Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:16]([OH:18])=O)[C:7]3[CH:12]=[N:11][N:10]([CH:13]([CH3:15])[CH3:14])[C:8]=3[N:9]=2)[CH2:3][CH2:2]1.Cl.[NH2:20][CH2:21][C:22]1[C:23](=[O:32])[NH:24][C:25]([CH:29]2[CH2:31][CH2:30]2)=[CH:26][C:27]=1[CH3:28].ON1C2N=CC=CC=2N=N1.C(Cl)CCl.CN1CCOCC1>O.CS(C)=O>[CH:1]1([C:4]2[CH:5]=[C:6]([C:16]([NH:20][CH2:21][C:22]3[C:23](=[O:32])[NH:24][C:25]([CH:29]4[CH2:30][CH2:31]4)=[CH:26][C:27]=3[CH3:28])=[O:18])[C:7]3[CH:12]=[N:11][N:10]([CH:13]([CH3:14])[CH3:15])[C:8]=3[N:9]=2)[CH2:2][CH2:3]1
Reactant: Cc1cc(C2CC2)[nH]c(=O)c1CN
Reactant: CC(C)n1ncc2c(C(=O)O)cc(C3CC3)nc21
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CS(C)=O
Solvent: CN1CCOCC1
Solvent: O
Product: Cc1cc(C2CC2)[nH]c(=O)c1CNC(=O)c1cc(C2CC2)nc2c1cnn2C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 4 mL solution of DMSO were sequentially added 6-cyclopropyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (0.11 g, 0.448 mmol), 3-(aminomethyl)-6-cyclopropyl-4-methyl-2(1H)-pyridinone hydrochloride (0.106 g, 0.493 mmol), 1-hydroxy-7-azabenzotriazole (0.073 g, 0.538 mmol), EDC (0.103 g, 0.538 mmol), and then N-methylmorpholine (0.197 mL, 1.79 mmol) via syringe. After stirring overnight at room temperature, the suspension was diluted with 50 mL of water and stirred for 15 min. After standing at room temperature for 15 min., the reaction mixture was filtered and the collected solid washed with additional water. The solid was then dried in a vacuum oven at 45° C. for 4 h. The product was obtained as 0.165 g (89%). LCMS E-S (M+H)=406.5. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.76-0.82 (m, 2H), 0.91-0.98 (m, 2H), 1.03-1.12 (m, 4H), 1.46 (d, J=6.82 Hz, 6H), 1.74-1.84 (m, 1H), 2.19 (s, 3H), 2.21-2.31 (m, 1H), 4.34 (d, J=5.05 Hz, 2H), 5.05-5.18 (m, 1H), 5.73 (s, 1H), 7.42 (s, 1H), 8.21 (s, 1H), 8.72 (t, J=4.93 Hz, 1H), 11.61 (br. s., 1H).
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=2[CH:6]=1)[OH:4])#[CH:2].I[C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([O:30][CH3:31])[CH:21]=1>>[CH3:31][O:30][C:22]1[CH:21]=[C:20]([C:2]#[C:1][CH:3]([OH:4])[C:5]2[CH:14]=[CH:13][C:12]3[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=3[CH:6]=2)[CH:29]=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)c1ccc(I)cc1OC
Reactant: C#CC(O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Product: COC(=O)c1ccc(C#CC(O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1OC
Yield: 76 %

Procedure:
Following the basic procedure of Example 11(d), by reacting 1.66 g (6.8 mmol) of α-ethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanol with 2 g (6.9 mmol) of methyl 4-iodo-2-methoxybenzoate, 2.1 g (75%) of the expected ester were obtained, after chromatography on a silica column eluted with dichloromethane, in the form of a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([Cl:26])[CH:19]=1)=[CH:13][C:12]([Br:27])=[CH:11][C:10]=2[CH2:28][O:29]C(=O)C)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([Cl:26])[CH:19]=1)=[CH:13][C:12]([Br:27])=[CH:11][C:10]=2[CH2:28][OH:29])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(COC(C)=O)cc(Br)cc2c1NCc1ccc(OC)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1cnc2c(CO)cc(Br)cc2c1NCc1ccc(OC)c(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 96.3 %

