Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].C(N(CC)CC)C.[S:13]1[C:22]2[C:21](=[O:23])[NH:20][C:19]3[CH:24]=[CH:25][CH:26]=[N:27][C:18]=3[NH:17][C:16]=2[CH:15]=[CH:14]1>O1CCOCC1>[Cl:1][CH2:2][C:3]([N:17]1[C:16]2[CH:15]=[CH:14][S:13][C:22]=2[C:21](=[O:23])[NH:20][C:19]2[CH:24]=[CH:25][CH:26]=[N:27][C:18]1=2)=[O:4]
Reactant: O=C1Nc2cccnc2Nc2ccsc21
Reactant: O=C(Cl)CCl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C1Nc2cccnc2N(C(=O)CCl)c2ccsc21

Procedure:
Chloroacetyl chloride (1.9 ml) is added in 20 minutes, contemporaneously with triethylamine (3.4 ml), to a suspension of 4,9-dihydro-10H-pyrido[3,2-b]thieno[3,2-e][1,4]-diazepin-10-one (4.4 g) in dioxane (200 ml), heated to reflux.
Reaction SMILES: [OH:1][C@H:2]1[CH2:30][C@@:29]2([CH3:31])[C@@H:13]([CH2:14][CH2:15][C@:16]2([OH:32])[C:17](=[O:28])[CH2:18][O:19][C:20]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[O:21])[C@H:12]2[C@H:3]1[C@:4]1([CH3:34])[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:33])[CH2:6][CH2:5]1.[CH3:35][I:36]>CC(C)=O>[I-:36].[CH3:35][N+:24]1[CH:25]=[CH:26][CH:27]=[C:22]([C:20]([O:19][CH2:18][C:17](=[O:28])[C@:16]2([OH:32])[C@:29]3([CH3:31])[C@H:13]([C@H:12]4[C@H:3]([C@@H:2]([OH:1])[CH2:30]3)[C@:4]3([CH3:34])[C:9](=[CH:8][C:7](=[O:33])[CH2:6][CH2:5]3)[CH2:10][CH2:11]4)[CH2:14][CH2:15]2)=[O:21])[CH:23]=1
Reactant: CI
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)COC(=O)c1cccnc1
Solvent: CC(C)=O
Product: C[n+]1cccc(C(=O)OCC(=O)[C@@]2(O)CC[C@H]3[C@@H]4CCC5=CC(=O)CC[C@]5(C)[C@H]4[C@@H](O)C[C@@]32C)c1
Product: [I-]
Reaction time: 8 h
Yield: 98 %

Procedure:
The product of Example 119 (1 g, 2.1 mmol) was dissolved in 50 mL of acetone and 4 mL of methyl iodide were added. The solution was stirred at the reflux temperature overnight. Removal of the solvent gave the title compound as a yellow powder in 98% yield. Elemental analysis confirmed that the product had the formula: ##STR148##
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]2[O:17][C:16]3[CH:15]=[C:14]([OH:18])[CH:13]=[C:12]([OH:19])[C:11]=3[C:9](=[O:10])[CH2:8]2)=[CH:5][CH:6]=1.Cl.O.CO>CN(C=O)C.[Pd]>[CH:1]1[CH:6]=[CH:5][C:4]([C@@H:7]2[O:17][C:16]3[CH:15]=[C:14]([OH:18])[CH:13]=[C:12]([OH:19])[C:11]=3[C:9](=[O:10])[CH2:8]2)=[CH:3][CH:2]=1
Reactant: O=C1C[C@@H](c2ccccc2)Oc2cc(O)cc(O)c21
Agent: [Pd]
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: O=C1C[C@H](c2ccccc2)Oc2cc(O)cc(O)c21
Yield: 90 %

