Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:12]Cl)[C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][NH:15][C:16]([NH:18][CH3:19])=[S:17].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:14][N:15]=[C:16]1[N:18]([CH3:19])[C:9](=[O:10])[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12][S:17]1
Reactant: O=C(Cl)N(CCl)Cc1ccccc1
Reactant: CNC(=S)NC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CN=C1SCN(Cc2ccccc2)C(=O)N1C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
A mixture of 4.4 g (0.02 mole) of N-benzyl-N-chloromethylcarbamoyl chloride and 2.0 g (0.02 mole) of 1,3-dimethylthiourea was dissolved in 50 ml of ethyl alcohol and heated under reflux with stirring for 2 hours. After addition of 20 ml of a saturated aqueous potassium carbonate solution, the mixture was extracted with 100 ml of benzene. The benzene layer was washed with water, dried, and freed from the benzene by distillation under reduced pressure to obtain 4.0 g of crude crystals which were recrystallized from ether. Yield 3.2 g (63%); m.p. 93°-95° C.
Reaction SMILES: [O:1]=[C:2]1[CH:6]([CH2:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)[CH2:5][CH2:4][O:3]1.[BrH:18]>C(O)(=O)C>[Br:18][CH2:4][CH2:5][CH:6]([CH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1)[C:2]([OH:3])=[O:1]
Reactant: COC(=O)c1ccc(CC2CCOC2=O)cc1
Reactant: Br
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CC(CCBr)C(=O)O)cc1
Temperature: 80 °C
Reaction time: 0.67 h

Procedure:
9.00 g (38.42 mmol) of methyl 4-[(2-oxotetrahydro-3-furanyl)methyl]benzoate from Ex. VI are suspended in 54 ml of a 33 percent strength HBr solution in glacial acetic acid, and the mixture is stirred at 80° C. for 40 min. The reaction solution is poured into ice-water and the resulting precipitate is filtered off with suction, washed with water and dried under reduced pressure at 40° C.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][C:15]([Cl:19])=[N:16]3)=[CH:11][CH:10]=2)[C:4]1=[O:20].[S:21]1[C:25]([S:26](Cl)(=[O:28])=[O:27])=[CH:24][C:23]2[CH:30]=[CH:31][CH:32]=[CH:33][C:22]1=2.COC1C=C2C(C=CC(S(Cl)(=O)=O)=C2)=CC=1>C(Cl)(Cl)Cl>[Cl:19][C:15]1[CH:14]=[CH:13][C:12]2[C:17](=[CH:18][C:9]([CH2:8][N:5]3[CH2:6][CH2:7][C@H:3]([NH:2][S:26]([C:25]4[S:21][C:22]5[CH:33]=[CH:32][CH:31]=[CH:30][C:23]=5[CH:24]=4)(=[O:27])=[O:28])[C:4]3=[O:20])=[CH:10][CH:11]=2)[N:16]=1
Reactant: N[C@H]1CCN(Cc2ccc3ccc(Cl)nc3c2)C1=O
Reactant: O=S(=O)(Cl)c1cc2ccccc2s1
Agent: COc1ccc2ccc(S(=O)(=O)Cl)cc2c1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: O=C1[C@@H](NS(=O)(=O)c2cc3ccccc3s2)CCN1Cc1ccc2ccc(Cl)nc2c1

Procedure:
The title compound is prepared in CHCl3 instead of CH3CN from 7-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)-2-chloro-quinoline hydrochloride as described in EXAMPLE 1, Part K using benzo[b]thiophene-2-sulfonyl chloride as prepared in EXAMPLE 8, Part A in place of 7-methoxynaphthalene-2-sulfonyl chloride. The crude product is triturated from CH2Cl2 to afford the title compound as a beige solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[C:9](OCC)(=[O:13])[C:10]([CH3:12])=O>C(Cl)(Cl)Cl>[CH3:12][C:10]1[C:9](=[O:13])[NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N:8]=1
Reactant: Nc1ccncc1N
Reactant: CCOC(=O)C(C)=O
Solvent: ClC(Cl)Cl
Product: Cc1nc2ccncc2[nH]c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
A mixture of 3,4-diamino pyridine (10 g) and ethyl pyruvate (53 g) in chloroform (100 mL) was stirred at ambient temperature overnight. The precipitated solid was filtered off, washed with DCM, and dried to afford 2-methyl-4H-pyrido[3,4-b]pyrazin-3-one (14 g) as a yellowish solid. 2 g of this material was suspended in DMF (10 mL) and treated with PyBroP (6 g) and DIPEA (3.3 mL,) at ambient temperature overnight. The precipitated solid was filtered off, washed with ethanol, and dried to afford 3-(benzotriazol-1-yloxy)-2-methyl-pyrido[3,4-b]pyrazine (1.7 g) as a white solid. This material was suspended in ethanol (50 mL), hydrazine hydrate was added, and resulting mixture was heated at 85° C. for 15 min. The solid was filtered off, washed with ethanol, and dried to afford IIc (0.95 g) as a yellow solid sufficiently pure for the next step.
Reaction SMILES: [OH:1][C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:12][C:13]1[CH:14]=[C:15](O)[CH:16]=[CH:17][CH:18]=1>>[F:11][C:8]1[CH:9]=[N:10][C:2]([O:1][C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([F:12])[CH:18]=2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(F)cnc1O
Reactant: Oc1cccc(F)c1
Product: O=C(O)c1cc(F)cnc1Oc1cccc(F)c1

