Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]C(C)(C)C.Br[C:7]1[C:16]2[C:15]3[N:17]=[CH:18][CH:19]=[CH:20][C:14]=3[CH2:13][CH2:12][CH2:11][C:10]=2[NH:9][N:8]=1.[C:21](=[O:23])=[O:22]>CCCCC.C1COCC1>[C:7]1([C:21]([OH:23])=[O:22])[C:16]2[C:15]3[N:17]=[CH:18][CH:19]=[CH:20][C:14]=3[CH2:13][CH2:12][CH2:11][C:10]=2[NH:9][N:8]=1
Reactant: Brc1n[nH]c2c1-c1ncccc1CCC2
Reactant: O=C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: O=C(O)c1n[nH]c2c1-c1ncccc1CCC2
Temperature: 25 °C

Procedure:
7.8 mL of 1.7 M of t-BuLi in pentane is added dropwise under argon to a stirred solution of 1-bromo-3,4,5,6-tetrahydro-2,3,10-triaza-benzo[e]azulene (1.4 g) in 75 mL of anhydrous THF at −78° C. After addition, dry carbon dioxide is bubbled into the mixture at the same temperature for 2 hours. The reaction mixture is allowed to warm to room temperature, quenched with 1N HCl solution, and diluted with water. The mixture is basified with 1N NaOH to pH 8-9, and then extracted with EtOAc. The aqueous layer is then acidified with HOAc to pH 4-5 and extracted with CH2Cl2 eight times. The combined extracts are washed with water, dried, and concentrated to give 3,4,5,6-tetrahydro-2,3,10-triaza-benzo[e]azulene-1-carboxylic acid as a tan solid. 1H NMR(DMSO): 1.95(m, 2H), 2.96(m, 2H), 3.07(t, 2H), 7.45(m,1H), 7.97(d,1H), 8.52(d, 2H). LR-MS: MW 229.23, Found: 230.2(M+1). Step 6: A mixture of 3,4,5,6-tetrahydro-2,3,10-triaza-benzo[e]azulene-1-carboxylic acid (80 mg), 1-(3-azetidin-1-yl-propyl)-1H-pyrazol-3-ylamine (68 mg), EDCI(85 mg) and DMAP(55 mg) in 10 mL of 1,2-dichloroethane is refluxed overnight, cooled and diluted with CH2Cl2. The mixture is washed with aqueous NaHCO3 solution, water, dried over Na2SO4 and concentrated under vacuum. Purification on a silica gel plate, eluting with 10% MeOH in CH2Cl2 yields 12 mg of 3,4,5,6-tetrahydro-2,3,10-triaza-benzo[e]azulene-1-carboxylic acid [1-(3-azetidin-1-yl-propyl)-1H-pyrazol-3-yl]-amide as a colorless foam. 1H NMR (CDCl3): 2.01-2.31(m, 6H), 2.67-2.92(m, 8H), 3.63(m, 2H), 4.17(t, 2H), 6.65(d, 1H), 7.23(m, 1H), 7.33(d, 1H), 7.65(d, 1H), 8.62(d, 1H), 14.13(bs, 1H). LR-MS: MW 391.48, Found: 392.2 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:15][CH:14]2[CH:10]([N:11]=[C:12]([NH:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]=[CH:22][N:21]=[C:20]4[NH:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]4[S:37][CH:38]=[CH:39][N:40]=4)=[C:30]([Cl:41])[CH:29]=3)[O:13]2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:41][C:30]1[CH:29]=[C:28]([NH:27][C:20]2[C:19]3[C:24](=[CH:25][CH:26]=[C:17]([NH:16][C:12]4[O:13][CH:14]5[CH2:15][NH:8][CH2:9][CH:10]5[N:11]=4)[CH:18]=3)[N:23]=[CH:22][N:21]=2)[CH:33]=[CH:32][C:31]=1[O:34][CH2:35][C:36]1[S:37][CH:38]=[CH:39][N:40]=1
Reactant: CC(C)(C)OC(=O)N1CC2N=C(Nc3ccc4ncnc(Nc5ccc(OCc6nccs6)c(Cl)c5)c4c3)OC2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1cc(Nc2ncnc3ccc(NC4=NC5CNCC5O4)cc23)ccc1OCc1nccs1

