Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.N1[CH:17]=[CH:16]N=C1.C(Cl)(=O)C.Cl.[NH2:23][CH:24]1[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:25]1=[O:31].P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>C(#N)C>[Cl:12][C:8]1[CH:7]=[C:3]2[C:2](=[C:10]([Cl:11])[CH:9]=1)[N:1]=[C:16]([CH3:17])[N:23]([CH:24]1[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:25]1=[O:31])[C:4]2=[O:6]
Reactant: NC1CCC(=O)NC1=O
Reactant: c1c[nH]cn1
Reactant: Nc1c(Cl)cc(Cl)cc1C(=O)O
Agent: Cl
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: CC(=O)Cl
Solvent: CC#N
Product: Cc1nc2c(Cl)cc(Cl)cc2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
To a stirred mixture of 2-amino-3,5-dichlorobenzoic acid (5.0 g, 24 mmol) and imidazole (1.9 g, 28 mmol) in acetonitrile (60 mL), was added acetyl chloride (2.0 mL, 28 mmol) at room temperature. The mixture was stirred at room temperature overnight. To the mixture, was added 3-amino-piperidine-2,6-dione hydrogen chloride (3.9 g, 24 mmol), imidazole (3.5 g, 52 mmol) and triphenyl phosphite (6.8 mL, 26 mmol) and heated to reflux for 22 hours. The suspension was filtered and washed with acetonitrile (30 mL), water (2×30 mL), and ethyl acetate (30 mL) to give 3-(6,8-dichloro-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a white solid (4.65 g, 58% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 4.78 min (100%); mp: 238-240° C.; 1H NMR (DMSO-d6) δ 2.15-2.22 (m, 1H, CHH), 2.55-2.69 (m, 5H, CH, 2CHH), 2.78-2.91 (m, 1H, CHH), 5.33 (dd, J=6, 11 Hz, 1H, NCH), 7.96 (d, J=2 Hz, 1H. Ar), 8.15 (d, J=2 Hz, 1H, Ar), 11.09 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.63, 23.85, 30.54, 56.92, 122.55, 24.24, 130.51, 131.72, 134.38, 142.25, 156.80, 159.07, 169.12, 172.53; LCMS: MH=340, 342; Anal Calcd for C14H11N3O3Cl2: C, 49.43; H, 3.26; N, 12.35; Cl, 20.84. Found: C, 49.21; H, 3.11; N, 12.30; Cl, 19.43.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][CH2:9][N:10]1[C:19]([CH2:20]N)=[C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:28][CH3:29])[CH:16]=2)[C:11]1=[O:30])([CH3:4])([CH3:3])[CH3:2].[CH2:32]=O.[C:34]([BH3-])#[N:35].[Na+].CO>CCCCCC.CCOCC>[C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][CH2:9][N:10]1[C:19]([CH2:20][N:35]([CH3:34])[CH3:32])=[C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:28][CH3:29])[CH:16]=2)[C:11]1=[O:30])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc2c(=O)n(CCNC(=O)OC(C)(C)C)c(CN)c(-c3ccccc3)c2c1
Reactant: C=O
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CCCCCC
Solvent: CO
Solvent: CCOCC
Product: COc1ccc2c(=O)n(CCNC(=O)OC(C)(C)C)c(CN(C)C)c(-c3ccccc3)c2c1
Yield: 76.2 %

Procedure:
A solution of 114 (2.72 g, 6.43 mmol), formaldehyde (12.3M, 2.62 mL, 32.2 mmol), sodium cyanoborohydride (1.0M in tetrahydrofuran, 32.2 mL, 32.2 mmol), and methanol (100 mL) were heated at reflux for 1 h. The contents of the reaction flask were cooled and the solvent was removed in vacuo. Sat. sodium bicarbonate was added and the resulting mixture was extracted with ethyl acetate (3×). The combined organic extracts were dried with magnesium sulfate (anh.) and filtered. The filtrate was removed by rotary evaporation to give a colorless oil. Trituration with hexane:ether (1:1) gave 115 as a white solid (2.21 g, 4.90 mmol, 76.2%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:15]([O-])([O-])=O.[Na+].[Na+].IC>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:15])=[O:8]
Reactant: Cc1c(C(=O)O)cc(Br)cc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 109.5 %