Procedure:
4.8 g of the benzyl protected pinocembrin in R-configuration obtained in Example 4 was dissolved in 100 ml of DMF, 20 ml of 10% aqueous HCl and 3.5 g of 10% Pd—C with a water content of 62.9% were added, and then a hydrogenation at normal pressure was performed. The reaction was monitored by TLC until completion (about 5 h). Then stop stirring, the reaction mixture was filtered and extracted with ethyl acetate and water. The organic phase was collected, evaporated to remove solvent and recrystallized with 95% ethanol to give a white solid of (R)-pinocembrin (3.1 g, yield 90%) with specific rotation [α]D20=+45.83° (c=0.515, methanol), and e.e %>99.3%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:12]2[C:15]3[C:4]=1[CH2:5][CH:6]([NH:16]C(=O)C)[CH2:7][C:8]=3[CH:9]=[CH:10][CH:11]=2.Cl.[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:12]2[C:15]3[C:4]=1[CH2:5][CH:6]([NH2:16])[CH2:7][C:8]=3[CH:9]=[CH:10][CH:11]=2
Reactant: COc1ccc2cccc3c2c1CC(NC(C)=O)C3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2cccc3c2c1CC(N)C3
Temperature: 90 °C
Yield: 79 %

Procedure:
N-(4-Methoxy-2,3-dihydro-1H-phenalen-2-yl)acetamide (5.95 mmol; 1.52 g) is dissolved in 20 cm3 of ethanol to which are added 54 cm3 of 10% HCl. The mixture is maintained at 90° C. for 20 h. After cooling, 10% NaOH solution is added until the pH is basic and the amine is extracted with CH2Cl2. The organic phase is dried over MgSO4 and evaporated under reduced pressure. The title amine is thus isolated without further purification.
Reaction SMILES: CI.[Mg].C(C1NC(C(OCC)=O)=[C:9]([C:11](OCC)=[S:12])N=1)C.[OH:21][C:22]([C:25]1[N:26]=[C:27](C)[NH:28][C:29]=1[C:30]([O:32][CH2:33][CH3:34])=S)([CH3:24])[CH3:23].C([O:38]CC)C>C(Cl)Cl>[CH2:11]([S:12][C:27]1[NH:28][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:38])=[C:25]([C:22]([OH:21])([CH3:24])[CH3:23])[N:26]=1)[CH3:9]
Reactant: CCOC(=O)c1[nH]c(CC)nc1C(=S)OCC
Reactant: CCOC(=S)c1[nH]c(C)nc1C(C)(C)O
Reactant: CCOCC
Agent: [Mg]
Solvent: ClCCl
Solvent: CI
Product: CCOC(=O)c1[nH]c(SCC)nc1C(C)(C)O
Reaction time: 0.5 h

Procedure:
4.20 g of methyl iodide were added dropwise to a mixture of 714 mg of magnesium in 30 ml of diethyl ether, under a nitrogen atmosphere, and the resulting solution was heated under reflux, whilst stirring, for 30 minutes. At the end of this time, a solution of 2.00 g of diethyl 2-ethylthioimidazole-4,5-dicarboxylate [prepared as described in step (i) above] in 20 ml of methylene chloride was added dropwise to the reaction solution, and the mixture was treated in a similar manner to that described in Preparation 49(ii). The resulting crystalline residue was washed with a mixture of hexane and diisopropyl ether, to give 1.32 g of title compound, melting at 82°-85° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C@@H:8]1[CH2:25][C:24]2[CH:23]=[C:22]([OH:26])[CH:21]=[CH:20][C:19]=2[C@@H:18]2[C@@H:9]1[C@H:10]1[C@@:14]([CH2:16][C@@H:17]2[F:27])([CH3:15])[CH:13]([OH:28])[CH2:12][CH2:11]1.[I-:29].[Na+]>C(C(C)=O)C.C(OCC)(=O)C>[F:27][C@H:17]1[CH2:16][C@@:14]2([CH3:15])[C@@H:10]([CH2:11][CH2:12][CH:13]2[OH:28])[C@H:9]2[C@H:18]1[C:19]1[CH:20]=[CH:21][C:22]([OH:26])=[CH:23][C:24]=1[CH2:25][C@H:8]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][I:29]
Reactant: [I-]
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCCl)[C@H]3[C@@H]1CCC2O
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCI)[C@H]3[C@@H]1CCC2O
Temperature: 90 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
599 mg of 7α-(6-chlorohexyl)-11β-fluor-estra-1,3,5(10)-triene-3,17-diol is dissolved in 10 ml of ethylmethylketone, mixed with 675 mg of sodium iodide and stirred overnight at a bath temperature of 90° C. For working-up, the reaction mixture is cooled to room temperature, taken up in ethyl acetate, extracted once with 10% sodium thiosulfate solution, washed with common salt solution, dried on magnesium sulfate and concentrated by evaporation in a vacuum. 691 mg of 11β-fluor-7α-(6-iodohexyl)-estra-1,3,5(10)-triene-3,17-diol is obtained as a crude product, which is used without further purification in the next stage.
Reaction SMILES: [C:1]([C:3]1([O:15][Si](C)(C)C)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:13][CH3:14])[CH2:6][CH2:5][CH2:4]1)#[N:2].[F-].[Na+].O>O1CCCC1>[NH2:2][CH2:1][C:3]1([OH:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:13][CH3:14])[CH2:6][CH2:5][CH2:4]1
Reactant: COc1cccc2c1C(C#N)(O[Si](C)(C)C)CCC2
Agent: [F-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc2c1C(O)(CN)CCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.2 %