Procedure:
N4-[3-Chloro-4-(thiazol-2-ylmethoxy)-phenyl]-N6-(4,5,6,6a-tetrahydro-3 aH-pyrrolo[3,4-d]oxazol-2-yl)-quinazoline-4,6-diamine is prepared from 2-{4-[3-chloro-4-(thiazol-2-ylmethoxy)-phenylamino]-quinazolin-6-ylamino}-3a,4,6,6a-tetrahydro-pyrrolo[3,4-d]oxazole-5-carboxylic acid tert-butyl ester by standard BOC deprotection methods using TFA in methylene chloride. MS APCI (+) m/z 494, 496 (M+1, Cl pattern) detected; 1H NMR (400 mHz, CD3OD) δ 8.44 (s, 1H), 8.19 (br. s, 1H), 7.96 (d, 1H), 7.83 (d, 1H), 7.67 (m, 3H), 7.58 (dd, 1H), 7.22 (d, 1H), 5.50 (s, 2H), 5.17 (m, 1H), 4.76 (m, 1H), 3.32 (d, 1H), 3.16 (d, 1H), 2.85 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[F:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[CH:54]=[CH:53][C:52]([C:55]3[N:60]=[C:59]([NH:61][C:62]4[CH:67]=[CH:66][C:65]([NH2:68])=[CH:64][CH:63]=4)[N:58]4[N:69]=[CH:70][CH:71]=[C:57]4[CH:56]=3)=[CH:51][CH:50]=2)=[CH:45][CH:44]=1>CN(C=O)C.C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:15](=[O:17])[NH:68][C:65]2[CH:66]=[CH:67][C:62]([NH:61][C:59]3[N:58]4[N:69]=[CH:70][CH:71]=[C:57]4[CH:56]=[C:55]([C:52]4[CH:53]=[CH:54][C:49]([C:46]5[CH:47]=[CH:48][C:43]([F:42])=[CH:44][CH:45]=5)=[CH:50][CH:51]=4)[N:60]=3)=[CH:63][CH:64]=2)=[CH:18][CH:19]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccc(Nc2nc(-c3ccc(-c4ccc(F)cc4)cc3)cc3ccnn23)cc1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCc1ccc(C(=O)Nc2ccc(Nc3nc(-c4ccc(-c5ccc(F)cc5)cc4)cc4ccnn34)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
To a solution of 4-(tert-butoxycarbonylamino-ethyl)-benzoic acid (78 mg) and N-hydroxy-benzotriazole (HOBt)(45 mg) in DMF (5 ml) are added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC)(150 mg) and triethylamine (0.27 ml). The mixture is stirred for 0.5 h at ambient temperature. To this solution is added N-[5-(4′-Fluoro-biphenyl-4-yl)-pyrazolo[1,5-c]pyrimidin-7-yl]-benzene-1,4-diamine (compound B4)(0.1 g). After completion of the reaction the mixture is evaporated at high vacuum and the residue is treated with methanol. The resulting solid is filtered and dried. A yellow solid (0.097 g) is obtained.
Reaction SMILES: [C:1]1(=O)[C:12]2=[C:13]3[C:8](=[CH:9][CH:10]=[CH:11]2)[CH:7]=[CH:6][CH:5]=[C:4]3[CH2:3][CH2:2]1.Cl.[NH2:16]O.CO.C([O-])(=O)C.[Na+]>O>[CH:1]1([NH2:16])[C:12]2=[C:13]3[C:8](=[CH:9][CH:10]=[CH:11]2)[CH:7]=[CH:6][CH:5]=[C:4]3[CH2:3][CH2:2]1
Reactant: O=C1CCc2cccc3cccc1c23
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: NC1CCc2cccc3cccc1c23
Yield: 71.6 %