Procedure:
To a solution of 5-bromo-2-methyl-3-nitrobenzoic acid (5.5 g, 21 mmol) in DMF (42 ml) under nitrogen, was added Na2CO3 (3.4 g, 32 mmol) followed by iodomethane (2.0 ml, 32 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with deionized water (150 ml) and extracted with EtOAc (4×50 ml). The combined organic phases were washed with saturated NaHCO3 (aq) (2×50 ml), dried over MgSO4, filtered and concentrated in-vacuum to give the title compound (6.3 g, 61%) as a yellow oil. LC-MS 57%, 2.20 min (3.5 minute LC-MS method), no ionization; 1H NMR (500 MHz, Chloroform-d) δ ppm 7.38 (d, J=2.05 Hz, 1H) 7.23 (d, J=2.05 Hz, 1H) 3.20 (s, 3H) 1.82 (s, 3H).
Reaction SMILES: C(O)(C(F)(F)F)=O.Cl[C:9]1[CH:14]=[C:13]([N:15]2[CH:24]([CH3:25])[CH2:23][C:22]3[C:17](=[CH:18][C:19]([C:26]4[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=4)=[CH:20][CH:21]=3)[CH2:16]2)[N:12]=[C:11]([NH2:32])[N:10]=1.[NH:33]1[CH2:38][CH2:37][CH2:36][C@H:35]([NH:39]C(=O)OC(C)(C)C)[CH2:34]1>>[NH2:39][C@H:35]1[CH2:36][CH2:37][CH2:38][N:33]([C:9]2[CH:14]=[C:13]([N:15]3[CH:24]([CH3:25])[CH2:23][C:22]4[C:17](=[CH:18][C:19]([C:26]5[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=5)=[CH:20][CH:21]=4)[CH2:16]3)[N:12]=[C:11]([NH2:32])[N:10]=2)[CH2:34]1
Reactant: CC1Cc2ccc(-c3cnn(C)c3)cc2CN1c1cc(Cl)nc(N)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Solvent: O=C(O)C(F)(F)F
Product: CC1Cc2ccc(-c3cnn(C)c3)cc2CN1c1cc(N2CCC[C@H](N)C2)nc(N)n1

Procedure:
This compound was prepared as TFA salt by using procedures analogous to those described for the synthesis of Example 118 starting from 4-chloro-6-[3-methyl-7-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine and tert-butyl(3S)-piperidin-3-ylcarbamate (CNH Technologies, Cat. No. C-3102S). LCMS (M+H)+: m/z=419.2.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH:16]([OH:34])[CH2:17][CH2:18][NH:19][C:20](=[O:33])[C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[CH:23][CH:22]=2)[CH2:11][CH2:10]1.[C:35](OC(=O)C)(=[O:37])[CH3:36].C(N(CC)CC)C>C(Cl)Cl>[C:35]([O:34][CH:16]([CH2:17][CH2:18][NH:19][C:20](=[O:33])[C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[CH:23][CH:22]=1)[CH2:15][N:12]1[CH2:11][CH2:10][N:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])[CH2:14][CH2:13]1)(=[O:37])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(NCCC(O)CN1CCN(c2cccc(Cl)c2Cl)CC1)c1ccc(-c2ccccn2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC(CCNC(=O)c1ccc(-c2ccccn2)cc1)CN1CCN(c2cccc(Cl)c2Cl)CC1
Reaction time: 16 h

Procedure:
A solution of 16 (0.25 g, 0.5 mmol) in 10 mL of CH2Cl2 was treated with 70 μL (0.75 mmol) acetic anhydride followed by 140 μL (1.0 mmol) triethylamine. After stirring for 16 h, the mixture was washed with sodium bicarbonate solution, dried with sodium sulphate and purified by flash chromatography. Yield: 0.22 g (82%). Mp. (oxalate): foam. 1H NMR (CDCl3): δ 1.84 (m, 1H), 2.05 (m, 1H), 2.12 (s, 3H), 2.52 (dd, J 13.2, 5.2, 1H), 2.65 (m, 5H), 2.99 (s, 4H), 3.25 (dq, J 9.7, 5.00, 1H), 3.81 (dt, J 12.3, 5.7, 1H), 5.19 (m, 1H), 6.89 (dd, J 7.7, 1.8, 1H), 7.06-7.17 (m, 3H), 7.26 (ddd, J 6.1, 4.8, 2.44, 1H), 7.73-7.76 (m, 2H), 7.93 (d, J 8.6, 2H), 8.07 (d, J 8.6, 2H), 8.70 (td, J 4.83, 1.50, 1.50, 1H). 13C NMR (CDCl3): δ 21.0, 32.4, 36.1, 51.3, 53.7, 61.5, 69.6, 118.6, 120.8, 122.7, 124.5, 127.0, 127.4, 127.5, 133.9, 134.7, 136.9, 142.1, 149.8, 151.1, 156.2, 167.1, 171.5, Anal. (C26H30Cl2N4O3.1.5(COOH)2.H2O) C, H, N.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([CH3:14])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>ClCCl>[CH2:26]([O:25][C:23]([N:11]1[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][C@H:10]1[CH3:14])=[O:24])[CH3:27]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1CCN(C(=O)OC(C)(C)C)C[C@H]1C