Procedure:
To a mixture of lithiumaluminumhydride (0.99 g) in tetrahydrofuran (18 ml) was added dropwise a solution of 1-cyano-8-methoxy-1-trimethylsilyloxy-1,2,3,4-tetrahydronaphthalene (3.59 g) in tetrahydrofuran (18 ml) under ice-cooling and a nitrogen atmosphere. After stirring at room temperature for 3 hours, sodium fluoride (1.09 g) and water (1.41 ml) were added to the reaction mixture under ice-cooling. After stirring for additional 30 minutes, insoluble materials were filtered off and washed with 5% ethanol in ethyl acetate. The filtrate was evaporated in vacuo to afford 1-aminomethyl-1-hydroxy-8-methoxy-1,2,3,4-tetrahydronaphthalene (2.60 g), which was used in the next step without purification.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.[NH2:34][CH2:35][CH:36]([OH:39])[CH2:37][OH:38]>>[C:28]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:29]=[CH:30][C:31]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:34][CH2:35][CH:36]([OH:39])[CH2:37][OH:38])=[O:18])=[O:7])=[CH:32][CH:33]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: NCC(O)CO
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)NCC(O)CO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbonyl chloride, and (2RS)-3-amino-1,2-propanediol, the title compound was obtained in 73% purity by HPLC. MS(ESI+): m/z=412.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Br:15]Br.O>C(O)(=O)C>[Br:15][C:5]1[CH:4]=[C:3]([C:12]([OH:14])=[O:13])[C:2]([OH:1])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2
Reactant: BrBr
Reactant: O=C(O)c1ccc2cccnc2c1O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cc(Br)c2cccnc2c1O
Yield: 100.9 %

Procedure:
8-Hydroxyquinoline-7-carboxylic acid (1.00 g) is suspended in 25 mL acetic acid. To this is added bromine (0.845 g) dropwise. The mixture is heated to reflux for 1 h, then poured into cold water. The resulting solid is collected, washed with water and dried to yield 1.43 g of the title product as a yellow solid.
Reaction SMILES: [CH:1]([C:3]1[NH:4][CH:5]=[CH:6][CH:7]=1)=[O:2].[OH-].[K+].CS(C)=O.[Br:14][CH2:15][CH2:16]Br>O>[Br:14][CH2:15][CH2:16][N:4]1[CH:5]=[CH:6][CH:7]=[C:3]1[CH:1]=[O:2]
Reactant: BrCCBr
Reactant: O=Cc1ccc[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1cccn1CCBr

Procedure:
A mixture of 2-formylpyrrole (1 g), potassium hydroxide (2.3 g) and dry DMSO (20 mL) was stirred under nitrogen atmosphere. 1,2-dibromoethane (7.9 g) was added dropwise at 20–25° C. and stirred till the reaction is complete. Water (50 mL) was added and the reaction mixture was extracted with diethyl ether (3×50 mL). The combined organic layer was washed with water (30 mL), followed by brine (30 mL) and was dried over Na2SO4. The solvent was evaporated and the compound obtained was purified by column chromatography (silica gel 100–200) using ethyl acetate: hexane (2:8) as an eluent to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:14]([O-:16])=[O:15])[C:5]([C:8]#CC(C)(O)C)=[N:6][CH:7]=1.[O-:17][Mn](=O)(=O)=O.[K+].[OH-:23].[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:14]([O-:16])=[O:15])[C:5]([C:8]([OH:17])=[O:23])=[N:6][CH:7]=1
Reactant: CC(C)(O)C#Cc1ncc(Cl)cc1[N+](=O)[O-]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: [OH-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ncc(Cl)cc1[N+](=O)[O-]
Temperature: 77.5 °C
Reaction time: 0.75 h