Procedure:
To a stirred mixture of 2,3-dihydro-phenalen-1-one (1.32 g, 7.24 mmol), hydroxylamine hydrochloride (0.85 g, 12.2 mmol) and water (6 ml) was added dropwise at 75° C. MeOH (7.5 ml) and afterwards a solution of sodium acetate (2.58 g, 19.0 mmol) in water (4 ml). Stirring was continued over a period of 1.5, h, water (20 ml) was added and after cooling (ice bath) the solid was collected by filtration. After drying in vacuo the crude product was dissolved in 3.5 N NH3 /MeOH (100 ml) and hydrogenated over Raney-Nickel (0.5 g, washed with MeOH) at RT for 17h. The catalyst was filtered off, the solution evaporated in vacuo and the residue purified by column chromatography on silica gel (dichloromethane/MeOH 9:1) to yield (RS)-2,3-dihydro-1H-phenalen-1-yl-amine (0.95 g) as a brown oil.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:9][C:10]([C:12]2[C:13]([OH:42])=[C:14]3[C:19](=[C:20]([C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)[N:21]=2)[N:18]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:17](=[O:35])[C:16]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:15]3)=[O:11])[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].CO.C1COCC1>C([O-])(O)=O.[Na+]>[CH2:28]([N:18]1[C:19]2[C:14](=[C:13]([OH:42])[C:12]([C:10]([NH:9][C:6]3([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]3)=[O:11])=[N:21][C:20]=2[C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH:15]=[C:16]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:17]1=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(=O)C1(NC(=O)c2nc(-c3cccnc3)c3c(cc(-c4ccccc4)c(=O)n3Cc3ccccc3)c2O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NC1(C(=O)O)CC1)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.8 %

Procedure:
A mixture of 1-[(1-benzyl-5-hydroxy-2-oxo-3-phenyl-8-pyridin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carbonyl)-amino]-cyclopropanecarboxylic acid ethyl ester (24 mg, 0.043 mmol), 2 M NaOH (3 mL), MeOH (3 mL) and THF (3 mL) was stirred at r.t. for 16 h, then concentrated to approximately one-third of its original volume. 1 M HCl was added to acidify the mixture, and the resulting suspension was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (10-100% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4, and the resulting precipitate was isolated by filtration to give 13 mg of the title compound as a light yellow solid. MS: (+) m/z 533.37 (M+1).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:8]2)=[CH:2]1.C([O:24][C:25](=[O:36])[C:26]1[CH:31]=[C:30]([CH2:32]Br)[CH:29]=[CH:28][C:27]=1[O:34][CH3:35])C>>[O:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH:16]3[CH2:21][CH2:20][N:19]([CH2:32][C:30]4[CH:29]=[CH:28][C:27]([O:34][CH3:35])=[C:26]([CH:31]=4)[C:25]([OH:36])=[O:24])[CH2:18][CH2:17]3)=[CH:8]2)=[CH:2]1
Reactant: CCOC(=O)c1cc(CBr)ccc1OC
Reactant: c1ccc2c(c1)c(C1CCNCC1)cn2Cc1ccoc1
Product: COc1ccc(CN2CCC(c3cn(Cc4ccoc4)c4ccccc34)CC2)cc1C(=O)O

Procedure:
This compound was prepared following the procedure described in example 13 (part D) starting with 1.9 g (6.5 mmol) of 1-furan-3-ylmethyl-3-piperidin-4-yl-1H-indole and 1.9 g (7.1 mmol) 5-bromomethyl-2-methoxy-benzoic acid ethyl ester. After standard work-up, 1.2 g (42% of yield) of the expected acid were obtained.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([S:18][CH:19]([CH2:22][OH:23])[CH2:20][OH:21])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1/[CH:34]=[CH:35]/[CH:36]=[CH:37]/[CH:38]=O)[C:29]#[N:30].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:29]([C:28]1[CH:31]=[CH:32][C:33](/[CH:34]=[CH:35]/[CH:36]=[CH:37]/[C@H:38]2[O:21][CH2:20][C@H:19]([S:18][C@H:16]([CH3:17])[C@:9]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=3[F:1])([OH:24])[CH2:10][N:11]3[CH:15]=[N:14][CH:13]=[N:12]3)[CH2:22][O:23]2)=[C:26]([F:25])[CH:27]=1)#[N:30]
Reactant: N#Cc1ccc(/C=C/C=C/C=O)c(F)c1
Reactant: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1cccc(F)c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@](O)(Cn1cncn1)c1cccc(F)c1F
Yield: 54.6 %