Procedure:
To a solution of 1.50 g (R)-4-N-Boc-2-methyl-piperazine in 10 ml dichloromethane were added at 0° C. 2.29 ml triethylamine and 0.72 ml ethyl chloroformate. After 12 h the reaction mixture was diluted with dichloromethane and extracted with 0.1 M HCl and saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and the crude product obtained after evaporation of the solvent was used in the subsequent reaction.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[CH:5]1[C:17]2[CH:16]([CH2:18][O:19][C:20](Cl)=[O:21])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1.[NH3:23].C(O)C>C(OCC)(=O)C>[C:20]([NH:3][C:2]([NH2:23])=[S:1])([O:19][CH2:18][CH:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]2[C:17]1=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:21]
Reactant: N#C[S-]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: N
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: NC(=S)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C

Procedure:
To a suspension of potassium thiocyanate (8.55 g, 88 mmol) in ethyl acetate (100 mL) cooled to 0° C. was added dropwise a solution of 9-fluorenylmethoxycarbonyl chloride (20.7 g, 80 mmol) in ethyl acetate (100 mL) over a period of 15 min. The resulting suspension was allowed to warm to ambient temperature overnight with stirring. The formed solid was filtered off and the filtrate was concentrated in vacuo to afford an orange oil. Without further purification, the oil was dissolved in ethanol (50 mL) and treated by dropwise addition with a cold solution of ammonia in ethanol (7N, 91 mL, 637 mmol). A precipitate formed upon addition of the ammonia solution. The suspension was stirred vigorously at 0° C. for 15 min and then the solids were filtered off, washed with cold ethanol (3×20 mL) and dried to afford N-Fmoc-thiourea (16.8 g, 70%) as an off-white solid: EI-HRMS m/e calcd for C16H14N2O2S (M+) 298.0776, found 298.0770.
Reaction SMILES: [CH3:1][N:2]1[C:9]([NH:10][OH:11])=[CH:8][C:6](=[O:7])[N:5]([CH3:12])[C:3]1=[O:4].[CH:13]([O-])([O-])OCC>CN(C)C=O>[CH3:12][N:5]1[C:6](=[O:7])[C:8]2=[CH:13][O:11][N:10]=[C:9]2[N:2]([CH3:1])[C:3]1=[O:4]
Reactant: Cn1c(NO)cc(=O)n(C)c1=O
Reactant: CCOC([O-])[O-]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2conc2n(C)c1=O

Procedure:
A mixture of 2 g of 1,3-dimethyl-6-hydroxyaminouracil, 20 ml of dimethylformamide and 20 ml of ethyl orthoformate is boiled at 160° C. for 1 hour, after which the solvent is distilled off. To the residue is added ethanol and the resultant crystals are collected by filtration. As recrystallized from hot water, 1.0 g of the captioned compound is obtained as colorless prisms, melting point: 170°-171° C.
Reaction SMILES: [OH-:1].[Na+:2].CN(C=[O:7])C.[CH:8]1[N:12]=[CH:11][N:10]([CH2:13][C:14]([P:20]([OH:23])([OH:22])=[O:21])([P:16]([OH:19])([OH:18])=[O:17])[OH:15])[CH:9]=1.CO>O>[CH:8]1[N:12]=[CH:11][N:10]([CH2:13][C:14]([P:16]([O-:19])([OH:18])=[O:17])([P:20]([O-:22])([OH:23])=[O:21])[OH:15])[CH:9]=1.[OH2:7].[OH2:1].[OH2:7].[OH2:7].[Na+:2].[Na+:2]
Reactant: [OH-]
Reactant: O=P(O)(O)C(O)(Cn1ccnc1)P(=O)(O)O
Reactant: CN(C)C=O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=P([O-])(O)C(O)(Cn1ccnc1)P(=O)([O-])O
Temperature: 25 °C
Yield: 90 %