Procedure:
The title compound was prepared according to the procedure described in step 1 & 2 of Example 1 from 2-hydroxy-5-fluoronicotinic acid and 3-fluorophenol; 1H-NMR (DMSO-d6) δ 8.37 (1H, m), 8.23–8.15(1H, m), 7.49–7.35 (1H, m), 7.10–6.90 (3H, m).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[C:18]([C:20]([N:22]2[CH2:27][CH2:26][CH:25]([C:28]([O:30]C)=[O:29])[CH2:24][CH2:23]2)=[O:21])[CH:17]=[C:16]2[C:3]=1[C@@:4]1([CH3:37])[C@H:13]([CH2:14][S:15]2(=[O:33])=[O:32])[C@:12]2([CH3:34])[C@H:7]([C:8]([CH3:36])([CH3:35])[CH2:9][CH2:10][CH2:11]2)[CH2:6][CH2:5]1.O[Li].O>CO.O>[OH:1][C:2]1[CH:19]=[C:18]([C:20]([N:22]2[CH2:27][CH2:26][CH:25]([C:28]([OH:30])=[O:29])[CH2:24][CH2:23]2)=[O:21])[CH:17]=[C:16]2[C:3]=1[C@@:4]1([CH3:37])[C@H:13]([CH2:14][S:15]2(=[O:33])=[O:32])[C@:12]2([CH3:34])[C@H:7]([C:8]([CH3:36])([CH3:35])[CH2:9][CH2:10][CH2:11]2)[CH2:6][CH2:5]1
Reactant: COC(=O)C1CCN(C(=O)c2cc(O)c3c(c2)S(=O)(=O)C[C@@H]2[C@@]4(C)CCCC(C)(C)[C@@H]4CC[C@@]32C)CC1
Agent: [Li]O
Solvent: CO
Solvent: O
Product: CC1(C)CCC[C@]2(C)[C@H]3CS(=O)(=O)c4cc(C(=O)N5CCC(C(=O)O)CC5)cc(O)c4[C@]3(C)CC[C@@H]12
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.4 %

Procedure:
A mixture of methyl 1-{[(1R,10R,11S,16S)-3-hydroxy-1,11,15,15-tetramethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-trien-5-yl]carbonyl}piperidine-4-carboxylate (97) (0.10 g, 0.18 mmol) and LiOH.H2O (0.10 g, 2.4 mmol) in MeOH (10 mL) and water (2.0 mL) was stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure and acidified with 1 M HCl. The resulting solid was collected by filtration to give 1-{[(1R,10R,11S,16S)-3-hydroxy-1,11,15,15-tetramethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-trien-5-yl]carbonyl}piperidine-4-carboxylic acid (98) (0.06 g, 63%) as a white solid. 1H NMR (CD3OD): δ 7.29 (d, 1H), 6.97 (d, 1H), 4.43 (m, 1H), 3.70 (m, 1H), 3.58 (m, 1H), 3.36 (m, 2H), 3.26-2.96 (m, 4H), 2.62 (m, 1H), 2.24 9d, 1H), 2.10-1.16 (m, 13H), 1.09-0.99 (m, 5H), 0.90 (s, 3H), 0.88 (s, 3H). MS m/z 516 (C28H39NO6S−H+).
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])=[NH:7])=[CH:4][CH:3]=1.C([Li])CCC.Cl[P:25]([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27]>>[CH:26]([P:25]([CH:29]([CH3:31])[CH3:30])[N:7]=[C:6]([NH:8][C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:16])[C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:18][CH:17]=1)([CH3:28])[CH3:27]
Reactant: CC(C)P(Cl)C(C)C
Reactant: Cc1ccc(C(=N)Nc2c(C)cccc2C)cc1
Agent: [Li]CCCC
Product: Cc1ccc(C(=NP(C(C)C)C(C)C)Nc2c(C)cccc2C)cc1