Procedure:
Crude title compound was obtained as an oil in a similar manner to that described in Example 1(iii) above using 643.3 mg (1.80 mmol) of (2R,3R)-2-(2,3-difluorophenyl)-3-[[1-(hydroxymethyl)-2-hydroxyethyl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol [prepared as described in Step 7(vi) above], 361.8 mg (1.80 mmol) of 3-fluoro-4-[(1E,3E)-5-oxo-1,3-pentadienyl]-benzonitrile [prepared as described in Example 1(ii) above] and 376.3 mg (1.98 mmol) of p-toluenesulfonic acid monohydrate. The oil was purified by chromatography on a silica gel (50 g) column using a 1:1 mixture of ethyl acetate and hexane as the eluant to give 533.7 mg (yield 55%) of the title compound as a colorless non-crystalline solid.
Reaction SMILES: Cl.[OH:2][C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[OH-].[Na+].Br[C@@H:12]([CH3:16])[C:13]([OH:15])=[O:14].Cl>>[O:2]=[C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]1[CH:12]([CH3:16])[C:13]([OH:15])=[O:14]
Reactant: C[C@H](Br)C(=O)O
Reactant: Oc1ncccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C(=O)O)n1cccnc1=O
Temperature: 80 °C

Procedure:
To 2-hydroxypyrimidine hydrochloride (1.27 g, 9.54 mmol) was added 5 N sodium hydroxide solution (5.7 ml) followed by (2S)-2-bromopropanoic acid (0.95 ml, 11 mmol). The reaction mixture was heated at 80° C. for 4 h. After cooling to ambient temperature, the reaction was neutralized with 2N hydrochloric acid (4.8 ml) and then directly purified by reverse phase HPLC (TMC Pro-Pac C18; 0-50% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient). Removal of the volatiles in vacuo afforded the title compound as a white solid. LC/MS 169.1 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]=[N:12][N:11]=[C:10]1[C:14]1[S:23][C:22]2[C:21]3[CH:24]=[C:25]([C:28](O)=[O:29])[CH:26]=[CH:27][C:20]=3[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=1.[CH2:31]([CH2:33][NH2:34])[OH:32]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]=[N:12][N:11]=[C:10]1[C:14]1[S:23][C:22]2[C:21]3[CH:24]=[C:25]([C:28]([NH:34][CH2:33][CH2:31][OH:32])=[O:29])[CH:26]=[CH:27][C:20]=3[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=1
Reactant: NCCO
Reactant: O=C(O)c1ccc2c(c1)-c1sc(-c3nncn3-c3ccc(F)cc3F)cc1CCO2
Product: O=C(NCCO)c1ccc2c(c1)-c1sc(-c3nncn3-c3ccc(F)cc3F)cc1CCO2

Procedure:
2-[4-(2,4-Difluoro-phenyl)-4H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-9-carboxylic acid and ethanolamine were reacted in the general amide coupling procedure to give 375. NMR: (CDCl3): 2.72 (1 H, s, OH), 3.01-3.04 (2 H, m), 3.57-3.61 (2 H, m), 3.72-3.81 (2 H, m), 4.20-4.23 (2 H, m), 6.68-6.72 (1 H, m, NH), 6.79 (1 H, s, Ar), 6.94 (1 H, d, J 8.4, Ar), 7.02-7.06 (2 H, m, Ar), 7.33-7.40 (1 H, m, Ar), 7.50-7.53 (1 H, m, Ar), 7.89-7.90 (1 H, m, Ar) and 8.16 (1 H, s, Ar). MS: (ESI+) MH+=469.04
Reaction SMILES: [I-].[K+].[CH2:3]([N:5]([CH2:30][CH3:31])[C:6]([C:8]1[N:12]=[C:11]([CH2:13]Cl)[N:10]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[C:22](=O)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:9]=1)=[O:7])[CH3:4].[NH3:32]>O.O1CCOCC1>[CH2:30]([N:5]([CH2:3][CH3:4])[C:6]([C:8]1[N:12]=[C:11]2[CH2:13][N:32]=[C:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:16]3[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=3[N:10]2[N:9]=1)=[O:7])[CH3:31]
Reactant: N
Reactant: CCN(CC)C(=O)c1nc(CCl)n(-c2ccc(Cl)cc2C(=O)c2ccccc2)n1
Agent: [I-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCN(CC)C(=O)c1nc2n(n1)-c1ccc(Cl)cc1C(c1ccccc1)=NC2