Procedure:
A mixture of 1.84 mmole 6-bromo-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-8-(acetoxymethyl)quinoline-3-carboxylic acid ethyl ester (i.e., Example 14) and 1.84 mmole of potassium carbonate in 20 mL of ethanol was stirred at RT for 20 hours. The mixture was concentrated, and the residue was diluted with water and extracted with ethyl acetate. The resultant organic layer was dried over MgSO4 and filtered, and the filtrate concentrated to give 0.85 g of the title compound as a tan solid. MS: 481; LC: 3.43′.
Reaction SMILES: C(N(CC)C(C)C)C.[C:9]1([C:15]2[N:20]=[CH:19][C:18]([C:21](Cl)=[O:22])=[CH:17][N:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([NH2:34])[CH:29]=[CH:28]2>C(Cl)Cl>[F:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([NH:34][C:21]([C:18]1[CH:17]=[N:16][C:15]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:20][CH:19]=1)=[O:22])[CH:29]=[CH:28]2
Reactant: O=C(Cl)c1cnc(-c2ccccc2)nc1
Reactant: Nn1ccc2cc(F)ccc21
Agent: CCN(CC)C(C)C
Solvent: ClCCl
Product: O=C(Nn1ccc2cc(F)ccc21)c1cnc(-c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
Diethyl-iso-propylamine (2.30 mmol) is added to a stirred solution of 2-phenyl-pyrimidine-5-carboxylic acid chloride (1.15 mmol) and 5-fluor-indol-1-ylamine (1.15 mmol) in DCM (20 mL) at rt. The reaction mixture is stirred at rt overnight and concentrated in vacuo. The residue is dissolved in EtOAc (30 mL), then washed with 5% HCl (10 mL), water (10 mL) and brine (10 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 10-40% EtOAc in heptane to afford 2-phenyl-pyrimidine-5-carboxylic acid (5-fluoro-indol-1-yl)-amide (185 mg, 49%) as a solid. MS: 333 (M+H); 1H NMR (300 MHz, CDCl3): δ 6.56 (s, H) 7.02 (m, H), 7.10-7.38 (m, 4H), 7.55 (s, 3H), 8.53 (s, 2H), 8.70-9.40 (br, 2H). IC50=3 nM.
Reaction SMILES: [CH3:1][N:2]([CH3:45])[C:3](=[O:44])[CH2:4][NH:5][C@:6]12[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:7]1[C@@H:8]1[C@@:21]([CH3:24])([CH2:22][CH2:23]2)[C@@:20]2([CH3:25])[C@@H:11]([C@:12]3([CH3:37])[C@@H:17]([CH2:18][CH2:19]2)[C:16]([CH3:27])([CH3:26])[C:15]([C:28]2[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1.Cl[CH2:47][C:48](N1CCCC1)=O>>[CH3:24][C@:21]12[C@@:20]3([CH3:25])[C@@H:11]([C@:12]4([CH3:37])[C@@H:17]([CH2:18][CH2:19]3)[C:16]([CH3:27])([CH3:26])[C:15]([C:28]3[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:35][CH:36]=3)=[CH:14][CH2:13]4)[CH2:10][CH2:9][C@@H:8]1[C@H:7]1[C@H:38]([C:41]([CH3:43])=[CH2:42])[CH2:39][CH2:40][C@:6]1([NH:5][CH2:4][C:3](=[O:44])[N:2]1[CH2:1][CH2:48][CH2:47][CH2:45]1)[CH2:23][CH2:22]2
Reactant: O=C(CCl)N1CCCC1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCC(=O)N(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NCC(=O)N3CCCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(dimethylamino)-2-oxoethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid using 2-chloro-1-(pyrrolidin-1-yl)ethanone as the alkylating reagent in Step 1. The product was isolated as a white solid (19 mg, 46%). LCMS: m/e 641.46 (M+H)+, 2.55 min (method 10). 1H NMR (500 MHz, Acetic acid d4) δ ppm 8.04 (d, J=8.24 Hz, 2H), 7.30 (d, J=8.24 Hz, 2H), 5.38 (d, J=4.58 Hz, 1H), 4.89 (s, 1H), 4.76 (s, 1H), 4.43 (d, J=16.48 Hz, 1H), 3.99 (d, J=16.17 Hz, 1H), 3.73-3.42 (m, 4H), 3.15-2.86 (m, 1H), 2.41-1.19 (m, 26H), 1.79 (s, 3H), 1.28 (s, 3H), 1.14 (s, 3H), 1.10 (s, 3H), 1.03 (s, 3H), 1.00 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14](Cl)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: Clc1ncnc2c1CCN(Cc1ccccc1)C2
Solvent: CC#N
Product: c1ccc(CN2CCc3c(ncnc3Nc3ccccc3)C2)cc1
Temperature: 180 °C