Procedure:
Procedure as described for NP Amidine I using the following amounts: 1.19 g of 4-methyl-N1-(2,6-dimethylphenyl)benzamidine (Amidine III, 5.0 mmol), 2.50 mL of 2.0 M butyllithium (5.0 mmol), 0.80 mL chlorodiisopropylphosphine (5.0 mmol). After filtration to remove lithium chloride and removal of solvent, a yellow oil was isolated (1.76 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]2[CH:12]=[C:13]([C:16]3[C:17]([C:40]4[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=4)=[N:18][N:19]([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)[CH:20]=3)[CH:14]=[CH:15][C:10]2=[N:9][CH:8]=1.Cl[CH2:48][C:49]([N:51]([CH3:53])[CH3:52])=[O:50]>>[CH3:52][N:51]([CH3:53])[C:49](=[O:50])[CH2:48][O:46][C:43]1[CH:42]=[CH:41][C:40]([C:17]2[C:16]([C:13]3[CH:14]=[CH:15][C:10]4[N:11]([C:7]([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=5)=[CH:8][N:9]=4)[CH:12]=3)=[CH:20][N:19]([C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:18]=2)=[CH:45][CH:44]=1
Reactant: CN(C)C(=O)CCl
Reactant: Oc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4ccccn4)n3c2)cc1
Product: CN(C)C(=O)COc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4ccccn4)n3c2)cc1
Yield: 77.8 %

Procedure:
90 mg 4-{4-[3-(pyridin-2-yl)imidazo[1,2-a]pyridin-6-yl]-1-trityl-1H-pyrazol-3-yl}phenol (compound in Example 353) and 28 mg 2-chloro-N,N-dimethylacetamide were reacted under the same conditions as in Example 190, to give 80 mg of the title compound as a pale yellow amorphous matter.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:20][CH2:19][C:18]3[C@:13]([C:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)=[O:32])([CH2:14][C:15]4[CH:23]=[N:22][N:21]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:16]=4[CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>C(#N)C>[F:30][C:27]1[CH:26]=[CH:25][C:24]([N:21]2[C:16]3[CH:17]=[C:18]4[C@:13]([C:31]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=5)=[O:32])([CH2:14][C:15]=3[CH:23]=[N:22]2)[CH2:12][N:11]([S:8]([C:5]2[CH:6]=[N:7][C:2]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[CH:3][CH:4]=2)(=[O:9])=[O:10])[CH2:20][CH2:19]4)=[CH:29][CH:28]=1
Reactant: C1COCCN1
Reactant: O=C(c1ccccn1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(Cl)nc1)C2
Solvent: CC#N
Product: O=C(c1ccccn1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCOCC3)nc1)C2
Yield: 83.2 %

Procedure:
A solution of (R)-(6-((6-chloropyridin-3-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone (80 mg, 0.14 mmol) and morpholine (150 μL, 1.73 mmol) in acetonitrile (2.5 mL) was heated at 100° C. for 70 minutes in a microwave reactor. The reaction mixture was concentrated and the residue purified by column chromatography on silica gel (gradient: 30-60% ethyl acetate in cyclohexane) to afford (R)-(1-(4-fluorophenyl)-6-((6-morpholinopyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone as a colourless glass (70 mg). LCMS (Method D, ESI): RT 4.94 min, m+H=601.0; 1H NMR (400 MHz, CDCl3): δ 8.63 (ddd, J=4.8, 1.7, 0.9 Hz, 1 H); 8.44 (d, J=2.5 Hz, 1 H); 7.84-7.85 (m, 2 H); 7.66 (dd, J=9.1, 2.5 Hz, 1 H); 7.44-7.45 (m, 3 H); 7.29 (s, 1 H); 7.16 (t, J=8.5 Hz, 2 H); 6.49-6.50 (m, 2 H); 5.49 (dd, J=12.1, 2.1 Hz, 1 H); 4.28 (d, J=16.9 Hz, 1 H); 3.80 (t, J=4.8 Hz, 5H); 3.63 (t, J=4.8 Hz, 4H); 2.83-2.85 (m, 2 H); 2.71 (d, J=12.1 Hz, 1 H); 2.47-2.50 (m, 2 H).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[N:9]([C:17]1[C:22]([F:23])=[C:21](Cl)[N:20]=[C:19]([Cl:25])[N:18]=1)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])[CH3:3].C(N(CC)CC)C.[CH3:40][NH:41][CH2:42][C:43]1[S:44][CH:45]=[CH:46][N:47]=1>C1COCC1.O>[CH3:4][C:2]([O:5][C:6]([N:8]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[N:9]([C:17]1[C:22]([F:23])=[C:21]([N:41]([CH3:40])[CH2:42][C:43]2[S:44][CH:45]=[CH:46][N:47]=2)[N:20]=[C:19]([Cl:25])[N:18]=1)[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])=[O:7])([CH3:3])[CH3:1]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(Cl)c1F
Reactant: CNCc1nccs1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(Cc1nccs1)c1nc(Cl)nc(N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1F
Reaction time: 8 h
Yield: 109.6 %