Procedure:
An amount of 1.99 g (0.012 mole) of potassium iodide is dissolved in 6 ml of water. The obtained solution is diluted with 20 ml of dioxane; an addition is then made at 25°, with stirring, of a solution of 4.3 g (0.01 mole) of N,N-diethyl-1-(2-benzoyl-4-chlorophenyl)-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxamide in 40 ml of dioxane, and the reaction solution heated for one hour at 50°. There is then added 35 ml of conc. aqueous ammonia solution, the mixture heated for a further 2 hours at 50°, and subsequently concentrated in vacuo. Water is added to the residue and extraction performed twice with methylene chloride. The organic phase is washed with water and saturated sodium chloride solution; it is then dried over sodium sulphate and concentrated in vacuo to dryness. The residue is recrystallized from benzene/cyclohexane to obtain pure N,N-diethyl-6-phenyl-8-chloro-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-carboxamide, M.P. 175°-177°.
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17]([S:20]([C:23]5[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=5)(=[O:22])=[O:21])[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([NH:30][C:31]2[C:32](=[O:38])[C:33](=[O:37])[C:34]=2OC)[CH2:4]1)[CH3:2].Cl.[F:40][C:41]([F:46])([F:45])[CH2:42][CH2:43][NH2:44].CCN(C(C)C)C(C)C>CO>[CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17]([S:20]([C:23]5[CH:24]=[CH:25][C:26]([CH3:27])=[CH:28][CH:29]=5)(=[O:21])=[O:22])[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([NH:30][C:31]2[C:32](=[O:38])[C:33](=[O:37])[C:34]=2[NH:44][CH2:43][CH2:42][C:41]([F:46])([F:45])[F:40])[CH2:4]1)[CH3:2]
Reactant: CC[C@@H]1C[C@H](Nc2c(OC)c(=O)c2=O)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Reactant: NCCC(F)(F)F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC[C@@H]1C[C@H](Nc2c(NCCC(F)(F)F)c(=O)c2=O)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Temperature: 50 °C
Reaction time: 18 h
Yield: 79.3 %

Procedure:
A mixture of 3-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)-4-methoxycyclobut-3-ene-1,2-dione (0.090 g, 0.17 mmol, Preparation #29), 3,3,3-trifluoropropan-1-amine hydrochloride (0.050 g, 0.337 mmol, Fluorochem Limited), DIEA (0.18 mL, 1.0 mmol) and MeOH (1.2 mL) was heated at about 50° C. After about 18 h, the reaction was cooled to rt. The solid was collected via vacuum filtration, while washing with MeOH (about 3-5 mL), and then dried in a vacuum oven at about 60° C. to give 3-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)-4-(3,3,3-trifluoropropylamino)cyclobut-3-ene-1,2-dione (0.083 g, 79%) as an off-white solid: LC/MS (Table 1, Method a) Rt=2.27 min; MS m/z: 616 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH2:10][CH:9]1[C:12](=[O:50])[NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[C:22]3[C:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[O:35][CH3:36])=[N:27][N:26](COCC[Si](C)(C)C)[C:23]3=[N:24][CH:25]=2)=[CH:16][C:15]=1[C:45](=[O:49])[N:46]([CH3:48])[CH3:47])=O)(C)(C)C.C1(S)C=CC=CC=1.Cl>C(O)(=O)C>[CH3:48][N:46]([CH3:47])[C:45]([C:15]1[CH:16]=[C:17]([C:20]2[CH:21]=[C:22]3[C:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[O:35][CH3:36])=[N:27][NH:26][C:23]3=[N:24][CH:25]=2)[CH:18]=[CH:19][C:14]=1[NH:13][C:12]([CH:9]1[CH2:10][CH2:11][NH:8]1)=[O:50])=[O:49]
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3ccc(NC(=O)C4CCN4C(=O)OC(C)(C)C)c(C(=O)N(C)C)c3)cc12
Agent: Cl
Agent: Sc1ccccc1
Solvent: CC(=O)O
Product: COc1ccccc1-c1n[nH]c2ncc(-c3ccc(NC(=O)C4CCN4)c(C(=O)N(C)C)c3)cc12
Yield: 32.2 %