Procedure:
7-Benzyl-4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine prepared as described in Example 1.B. (1.0 g, 3.86 mmol) was dissolved in anhydrous acetonitrile (3 mL) and aniline was added (0.39 mL, 4.24 mmol). The mixture was heated at 180° C. for 600 s in a microwave (Emrys Optimizer model, Personal Chemistry). The solvents were removed under vacuum to give the desired product as a beige powder (1.5 g, quant.). The crude product was used for the subsequent step.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[O:11])=[CH:8][CH:7]=1.[CH2:15]1[C@H:19]2[CH2:20][CH2:21][CH2:22][C@H:18]2[CH2:17][NH:16]1.O.C(O)(C)C>C(N(CC)CC)C>[CH2:15]1[C@H:19]2[CH2:20][CH2:21][CH2:22][C@H:18]2[CH2:17][N:16]1[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[O:11])=[CH:8][CH:7]=1
Reactant: C1C[C@@H]2CNC[C@@H]2C1
Reactant: NC(=O)c1ccc(OCCCCl)cc1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Solvent: O
Product: NC(=O)c1ccc(OCCCN2C[C@H]3CCC[C@H]3C2)cc1
Temperature: 20 °C
Yield: 83 %

Procedure:
15.2 kg of 4-(3-chloropropoxy)benzamide, 40.28 kg of cis-octahydrocyclopenta[c]pyrrole in 30% aqueous solution, 63.84 kg of water, 21.48 kg of isopropanol and 14.39 kg of triethylamine are introduced into a reactor. The reaction mixture is stirred and heated at reflux until all the starting material has been consumed. The reaction mixture is then cooled to 20° C., before being filtered and washed with a mixture of isopropanol and water. The product is obtained in the form of a powder in a yield of 83% and with a chemical purity of 97%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:22])[CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(OCC)C>O1CCCC1>[CH2:23]([NH:30][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:22])[CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)CCC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: NCc1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)CCC(=O)c1cnc2c(OC)cccc2c1NCc1ccccc1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
In a flame-dried, three-necked round-bottomed reaction flask equipped with reflux condenser, magnetic stirring bar and rubber septum, there were placed 3.0 g (0.0093 mole) of 4-chloro-3-(3-ethoxycarbonylpropionyl)-8-methoxyquinoline (the product of Preparation C) dissolved in 30 mL of dry tetrahydrofuran. Stirring was commenced and to the resulting ethereal solution were then added with 2.0 g (0.0186 mole) of benzylamine (available from the Eastman Kodak Company of Rochester, N.Y.), which was added over a five-minute period at room temperature (ca. 20° C.). The well-stirred reaction mixture was then heated to 60° C. and thereafter kept at that temperature for a period of six hours. Upon completion of this step (as revealed by thin layer chromatography (TLC) analysis), the final reaction mixture was filtered to remove precipitated benzylamine hydrochloride and the filtrate was subsequently evaporated to near dryness while under reduced pressure to afford a solid material as the residue. Trituration of the latter material with diethyl ether then gave 880 mg (22%) of essentially pure 4-benzylamino-3-(3-ethoxycarbonylpropionyl)-8-methoxyquinoline as the free base compound: mass spectrum, m/e 392; NMR (CDCL3) consistent with product. The latter batch of material was next dissolved in dry benzene and thereafter treated with anhydrous hydrogen chloride gas to ultimately yield 320 mg (8%) of pure 4-benzylamino-3-(3-ethoxycarbonylpropionyl)-8-methoxyquinoline as the hydrochloride salt (in the form of a monohydrate), m.p. 201°- 202° C. after one recrystallization from methanol-diethyl ether. The pure product was further characterized by means of mass spectrum (MS) analysis, in addition to elemental analysis. Mass spectrum, m/e 392.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:30]([C:29]4[CH:33]=[CH:34][CH:35]=[C:27]([CH3:26])[CH:28]=4)=[O:31])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: Cc1cccc(C(=O)O)c1
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cccc(C)c4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 3-methylbenzoic acid as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) and by crystallization from DCM and diethyl ether to yield the title compound.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]([CH3:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([CH3:16])=[N:12]2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[Se](=O)=[O:18]>O1CCOCC1.O>[CH:1]([O:4][C:5]1[C:14]([CH3:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([CH:16]=[O:18])=[N:12]2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: O=[Se]=O
Reactant: Cc1ccc2ccc(OC(C)C)c(C)c2n1
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(OC(C)C)ccc2ccc(C=O)nc12
Yield: 35.2 %