Procedure:
Tris(1,1-dimethylethyl)2-(2,6-dichloro-5-fluoro-4-pyrimidinyl)-1,1,2-hydrazinetricarboxylate (1.16 g, 2.339 mmol) was dissolved in THF (5 mL). To this solution was added triethylamine (0.39 mL, 2.8 mmol), followed by N-methyl-1-(1,3-thiazol-2-yl)methanamine (0.30 g, 2.3437 mmol) in THF (2 mL). The reaction was left to stir overnight. Then the reaction mixture was diluted with water, and the aqueous layer was extracted with ethyl acetate. The organics were dried (Na2SO4) and concentrated to produce tris(1,1-dimethylethyl)2-{2-chloro-5-fluoro-6-[methyl(1,3-thiazol-2-ylmethyl)amino]-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate as a white solid (1.51 g). LCMS: (M+H−Boc)+=489.1.
Reaction SMILES: Cl.Cl.Cl.[CH2:4]([NH:11][C:12](=[NH:33])[C:13](=[NH:32])[NH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:20]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(Cl)Cl.[S:37](N1C(=O)C2=CC=CC=C2C1=O)N1C(=O)C2=CC=CC=C2C1=O>C(N(CC)CC)C>[CH2:4]([NH:11][C:12]1[C:13]([NH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH:20]=2)=[N:32][S:37][N:33]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C1c2ccccc2C(=O)N1SN1C(=O)c2ccccc2C1=O
Reactant: N=C(NCCCOc1cccc(CN2CCCCC2)c1)C(=N)NCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: c1ccc(CNc2nsnc2NCCCOc2cccc(CN3CCCCC3)c2)cc1
Reaction time: 1 h
Yield: 77.3 %

Procedure:
A mixture of N-benzyl-N'-[3-(3-piperidinomethylphenoxy)propyl]ethanediimidamide trihydrochloride (4.73 g; 9.16 mmoles) [prepared in Step A], 45 ml of CH2Cl2 and 3.8 ml of triethylamine was treated with N,N'-thiobisphthalimide (DMF solvate) (3.64 g; 9.16 mmoles) and stirred for one hour. The mixture was washed with 44 ml of 10% KOH, dried (MgSO4), filtered, diluted with toluene and concentrated. The residue was chromatographed by flash chromatography on 110 g of silica gel (230-400 mesh) using ethyl acetate as the eluent to give 3.1 g (77%) of the title compound. Treatment of the product with an equivalent amount of aqueous HCl in 2-propanol gave the hydrochloride salt of the title compound, mp 138°-141° C.
Reaction SMILES: OCCN(C)C(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2(N3C4=NC=CC=C4C=C3)CCCC2)N=1)=O.[Si]([O:45][CH2:46][CH2:47][N:48]([CH:81]([CH3:83])[CH3:82])[C:49]([C:51]1[C:56]([O:57][CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)=[C:55]([OH:65])[N:54]=[C:53]([CH2:66][C:67]2([N:72]3[C:76]4=[N:77][CH:78]=[CH:79][CH:80]=[C:75]4[CH:74]=[CH:73]3)[CH2:71][CH2:70][CH2:69][CH2:68]2)[N:52]=1)=[O:50])(C(C)(C)C)(C)C>>[OH:45][CH2:46][CH2:47][N:48]([CH:81]([CH3:83])[CH3:82])[C:49]([C:51]1[C:56]([O:57][CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)=[C:55]([OH:65])[N:54]=[C:53]([CH2:66][C:67]2([N:72]3[C:76]4=[N:77][CH:78]=[CH:79][CH:80]=[C:75]4[CH:74]=[CH:73]3)[CH2:71][CH2:70][CH2:69][CH2:68]2)[N:52]=1)=[O:50]
Reactant: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1
Agent: CN(CCO)C(=O)c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1
Product: CC(C)N(CCO)C(=O)c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1