Procedure:
A suspension of the alkyne from step 1 (1.96 g, 8.2 mmol) in water (20 mL) was heated at 75-80° C. KMnO4 (4.27 g, 27.1 mmol) was added portion wise over 30 min. After complete addition, heating was continued for 45 min. The reaction mixture was then cooled to room temperature and the pH adjusted to 9 by the addition of 1.0 M aqueous NaOH and filtered through filter paper. The filter cake was thoroughly washed with 0.3 M aqueous NaOH. The filtrate was extracted with EtOAc and discarded. The aqueous part was acidified to pH 3-4 with 1 M HCl and saturated with solid NaCl. This solution was extracted with EtOAc (4×30 mL). The combined extract was dried (Na2SO4) and concentrated under reduced pressure to provide the crude acid (500 mg). MS m/z: 200.8 (M−H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[O:18][C:19]([C:22]([OH:24])=O)=[CH:20][CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:27])=O>C1C=CC=CC=1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[O:18][C:19]([C:22]([Cl:27])=[O:24])=[CH:20][CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Solvent: c1ccccc1
Product: O=C(Cl)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1

Procedure:
15 g (0.05 mol) of 1-benzyl-3-(5-carboxy-2-furyl)indazole and 36.43 g (0.31 mol) of thionyl chloride in 400 ml of benzene were heated under reflux for 3 h. The cooled mixture was filtered and concentrated. This gave 11.95 g (approximately 76%) of the title compound which was used for subsequent reactions without any further purification.
Reaction SMILES: [CH:1]1[C:16]2[C:17]3[C:4]([C:5](=O)[O:6][C:7](=[O:18])[C:8]=3[CH:9]=[C:10]3[C:15]=2[CH2:14][O:13][CH2:12][O:11]3)=[CH:3][CH:2]=1.Cl.[NH2:21][OH:22]>N1C=CC=CC=1>[OH:22][N:21]1[C:5](=[O:6])[C:4]2=[CH:3][CH:2]=[CH:1][C:16]3[C:17]2=[C:8]([CH:9]=[C:10]2[C:15]=3[CH2:14][O:13][CH2:12][O:11]2)[C:7]1=[O:18]
Reactant: O=C1OC(=O)c2cc3c(c4cccc1c24)COCO3
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: O=C1c2cccc3c4c(cc(c23)C(=O)N1O)OCOC4
Yield: 110.6 %

Procedure:
11H-5,8,10-Trioxabenzo[de]anthracene-4,6-dione (0.14 g, 0.5 mmol, from Example K1) and hydroxylamine hydrochloride (0.06 g, 0.9 mmol) were reacted in pyridine (4.0 mL) following the procedure of Example 1 to give 0.15 g of the title compound, mp>350° C.;
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[N:55]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1[CH3:64])=[C:56]=[O:57]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:56]([NH:55][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=2[CH3:64])=[O:57])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: Cc1ccccc1N=C=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccccc1NC(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 31 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 1-isocyanato-2-methylbenzene as starting materials in 31% yield. LCMS for C32H34ClN8O2 (M+H)+: m/z=597.2.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[C:13]([NH:15][CH2:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:14].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:30][C:31]1[S:32][CH:33]=[C:34]([C:36]([O:38][CH3:39])=[O:37])[N:35]=1>C(#N)C.CCOC(C)=O>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[C:13]([NH:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:30][C:31]2[S:32][CH:33]=[C:34]([C:36]([O:38][CH3:39])=[O:37])[N:35]=2)[CH2:19][CH2:18]1)=[O:14]
Reactant: COc1ccc2[nH]nc(C(=O)NCC3CCNCC3)c2c1
Reactant: COC(=O)c1csc(CCl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1csc(CN2CCC(CNC(=O)c3n[nH]c4ccc(OC)cc34)CC2)n1
Yield: 32.2 %