Procedure:
To 7-isopropoxy-2,8-dimethylquinoline (120 mg, 0.557 mmol) in dioxane/water (5 mL/0.5 mL) at ambient temperature was added selenium dioxide (74.2 mg, 0.669 mmol) and the reaction was heated to reflux for 2 hours. After cooling, the reaction was filtered and the solids were washed with DCM. The filtrate was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (SP4, 12M, eluting with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield 7-isopropoxy-8-methylquinoline-2-carbaldehyde (45 mg, 35.2% yield) as a tan solid.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[N:36]=[CH:35][C:34]([OH:37])=[CH:33][N:32]=2)=[CH:27][CH:26]=1)[CH2:17][CH3:18].[C:38](O)(=[O:46])[CH2:39]/[CH:40]=[CH:41]\[CH2:42][CH2:43][CH2:44][CH3:45]>CN(C)C1C=CN=CC=1.ClCCl>[CH2:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[N:36]=[CH:35][C:34]([O:37][C:38](=[O:46])[CH2:39]/[CH:40]=[CH:41]\[CH2:42][CH2:43][CH2:44][CH3:45])=[CH:33][N:32]=2)=[CH:27][CH:26]=1)[CH2:17][CH3:18]
Reactant: CCCC/C=C\CC(=O)O
Reactant: CCCOCCCCCc1ccc(-c2ncc(O)cn2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCC/C=C\CC(=O)Oc1cnc(-c2ccc(CCCCCOCCC)cc2)nc1
Reaction time: 8 h
Yield: 83.7 %

Procedure:
0.8 g of N,N'-dicyclohexylcarbodiimide was added within 5 minutes while stirring to a solution of 1.0 g of 2-[4-(5[propyloxy]-1-pentyl)phenyl]-5-hydroxypyrimidine, 0.4 g of (Z)-3-octenoic acid and 0.05 g of 4-(dimethylamino)pyridine in 30 ml of dichloromethane. The reaction mixture was stirred overnight, then filtered and the filtrate was washed with saturated sodium bicarbonate solution and with water and concentrated. Chromatography of the residue on silica gel with hexane/ethyl acetate (vol. 4:1) and two-fold recrystallization of the thin-layer chromatographically pure fractions gave 1.0 g of 2-[4-(5-[propyloxy]-1-pentyl)phenyl]-5-{[(Z)-3-octenoyl]oxy}pyrimidine.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]=1)#[N:2]>[OH-].[NH4+].C(O)C.[Rh]>[NH2:2][CH2:1][CH2:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1
Reactant: N#CCC1=CCc2ccccc21
Agent: [Rh]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: NCCC1CCc2ccccc21
Reaction time: 8 h