Procedure:
5-Benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (2-hydroxyethyl)-isopropylamide (410) was prepared following the same method as described for 5-benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (2-hydroxyethyl)-methyl-amide (406) from 5-benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]isopropylamide (409) (220 mg, 0.34 mmol) and was obtained as an off-white sticky solid (110 mg, 61%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[NH:6][N:5]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:15]([N:6]1[N:5]=[C:4]([Cl:3])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=c1[nH]nc(Cl)c2ccccc12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1c2ccccc2c(Cl)nn1Cc1ccccc1
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 90.1 %

Procedure:
Sodium hydride (60% suspension in mineral oil, 0.92 g, 22.8 mmol) was added in one portion to a stirred suspension of 4-chloro-2H-phthalazin-1-one (3.74 g, 20.7 mmol) in anhydrous DMF (80 mL). The reaction was stirred for 15 min and then cooled to 10° C. Benzyl bromide (4.25 g, 24.8 mmol) was added drop wise and the reaction mixture was then stirred for 21 h at rt. After that time the reaction was diluted with ethyl acetate (200 mL), washed with water (5×80 mL) then brine (80 mL), dried over MgSO4 and concentrated under reduced pressure. The resulting pale yellow solid was suspended in hexanes (80 mL) and stirred for 3 h. After that time, the precipitate was collected by filtration, washed with hexanes and dried to give 2-benzyl-4-chloro-2H-phthalazin-1-one (5.05 g, 90%) as white solid: 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J=7.6 Hz, 1H), 7.98 (d, J=8.8 Hz, 1H), 7.97-7.83 (m, 2H), 7.50 (d, J=6.8 Hz, 2H), 7.36-7.7.29 (m, 3H), 5.37 (s, 2H).
Reaction SMILES: C([O:8][C:9](=[O:40])[CH:10]([CH:21]([C:26](=[O:39])[NH:27][CH:28]([C:33](=[O:38])[NH:34][CH:35]1[CH2:37][CH2:36]1)[C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH:23]([CH3:25])[CH3:24])[C:11](OCC1C=CC=CC=1)=O)C1C=CC=CC=1.[H][H].N1CCCCC1.C=O>C(O)C.[Pd]>[CH:35]1([NH:34][C:33]([CH:28]([NH:27][C:26]([CH:21]([C:10](=[CH2:11])[C:9]([OH:40])=[O:8])[CH2:22][CH:23]([CH3:25])[CH3:24])=[O:39])[C:29]([CH3:30])([CH3:32])[CH3:31])=[O:38])[CH2:37][CH2:36]1
Reactant: [H][H]
Reactant: CC(C)CC(C(=O)NC(C(=O)NC1CC1)C(C)(C)C)C(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Agent: C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: C=C(C(=O)O)C(CC(C)C)C(=O)NC(C(=O)NC1CC1)C(C)(C)C
Temperature: 25 °C