Procedure:
Finally, a mixture of compound 7b (637 mg, 1.96 mmoles) and potassium carbonate (813 mg, 5.88 mmoles) in acetonitrile (5 mL) was heated to reflux for 1 hour, then a solution of methyl 2-(chloromethyl)-1,3-thiazole-4-carboxylate (500 mg, 2.6 mmoles) in acetonitrile (5 mL) was added dropwise. The mixture was refluxed overnight then was cooled, diluted with EtOAc and filtered. The resulting solid was washed with water, dried and purified via flash chromatography (silica, from CHCl3 to CHCl3:MeOH 9:1) providing 280 mg (32% yield) of methyl 2-{[4-({[(5-methoxy-1H-indazol-3-yl)carbonyl]amino}methyl)piperidin-1-yl]methyl}-1,3-thiazole-4-carboxylate 7.
Reaction SMILES: [C:1]([C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[C:5]([Cl:10])[N:4]=1)#[N:2].Cl.[N:12]([O-])=O.[Na+].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O.C(O)C>[C:17]1([N:16]=[N:12][NH:9][C:8]2[C:3]([C:1]#[N:2])=[N:4][C:5]([Cl:10])=[CH:6][CH:7]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccccc1
Reactant: N#Cc1nc(Cl)ccc1N
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#Cc1nc(Cl)ccc1NN=Nc1ccccc1
Reaction time: 0.33 h
Yield: 45 %

Procedure:
2-cyano-6-chloro-3-pyridinylamine (0.153 g, 1 mmol) was added into 3 mL of hydrochloric acid (10 mol/L), and then cooled to 0° C. in ice-salt bath. Sodium nitrite (0.072 g) dissolved in water (1.0 mL) was added to the solution dropwise under stirring for 20 min. The diazonium solution was neutralized with 0.093 g of aniline (1.0 mmol) dissolved in anhydrous ethanol to pH 5-6 and stirred for 2 h at 0-5° C. The solution was kept overnight, filtered, and washed with water till colorless to yield the crude product. The crude product was purified on a silica gel column with petroleum ether:ethylacetate (v/v)=20:1 to yield yellow solid product (0.116 g) with a recovery rate of 45.1%.
Reaction SMILES: Cl.[C:2]1([C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH2:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C1([C@@H]2CCC[C@H]2N)C=CC=CC=1>>[CH:2]1([C@@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH2:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: N[C@@H]1CCC[C@@H]1c1ccccc1
Agent: Cl
Agent: N[C@@H]1CCC[C@H]1c1ccccc1
Product: N[C@@H]1CCC[C@H]1C1CCCCC1

Procedure:
By the procedure described in Example 25(A) only substituting for cis-2-phenylcyclopentylamine hydrochloride an appropriate amount of trans-2-phenylcyclopentylamine hydrochloride, M.P. 142°-143° C, the hydrochloride salt of trans-2-cyclohexylcyclopentylamine is obtained, M.P. 199°-200° C. Following the procedure of Example 23 only substituting for cis-2-phenylcyclopentylamine hydrochloride and appropriate amount of trans-2-cyclohexylcyclopentylamine hydrochloride and employing a reaction time of 38 days, the desired product is obtained, M.P. 208°-210° C.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:17]([CH3:33])[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:31])[F:30])[CH:23]=3)=[N:19][C:20]=2I)=[O:15])[CH2:10][CH2:9]1.[N:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>>[OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:17]([CH3:33])[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:31])[F:30])[CH:23]=3)=[N:19][C:20]=2[C:37]2[CH:38]=[CH:39][N:34]=[CH:35][CH:36]=2)=[O:15])[CH2:10][CH2:9]1
Reactant: OB(O)c1ccncc1
Reactant: Cn1c(-c2cccc(OC(F)(F)F)c2)nc(I)c1C(=O)N1CCC(N2CCC[C@H]2CO)CC1
Product: Cn1c(-c2cccc(OC(F)(F)F)c2)nc(-c2ccncc2)c1C(=O)N1CCC(N2CCC[C@H]2CO)CC1

