diluted with ether and extracted twice with aq 10% HCl, and once with sat aq NaHCO3. The ether solution was dried (MgSO4), concentrated, and purified by HPLC with 1:4 ethyl acetate/hexanes to afford 1.37 g of the title compound, an 81% yield, as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[C:13]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)[C:5]([Cl:25])=[CH:4][N:3]=1.Cl.[CH3:27][N:28]1[CH:32]=[C:31]([NH2:33])[CH:30]=[N:29]1.CCN(C(C)C)C(C)C>CCCCO>[Cl:25][C:5]1[C:6]([NH:8][CH:9]2[C:13]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)=[N:7][C:2]([NH:33][C:31]2[CH:30]=[N:29][N:28]([CH3:27])[CH:32]=2)=[N:3][CH:4]=1
Reactant: Cn1cc(N)cn1
Reactant: CC(C)(C)OC(=O)N1CC(Nc2nc(Cl)ncc2Cl)C2(CCCC2)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cn1cc(Nc2ncc(Cl)c(NC3CN(C(=O)OC(C)(C)C)CC34CCCC4)n2)cn1
Temperature: 150 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
To a solution of tert-butyl 4-((2,5-dichloropyrimidin-4-yl)amino)-2-azaspiro[4.4]nonane-2-carboxylate (830 mg, 2.15 mmol) and 1-methyl-1H-pyrazol-4-amine hydrochloride (344.74 mg, 2.58 mmol) in n-BuOH (8 mL) was added DIPEA (833.60 mg, 6.45 mmol) and the reaction mixture was stirred at 150° C. overnight. The resulting mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=100/1) to give the product as a white solid (800 mg, 83%).
Reaction SMILES: COC1C=CC(CN2C=C(/C=[C:14]3\[CH2:15][N:16]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:17][CH2:18][CH:19]\3O)N=N2)=CC=1.C(O)(=S)C.C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C.[Cl-].[Na+].C(SC1CCN(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C/C/1=C\C1N=NN(CC2C=CC(OC)=CC=2)C=1)(=O)C>C1(C)C=CC=CC=1>[C:22]1([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:16]2[CH2:15][CH:14]=[CH:19][CH2:18][CH2:17]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COc1ccc(Cn2cc(/C=C3\CN(C(c4ccccc4)(c4ccccc4)c4ccccc4)CCC3O)nn2)cc1
Agent: CC(O)=S
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Agent: COc1ccc(Cn2cc(/C=C3\CN(C(c4ccccc4)(c4ccccc4)c4ccccc4)CCC3SC(C)=O)nn2)cc1
Solvent: Cc1ccccc1
Product: C1=CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 170.4 %

Procedure:
To a solution of (E)-3-{[1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl]methylidene}-1-(triphenylmethyl)piperidin-4-ol (17.45 g) in toluene (300 ml) were added thioacetic acid (4.6 ml) and N,N-dimethylformamide dineopentylacetal (18 ml). The resulting solution was stirred at room temperature for 15 minutes, and the reaction was stopped by an addition of a saturated aqueous sodium chloride solution. The products were extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel using a mixture of hexane, ethyl acetate and dichloromethane (1:1:1) as the eluent to afford an approximately 1:3 mixture of (E)-4-(acetylsulfanyl)-3-{[1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl]methylidene}-1-(triphenylmethyl)piperidine and 5-(acetylsulfanyl){[1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl]methylidene}methyl)-1-(triphenylmethyl)-1,2,3,6-tetrahydropyridine (17.83 g, yield: 92%).
Reaction SMILES: C([N:8]1[C:12]([C:13]([NH:15][C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([C:23]([O:25][CH3:26])=[O:24])[C:17]=2[OH:27])=[O:14])=[N:11][N:10]=[N:9]1)C1C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl.C>ClCCl.C(=O)(O)[O-].[K+].C(OCC)(=O)C>[OH:27][C:17]1[C:18]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][C:20]([CH3:22])=[CH:21][C:16]=1[NH:15][C:13]([C:12]1[NH:11][N:10]=[N:9][N:8]=1)=[O:14]
Reactant: COC(=O)c1cc(C)cc(NC(=O)c2nnnn2Cc2ccccc2)c1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Al+3]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C)cc(NC(=O)c2nnn[nH]2)c1O
Temperature: 0 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
1-Benzyl-2'-hydroxy-3'-methoxycarbonyl-5'-methyl-1H-tetrazole-5-carboxanilide (3.0 g) was added, with stirring, to a suspension of anhydrous aluminium chloride (3.6 g) in dichloromethane (150 ml). After stirring and heating at reflux for 150 minutes, the mixture was poured into a mixture of ice (100 g), aqueous hydrochloric acid (2 N; 100 ml) and ethyl acetate (100 ml), and stirring was continued for a further period of 2 hours. The remaining insoluble material was filtered off and the organic layer was washed with water (3×20 ml) and dried over anhydrous sodium sulphate. Evaporation of the solvent gave a yellow solid, which was then digested in aqueous potassium bicarbonate solution (5% w/v; 100 ml), and the resulting solution was treated with charcoal and filtered. Acidification of the filtrate gave a solid, which was recrystallised from nitromethane to give 2'-hydroxy-3'-methoxycarbonyl-5'-methyltetrazole-5-carboxanilide (1.2 g), m.p. 238°-240° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH:41]=[O:42])=[C:19]([N:23]3[CH:27]=[C:26]([C:28]#[N:29])[C:25]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]([OH:40])([CH3:39])[CH3:38])=[CH:33][CH:32]=4)=[N:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[O:43]1CCCC1>O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH:41]=[O:42])=[C:19]([N:23]3[CH:27]=[C:26]([C:28]([NH2:29])=[O:43])[C:25]([NH:30][C:31]4[CH:32]=[CH:33][C:34]([C:37]([OH:40])([CH3:39])[CH3:38])=[CH:35][CH:36]=4)=[N:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CCOC1
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C#N)c(Nc5ccc(C(C)(C)O)cc5)n4)c3C=O)ncc2c1
Solvent: O
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C(N)=O)c(Nc5ccc(C(C)(C)O)cc5)n4)c3C=O)ncc2c1

Procedure:
1-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-formyl-phenyl]-3-[4-(1-hydroxy-1-methyl-ethyl)-phenylamino]-1H-pyrazole-4-carbonitrile (78 mg, 0.14 mmol) and dihydrogen tris(dimethylphosphinito)hydroplatinate (7.1 mg, 0.12 eq) were taken up in tetrahydrofuran (3.1 ml) and water (0.31 ml). The material was stirred and heated to reflux (oil bath) for 1 hour. The mixture was cooled to ambient and the volatiles were stripped (rotary evaporator). The crude material was purified by preparative thin layer chromatography (2 plates, eluting first with 7% methanol in methylene chloride and then re-developing with 6% methanol in methylene chloride). The product band was collected, providing desired 1-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-formyl-phenyl]-3-[4-(1-hydroxy-1-methyl-ethyl)-phenylamino]-1H-pyrazole-4-carboxylic acid amide as a light yellow powder (41 mg). LC/MS calcd for C32H31FN6O4 (m/e) 582.62, obsd 581.0 (M−H, ES−).