Procedure:
2-[1-(1-Cyclopropylcarbamoyl-2,2-dimethyl-propylcarbamoyl)-3-methyl-butyl]-malonic acid dibenzyl ester (14.53 g, 25.7 mmol) was dissolved in ethanol (200 ml) and the solution was placed under a blanket of argon. 10% Palladium on charcoal (3.2 g) was added and a fine stream of hydrogen gas was passed through the suspension for 3h with stirring. TLC showed that all the starting material had been consumed. The system was purged with argon and the catalyst was removed by filtration. The filtrate was cooled and stirred in an ice bath and treated with piperidine (2.39 g, 28.1 mmol) which was added dropwise, followed by 37% formaldehyde solution (22.6 ml, ca. 257 mmol). The reaction mixture was allowed to warm slowly to room temperature, then stirred overnight. The solvents were removed under reduced pressure and the residual oil was partitioned between ethyl acetate (300 ml) and 1 M hydrochloric acid (300 ml). The organic layer was separated, washed with 1M HCl and brine, dried over MgSO4, filtered and evaporated to dryness. The remaining pale brown foam (4.40 g, crude) contained a number of minor impurities but was used in Step C without purification. 1H-NMR; δ (CDCl3), 8.34 (1H, d, J=10.0 Hz), 7.37 (1H, m), 6.47 (1H, s), 5.99 (1H, s), 4.50 (1H, d, J=9.9 Hz), 4.07 (1H, m), 2.73 (1H, m), 1.79 (1H, m), 1.52 (2H, m), 1.00-0.82 (1 5H, br m), 0.78 (2H, m) and 0.55 (2H, m).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4C=CC=CC=4)([C:28]4C=CC=CC=4)[C:22]4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[CH:47]1([C:52](Cl)=[O:53])[CH2:51][CH2:50][CH2:49][CH2:48]1.C(N(CC)CC)C>O1CCCC1>[CH:47]1([C:52]([NH:46][C:42]2[CH:43]=[CH:44][CH:45]=[C:40]([C:9]3[C:10]4[C:15](=[CH:14][CH:13]=[C:12]([C:16]5[N:20]=[CH:19][N:18]([C:21]([CH3:22])([CH3:34])[CH3:28])[N:17]=5)[CH:11]=4)[N:7]([CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)[N:8]=3)[CH:41]=2)=[O:53])[CH2:51][CH2:50][CH2:49][CH2:48]1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: O=C(Cl)C1CCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)n1cnc(-c2ccc3c(c2)c(-c2cccc(NC(=O)C4CCCC4)c2)nn3C2CCCCO2)n1

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.150 g, 0.248 mmol) in 2.5 mL of tetrahydrofuran was added cyclopentanecarbonyl chloride (0.060 mL, 0.496 mmol), followed by triethyl amine (0.173 mL, 1.24 mmol). Completion of the reaction necessitated the addition of 2 more equivalents of reagents and a total reaction time of 48 hours at room temperature. The reaction mixture was then partitioned between ethyl acetate and water. The crude material that was obtained from evaporation of the extracts was not purified further. (Yield not calculated) ES-MS (m/z) 699 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([C:8](=O)[CH2:9][C:10](=O)[CH3:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4].O.[NH2:15][NH2:16]>C1COCC1>[CH3:11][C:10]1[CH:9]=[C:8]([CH:2]([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[NH:16][N:15]=1
Reactant: NN
Reactant: CCOC(=O)C(C)C(=O)CC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C)c1cc(C)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.4 %

Procedure:
To a solution of 18.6 g (100 mmol) of ethyl 2-methyl-3,5-dioxohexanoate from step A above in 200 mL of THF and 50 mL of water was added 3.45 mL (110 mmol) of anhydrous hydrazine. The biphasic reaction mixture was stirred at ambient temperature overnight then evaporated to dryness in vacuo. The crude yellow residue was dissolved in an ethyl acetate and water mixture and flushed through a 50 g silica gel plug. The filtrate was then evaporated to dryness in vacuo and the residue purified by silica gel chromatography eluting with a 0-100% ethyl acetate in hexanes gradient to afford the title compound as a yellow oil (1.89 g, 10%). 1H NMR (CDCl3, 500 MHz) δ 7.26 (s, 1H), 5.98 (s, 1H), 4.20-4.12 (m, 2H), 3.81 (q, J=7.3 Hz, 1H), 2.28 (s, 3H), 1.51 (d, J=7.3 Hz, 3H), 1.25 (t, J=7.1 Hz, 3H). LC-MS: m/z (ES) 183 (MH)+.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[C:5]([CH3:18])[CH:4]=1)#[N:2].[C:19](OC)(=[O:27])[C:20]1[C:21](=[CH:23][CH:24]=[CH:25][CH:26]=1)[SH:22].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:18][C:5]1[CH:4]=[C:3]([C:1]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19](=[O:27])[N:2]=2)[N:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH:6]=1
Reactant: COC(=O)c1ccccc1S
Reactant: Cc1cc(C#N)nc(CCC(=O)OC(C)(C)C)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1cc(CCC(=O)OC(C)(C)C)nc(-c2nc(=O)c3ccccc3s2)c1
Yield: 55 %

Procedure:
tert-Butyl 3-(6-cyano-4-methyl-2-pyridyl)propanoate (0.72 g, 2.9 mmol) and methyl thiosalicylate (0.99 g, 5.9 mmol) were dissolved in toluene (4 ml), and triethylamine (2.0 ml, 14.3 mmol) was added thereto. The mixture was refluxed for 14 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (1:2, v/v) were collected, concentrated and recrystallized from ethyl acetate-hexane to give the titled compound (0.61 g, 54%) as white crystals.