Procedure:
In analogy to the procedure described for example 7, [4-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-piperidin-1-yl]-[5-iodo-3-methyl-2-(3-trifluoromethoxy-phenyl)-3H-imidazol-4-yl]-methanone (example 53) was reacted with pyridin-4-yl-boronic acid to give the title compound as colorless foam. MS: 530.1 (MH+).
Reaction SMILES: [CH:1]([SiH:4]([CH:13]([CH3:15])[CH3:14])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[Cl:16]N1C(=O)N(Cl)C(=O)N(Cl)C1=O.Cl[SiH3]>C(Cl)Cl>[Cl:16][Si:4]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)([CH:1]([CH3:3])[CH3:2])[CH:13]([CH3:15])[CH3:14]
Reactant: COc1ccc([SiH](C(C)C)C(C)C)cc1
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Agent: [SiH3]Cl
Solvent: ClCCl
Product: COc1ccc([Si](Cl)(C(C)C)C(C)C)cc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
Diisopropyl(4-methoxyphenyl)silane (47.7 g, 214 mmol, 1.0 equiv.), was taken up in CH2Cl2 (700 mL). The solution was cooled to 0° C. and trichloroisocyanuric acid (16.6 g, 71.3 mmol, 0.33 equiv.) was carefully added in three equal portions, making sure that each portion has at least 7 min to react before the next is added (caution: adding trichloroisocyanuric acid too rapidly results in a rapid evolution of gas). The mixture was stirred at 0° C. for 40 min followed by warming to 23° C. with stirring. The solids were filtered under an inert atmosphere and the filtrate concentrated in vacuo to yield 54.8 g (98%) of a cloudy oil. The chlorosilane, which is unstable, was used immediately and without purification in the next step.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:29])[N:4]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=2[CH3:28])C(O)=O)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].C(Cl)(=O)C(Cl)=O.[C:36]([O:42][CH2:43][CH3:44])(=[O:41])[CH2:37][C:38]([O-])=[O:39].C([Mg]Cl)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.C1COCC1.C(Cl)Cl>[Br:1][C:2]1[C:3](=[O:29])[N:4]([C:19]2[CH:20]=[C:21]([C:38](=[O:39])[CH2:37][C:36]([O:42][CH2:43][CH3:44])=[O:41])[CH:25]=[CH:26][C:27]=2[CH3:28])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: Cc1ccc(C(=O)O)cc1-n1c(C)cc(OCc2ccc(F)cc2F)c(Br)c1=O
Agent: CC(C)[Mg]Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)CC(=O)c1ccc(C)c(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In an oven-dried round bottom flask, 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoic acid (see Example 487) (0.75 g, 1.62 mmol), DCM (2.00 mL), and oxalyl chloride (0.97 mL, 1.94 mmol) were combined under argon. DMF (3-5 drops) was added to aid in dissolution. Stirred at RT overnight. Solvent was removed and the crude acid chloride was coevaporated with DCM (3-5 mL×3) and dried in vacuo to give an orange solid. In a separate oven-dried flask, in an argon atmosphere, a solution of monoethyl malonate (0.38 mL, 3.23 mmol) in THF (3.00 mL) was cooled to −78° C. Isopropyl magnesium chloride (3.23 mL, 6.46 mmol) was added dropwise. The solution was stirred for 30 min at −78° C. The acid chloride prepared as described above was added dropwise as a solution in THF. The reaction was warmed to RT. After 30 min, the reaction was cooled (0° C.) and 10% citric acid (5.0 mL) added. The crude product was extracted in EtOAc, washed with 5% NaHCO3, dried over Na2SO4, filtered, and concentrated to a crude brown oil. Recrystallization from DCM and hexane. Filtered a beige solid, dried in vacuo (0.41 g, 47%). 1H NMR (CD3OD/400 MHz) δ 8.02 (m, 1H), 7.79 (s, 1H), 7.65 (m, 2H), 7.05 (t, 2H, J=9.2 Hz), 6.66 (s, 1H), 5.36 (s, 2H), 4.16 (q, 2H, J=7.2 Hz), 2.11 (s, 3H), 2.07 (s, 2H), 1.99 (s, 3H), 1.23 (t, 3H, J=7.2 Hz). ES HRMS m/z 534.0744 and 536.0746 (M+H calculated for C25H23BrF2NO5 requires 534.0722 and 536.0706).
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][C:29]=2N)[CH:24]=[N:23]1>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:29]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:30]=1[NH:22][N:23]=[CH:24]2)(=[O:3])[CH3:2]
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Reactant: Nc1cccc2cn[nH]c12
Solvent: CCO
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2cccc3cn[nH]c23)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
To a stirred solution of 80 mg (0.278 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) in ethanol (4 mL), 1H-indazol-7-amine (56 mg, 0.417 mmol) was added. The resulting mixture was stirred at room temperature during one hour and the final product was collected by filtration and washed with diethylether to yield the title compound (90 mg, 86.5% yield).