Procedure:
Indene (2 ml), 1.99 g, 17.2 mmol) was dissolved in dry THF (2 ml) and stirred at -78° under nitrogen. n-Butyllithium (6.87 ml of a 2.5M solution in hexane: 17.2 mmol) was added, and the solution was then warmed to ambient temperature, stirred for 15 minutes, recooled to -78°, and added via syringe to a solution of chloroacetonitrile (1.09 ml, 1.30 g, 17.2 mmol) in THF (2 ml) stirred at -78°. After completion of the addition, the solution was diluted with ether (200 ml) and washed with 1M HCl followed by saturated sodium bicarbonate solution. The ether layer was dried over sodium sulfate, filtered, and evaporated to dryness in vacuo. The residue was chromatographed on a silica gel column eluted with 10% EtOAc in hexane and the product fractions evaporated in vacuo to give 3-cyanomethylindene. 3-Cyanomethylindene (310 mg, 2.0 mmol) was dissolved in a 10% solution of conc. ammonium hydroxide in absolute ethanol. 5% Rhodium/alumina catalyst (60 mg) was added and the mixture was shaken under an atmosphere of hydrogen (40 psi) overnight. The mixture was filtered, and the filtrate was evaporated to dryness in vacuo. The residue was chromatographed on a silica gel column eluted with 93:7:0.7 CH2Cl2 :MeOH:NH4OH, and the product fractions were combined and evaporated to dryness in vacuo to provide 1-(2-aminoethyl)indane. 1-(2-Aminoethyl)indane (47 mg, 0.292 mmol) and (+)-10-camphorsulfonyl chloride (73 mg, 0.29 mmol) were combined in CH2Cl2 (2 ml), treated with triethylamine (2 drops), and stirred at ambient temperature overnight. The mixture was evaporated to dryness in vacuo and the residue chromatographed on a silica gel column eluted in with 20% EtOAc in hexane. The product fractions were combined and evaporated to dryness in vacuo. The resulting oil was dried in vacuo at ambient temperature for 3 hours to provide the title compound as a solid: (mp 52°-70°).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[C:6]([C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Br)=[CH:10][CH:9]=1)#[N:7]>C(#N)C>[CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:12][C:11]1[CH:14]=[CH:15][C:8]([C:6]#[N:7])=[CH:9][CH:10]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: COCCN
Solvent: CC#N
Product: COCCNCc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
2-Methoxyethylamine (2.2 mL, 25.5 mmol) was added into a solution of 4-cyanobenzyl bromide (1.0 g, 5.1 mmol) in ACN (10 mL) and the resulting mixture was stirred at RT for 1 hour. The reaction mixture was concentrated under vacuum. The crude product was dissolved in EtOAc, and then washed with a saturated aqueous solution of NaHCO3 and brine, dried (MgSO4) and concentrated under vacuum to give the title compound (958 mg, 99%). LC/MS (Method B): 191.0 (M+H)+. HPLC (Method A) Rt 1.44 min (Purity: 93.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([NH:14][C:15]([CH:17]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]3)=[O:16])=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]([C:27]1[CH:28]=[C:29](OB(O)O)[CH:30]=[CH:31][CH:32]=1)=[O:26]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([NH:14][C:15]([CH:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:31]4[CH:32]=[C:27]([CH:28]=[CH:29][CH:30]=4)[C:25]([O:24][CH3:23])=[O:26])[CH2:18]3)=[O:16])=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(OB(O)O)c1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1NC(=O)C1CCCNC1
Product: COC(=O)c1cccc(N2CCCC(C(=O)Nc3sc(-c4ccc(Cl)cc4)nc3C)C2)c1
Yield: 42.4 %

Procedure:
Using N-[2-(4-chlorophenyl)-4-methylthiazole-5-yl]piperidine-3-carboxamide (36.0 mg, 0.107 mmol) and 3-methoxycarbonylphenylboric acid (38.5 mg, 0.214 mmol), the same procedure was followed as in Example 4 to give 21.3 mg (42%) of the desired compound as a pale yellow powder.
Reaction SMILES: [CH:1]12[O:6][CH:2]1[CH2:3][CH2:4][CH2:5]2.[CH2:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CCOC(C)=O.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH2:7]([NH:14][C@@H:2]1[CH2:3][CH2:4][CH2:5][C@H:1]1[OH:6])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C1CC2OC2C1
Reactant: NCc1ccccc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CCOC(C)=O
Product: O[C@@H]1CCC[C@H]1NCc1ccccc1