Procedure:
A solution of sodium hydroxide (0.7 g) in a mixture of water (20% v/v)/Methanol (80% v/v, 10 volumes per grams of ZLD-Ac form XII) (10 ml) was added drop-wise to a suspension of Zoledronic acid form XII (4.98 g) in a mixture of water (20% v/v)/Methanol (80% v/v, 10 volumes per grams of ZLD-Ac) (53 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 16 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed with Methanol (2×15 ml) and dried in a vacuum oven at 50° C. for 24 hours to give 4.85 g (90%) of Zoledronate disodium crystal form XXVII (LOD by TGA=7.5%).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CN(C)P(N(C)C)(N(C)C)=O>O>[O:17]([CH2:16][CH2:15][CH2:14][NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: BrCCCOc1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCOC(=O)c1ccc(NCCCOc2ccccc2)cc1

Procedure:
A mixture of 33 g of ethyl p-aminobenzoate, 21.5 g of 3-bromopropylphenyl ether and 100 ml of hexamethylphosphoramide is heated at 100°-110° C. in an oil bath for 20 hours. The mixture is chilled, diluted with 50 ml of water, chilled and filtered. The solid is washed with ethanol-water (1:1) and with water to give yellow crystals, mp 73°-74° C.
Reaction SMILES: [SH:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].C[O-].[Na+].Cl[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26]Cl)[N:21]=1.[CH3:28][NH:29][CH3:30]>CO.C(Cl)Cl>[CH3:28][N:29]([CH2:19][C:20]1[N:21]=[C:22]([CH2:26][S:1][CH2:2][CH2:3][N:4]2[C:8](=[O:9])[C:7]3=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]3[C:5]2=[O:14])[CH:23]=[CH:24][CH:25]=1)[CH3:30]
Reactant: CNC
Reactant: ClCc1cccc(CCl)n1
Reactant: O=C1c2ccccc2C(=O)N1CCS
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CN(C)Cc1cccc(CSCCN2C(=O)c3ccccc3C2=O)n1

Procedure:
To a solution of N-(2-mercaptoethyl) phthalimide (28.8 g, 0.139 mol) in dry methanol (250 ml) is added sodium methoxide (7.5 g, 0.139 mol) with cooling and stirring. This mercaptide solution is added to 2,6-bis(chloromethyl)pyridine (24.5 g, 0.139 mol) in dry methanol (250 ml). The mixture is stirred at room temperature for 21/2 hours and is filtered to remove the precipitated solid. Then dimethylamine (6.9 g, 0.153 mol) in cold methanol (150 ml) is added to the filtrate and the mixture is stirred at room temperature overnight. The solvent is removed in vacuo leaving an amber gum. The gum is taken up in methylene chloride (200 ml) and is washed with aqueous sodium bicarbonate and with water. The methylene chloride layer is dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. This gives 24.3 g of 6-dimethylaminomethyl-2-[(2-phthalimidoethyl)thiomethyl]pyridine as a crude amber gum.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[CH:10][C:9]=2[OH:16])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[CH:10][C:9]=2[O:16][CH:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COC(=O)C(C)Br
Reactant: CCc1ccc(CN2CCOCC2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCc1ccc(CN2CCOCC2)c(OC(C)C(=O)OC)c1
Reaction time: 27 h
Yield: 100.8 %

Procedure:
To a 250 mL round bottom flask equipped with a mechanical stirrer and a thermometer was added 5.0 grams (0.0.023 mole--1.0 equiv.) of 2-(morpholin-4-ylmethyl)-5-ethylphenol, 4.54 grams (0.027 mole--1.2 equiv.) of methyl 2-bromopropanoate, 3.75 grams (0.027 mole--1.2 equiv.) of potassium carbonate, and 50 mL (%Wt/Vol. Phenol to Solvent--10%) of methylethylketone. The reaction mixture was heated to reflux where it stirred for 27 hours. After this period, the reaction mixture was analyzed by GC, which indicated the reaction was complete. The reaction mixture was filtered and washed with diethylether. The filtrate was concentrated under reduced pressure, yielding 7.0 grams of 96% pure methyl 2-[2-(morpholin4-ylmethyl)-5-ethylphenoxy]propanoate (95.2% yield).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[N:4]([CH2:12][CH2:13][CH3:14])[C:3]=1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.[CH2:21]([O:23][C:24](=[O:29])[C:25](Br)([CH3:27])[CH3:26])[CH3:22]>>[CH2:21]([O:23][C:24](=[O:29])[C:25]([CH3:27])([O:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([CH2:12][CH2:13][CH3:14])[C:3]([C:15]1[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=1)=[C:2]2[CH3:1])[CH3:26])[CH3:22]
Reactant: CCCn1c(-c2ccncc2)c(C)c2cc(O)ccc21
Reactant: CCOC(=O)C(C)(C)Br
Product: CCCn1c(-c2ccncc2)c(C)c2cc(OC(C)(C)C(=O)OCC)ccc21