Procedure:
2-{2-Dimethylcarbamoyl-4-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenylcarbamoyl}-azetidine-1-carboxylic acid tert-butyl ester (149.6 mg, 0.213 mmol) was treated with PS-thiophenol (Argonaut Technologies, Inc., 1.0 eq., 317 mg) and 5% hydrochloric acid in acetic acid (5 mL) for 3.5 h. The mixture was filtered and rinsed with ethyl acetate to remove the acetic acid (the solid product stuck in the resin) and then the product was eluted using methanol. The methanol solution was concentrated in vacuo and then lyophilized from acetonitrile/water to afford azetidine-2-carboxylic acid {2-dimethylcarbamoyl-4-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-amide (32.3 mg, 32.2%). 1H-NMR (500 MHz, dimethylsulfoxide-d6) δ 2.24 (m, 1H), 2.57 (m, 1H), 2.95 (s, 3H), 3.04 (s, 3H), 3.15 (m, 1H), 3.63 (q, J=7.5 Hz, 1H), 3.84 (s, 3H), 4.23 (m, 1H), 7.08 (t, J=7.0 Hz, 1H), 7.21 (d, J=8.5 Hz, 1H), 7.45 (dd, J=2.0, J=7.5 Hz 1H), 7.64 (dd, J=1.5 Hz, J=9.0 Hz, 1H), 8.33 (d, J=8.0 Hz, 1H), 8.35 (s, 1H), 8.87 (d, J=2.5 Hz, 1H), 10.31 (s, 1H). MS: m/z 471 (M+H+).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[Li]CCCC.[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:30]3[C:25](=[CH:26][C:27]([CH:31]=[O:32])=[CH:28][CH:29]=3)[CH:24]=[N:23]2)=[CH:18][CH:17]=1>C1COCC1>[F:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[C:30]3[C:25](=[CH:26][C:27]([CH:31]([OH:32])[C:2]4[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=4)=[CH:28][CH:29]=3)[CH:24]=[N:23]2)=[CH:20][CH:21]=1
Reactant: N#Cc1ccc(Br)cc1
Reactant: O=Cc1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#Cc1ccc(C(O)c2ccc3c(cnn3-c3ccc(F)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.4 %

Procedure:
To solution of 4-bromobenzonitrile (182 mg, 1.0 mmol) in 5 mL of dry THF at −78° C. was added n-BuLi (0.7 mL of 1.6 M hexanes solution, 1.1 mmol). The reaction was stirred 30 min and then 1-(4-fluorophenyl)-1H-indazol-5-carboxaldehyde (240 mg, 1.0 mmol) was added and the reaction mixture was allowed to warm to RT. After 12 h, quenched with brine and extracted 2×EtOAc. The organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified on SiO2 by MPLC eluting with a 0-30% EtOAc/hexane gradient to give 180 mg (52% yield) of 4-((1-(4-fluorophenyl)-1H-indazol-5-yl)(hydroxy)methyl)benzonitrile. MS found: (M+H)+=344.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]2[N:7]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:8][C@@H:9](OS(C3C=CC(C)=CC=3)(=O)=O)[C@H:5]2[O:4][CH2:3]1.[CH3:28][S-:29].[Na+].[Cl-].[NH4+]>CC(N(C)C)=O>[OH:1][C@@H:2]1[C@H:6]2[N:7]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:8][C@H:9]([S:29][CH3:28])[C@H:5]2[O:4][CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CN(C(=O)OC(C)(C)C)[C@H]3[C@@H]2OC[C@@H]3O)cc1
Reactant: C[S-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CS[C@H]1CN(C(=O)OC(C)(C)C)[C@H]2[C@@H]1OC[C@@H]2O
Temperature: 25 °C
Yield: 87.6 %