Procedure:
Cyclopentene oxide (5.0 g, 59.1 mmol), benzylamine (7.0 g, 65.3 mmol) and titanium isopropoxide (3.40 g, 12.0 mmol) were taken in a microwave vial and microwaved at 150° C. for 3 hours. The reaction mixture was then cooled and diluted with EtOAc (100 mL). The organic layer was washed with water and dried over anhydrous Na2SO4. Evaporation of the solvent in vacuo and purification on a silica gel column (0 to 20% MeOH/CH2Cl2) afforded trans-2-(benzylamino)cyclopentanol. MS APCl calc'd for C12H17NO [M+H]+ 192. found 192.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][O:20][C:21]([CH:23]1[CH2:30][CH:29]2[CH:31]([N:32]3[CH2:36][CH:35]([C:37](C4C=CC=CC=4)(C4C=CC=CC=4)[O:38][SiH2]C(C)(C)C)[C:34]([CH3:57])([CH3:56])[C:33]3=[O:58])[CH:25]([CH2:26][CH2:27][CH2:28]2)[CH2:24]1)=[O:22]>O1CCCC1>[CH3:19][O:20][C:21]([CH:23]1[CH2:30][CH:29]2[CH:31]([N:32]3[CH2:36][CH:35]([CH2:37][OH:38])[C:34]([CH3:56])([CH3:57])[C:33]3=[O:58])[CH:25]([CH2:26][CH2:27][CH2:28]2)[CH2:24]1)=[O:22]
Reactant: COC(=O)C1CC2CCCC(C1)C2N1CC(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)C(C)(C)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)C1CC2CCCC(C1)C2N1CC(CO)C(C)(C)C1=O
Reaction time: 2 h

Procedure:
Tetrabutyl ammonium fluoride (3.2 mL, 1 M in tetrahydrofuran, 3.2 mmol) was added to a stirred solution of Example 7C (0.9 g, 1.56 mmol) in tetrahydrofuran at room temperature. The resulting solution was stirred for two hours and then partitioned with ethyl acetate and water. The organic phase was washed with brine, dried (MgSO4), filtered, and evaporated. The residue was purified over silica gel using 20-100% ethyl acetate in hexanes to give the title product as a white solid.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]1[CH:22]=[C:21]([C:23]([NH2:25])=[O:24])[O:20][N:19]=1)C1C=CC=CC=1>C1COCC1.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]1[CH:22]=[C:21]([C:23]([NH2:25])=[O:24])[O:20][N:19]=1
Reactant: NC(=O)c1cc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)no1
Agent: [Pd]
Solvent: C1CCOC1
Product: NC(=O)c1cc([C@@H]2CC[C@@H]3CN2C(=O)N3O)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
A mixture of 3-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)isoxazole-5-carboxamide (0.25 g, 0.73 mmol) and 10% Pd/C (0.12 g) in THF (8 mL) was stirred at rt under H2 atmosphere for 2 hrs. The reaction mixture was then filtered and concentrated to afford 3-((2S,5R)-6-hydroxy-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)isoxazole-5-carboxamide (0.17 g, 90%) as a light yellow solid, which was used directly in the next step. ESI-MS (EI+, m/z): 253 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][N:8]2[C:13](Cl)=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[F:22])[C:11]([Cl:23])=[N:10][C:9]=12)=[O:4].C(O)(=O)C>CO.C1COCC1.[Zn].[Cu]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][N:8]2[CH:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[F:22])[C:11]([Cl:23])=[N:10][C:9]=12)=[O:4]
Reactant: COC(=O)c1cnn2c(Cl)c(-c3ccc(F)cc3F)c(Cl)nc12
Agent: [Cu]
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)c1cnn2cc(-c3ccc(F)cc3F)c(Cl)nc12
Temperature: 25 °C
Yield: 29.6 %

Procedure:
500 mg (1.4 mmol) 5,7-Dichloro-6-(2,4-difluorophenyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid methyl ester are dissolved in a mixture of 0.68 mL methanol and 3.9 mL THF. After addition of 0.16 mL acetic acid and 264 mg (2 mmol) zinc/copper pair, the mixture is vigorously stirred at rt over night. The reaction mixture is filtered via a glass microfibre filter and washed with plenty of methanol. The solvent has been removed and the residue purified by chromatography (silicagel, ethyl acetate/hexane). 134 mg (29.7%) of the desired product are obtained.