Procedure:
A stirred solution of tosylate (35b) (250 mg, 0.63 mmol) and sodium thiomethoxide [CAS 5188-07-8] (88 mg, 1.25 mmol) in 3 ml of DMA was heated under an atmosphere of argon in a sealed pressure vessel at 90° C. for 2 hours. The mixture was then allowed to cool to ambient temperature then an aqueous saturated solution of ammonium chloride (10 mL) was added. The aqueous phase was extracted with tert-butyl methyl ether (3×7 ml). The organic phase was dried (MgSO4), filtered and reduced in vacuo to leave an oil. Flash chromatography over silica, eluting with diethyl ether:pentane 2:1 gave thiomethylether (54) as colourless oil (0.152 g, 88%). TLC(Rf=0.29, Et2O:pentane 2:1), HPLC-MS 220.1 [M+2H−tBu]+, 573.2 [2M+H]+; δH (500 MHz, CDCl3) mixture of rotamers 1:1; 1.46 (4.5H, s, CCH3), 1.49 (4.5H, s, CCH3), 2.16 (3H, s, SCH3), 3.20 (1H, brs, BocNCH2), 3.47-4.05 (4H, m, OCH2CHOH, BocNCH2 and CHSCH3), 4.24-4.45 (2H, m, BocNCH and OCH2CHOH), 4.63 (1H, s, OCHCHSCH3).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].[F:16][C:17]1[C:18](F)=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=[O:21].O>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][C:22]2[CH:23]=[CH:24][C:17]([F:16])=[CH:18][C:19]=2[CH:20]=[O:21])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(O)cc1
Reactant: O=Cc1cccc(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc(F)cc2C=O)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To stirred solution of 4-cyanophenol (Aldrich, 5.00 g, 42 mmol) in DMF (100 mL), potassium carbonate (63 mmol) and 2-4, difluoro-benzaldehyde (Aldrich, 5.97 g, 42 mmol) were added and the mixture was stirred at 90° C. overnight. The mixture was cooled to room temperature and poured into water. The solid was filtered and dried to give a pale yellow solid. 5.2 g MS (H+), 242.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[C:8]([N+:12]([O-])=O)[CH:9]=[C:10]([CH3:11])[C:5]2=[N:4][N:3]=1.[H][H]>CO.[Pd]>[CH3:1][C:2]1[N:6]2[CH:7]=[C:8]([NH2:12])[CH:9]=[C:10]([CH3:11])[C:5]2=[N:4][N:3]=1
Reactant: Cc1cc([N+](=O)[O-])cn2c(C)nnc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1cc(N)cn2c(C)nnc12

Procedure:
A suspension of 3,8-dimethyl-6-nitro-[1,2,4]triazolo[4,3-a]pyridine (Step 67.3) (14.1 g, 71.9 mmol) and 10% Pd/C (2.75 g, 25.9 mmol) in MeOH (300 mL) was shaken for 5 h under 4 bar hydrogen atmosphere at RT. Further 10% Pd/C was added and the reaction mixture was shaken another 1 hh under hydrogen atmosphere. The mixture was filtered through Celite. The pad of Celite was washed with MeOH and the resulting filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane/(CH2Cl2-MeOH 19:1) 50-100% (CH2Cl2-MeOH 19:1)) to afford the title product as yellow solid. tR: 0.29 min (LC-MS 2); ESI-MS: 163 [M+H]+ (LC-MS 2); TLC (CH2Cl2-MeOH 9:1) Rf=0.26; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.43 (s, 3H) 2.54 (s, 3H) 5.05 (br. s, 2H) 6.75 (br. s, 1H) 7.18 (br. s, 1H).