Procedure:
The above compound was prepared from 3-methyl-1-propyl-2-(4-pyridyl)-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: C[Mg]I.[Mg].[CH3:5]I.[N:7]1[C:16]2[C:11](=[CH:12][C:13](C(OC)=O)=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.C([O:23][CH2:24][CH3:25])C>>[N:7]1[C:16]2[C:11](=[CH:12][C:13]([C:24]([OH:23])([CH3:25])[CH3:5])=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc2ncccc2c1
Reactant: CI
Reactant: CCOCC
Agent: C[Mg]I
Agent: [Mg]
Product: CC(C)(O)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To an ice-cold solution of methylmagnesium iodide prepared from magnesium (0.454 g, 18.69 mmol) and methyliodide (1.16 ml, 18.69 mmol) in diethyl ether (15 ml), methyl quinoline-6-carboxylate (0.50 g, 2.67 mmol) in diethyl ether (5 ml) was added and warmed to room temperature. After 12 h, the reaction mixture was cooled to 0° C., quenched with dil. 6N HCl and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure and column chromatographed with ethyl acetate: petroleum ether to afford the title compound as a yellow liquid brown oil (0.41 g, 84%), 1H-NMR (δ ppm. DMSO-d6, 400 MHz): 8.83 (dd, J=4.2, 1.7 Hz, 1H), 8.34 (dd, J=8.2, 1.1 Hz, 1H), 8.00 (d, J=1.9 Hz, 1H), 7.95 (d, J=8.8 Hz, 1H), 7.88 (dd, J=8.9, 2.0 Hz, 1H), 7.50 (q, J=4.1 Hz, 1H), 5.23 (s, 1H), 1.51 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.[N-:14]=[N+:15]=[N-:16].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[NH:16][N:15]=[N:14][N:12]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CC#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(Cc2nnn[nH]2)cc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 88 %

Procedure:
To a solution of 4-cyanomethyl benzoic acid methyl ester (2.63 g, 15 mmol) in anhydrous toluene (100 mL) was added sodium azide (1.95 g, 30 mmol) and triethylamine hydrochloride (4.13 g, 30 mmol). The reaction mixture was stirred at 100° C. for 24 hours under nitrogen. The reaction mixture was cooled to room temperature, then extracted with water (2×100 mL). The aqueous layer was acidified with concentrated HCl to pH approximately 4. The white solid was filtered off, washed with water, and dried under vacuum at 40° C. overnight, to give methyl-4-(1H-tetrazol-5-ylmethyl)benzoate (2.88 g, 88%) as an off-white solid.
Reaction SMILES: [C:1]1([CH2:7][CH:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][Si:11]([CH3:14])([CH3:13])Cl.C(N(CC)CC)C.CN(C)C=[O:25]>CCCCC>[CH3:10][Si:11]([CH3:14])([CH3:13])[O:25][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[CH2:8]
Reactant: C[Si](C)(C)Cl
Reactant: CN(C)C=O
Reactant: O=CCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCCCC
Product: C=C(O[Si](C)(C)C)c1ccccc1

Procedure:
A mixture of 30.0 g (0.25 mol) of phenylacetaldehyde, 32.6 g (0.3 mol) of trimethylchlorosilane, 60.6 g (0.6 mol) of triethylamine, and 100 ml of N,N-dimethylformamide was refluxed overnight, cooled and diluted with 200 ml of pentane. The mixture was washed successively with cold 5% aqueous sodium bicarbonate, 1.5 N hydrochloric acid, and 5% aqueous sodium bicarbonate, dried (over MgSO4), and then distilled to give 21.15 g of α-trimethylsiloxystyrene as a colorless liquid: bp 80°-83.5° C. (3.8 mm); 1H NMR (CDCl3) δ 0.07 ppm (s, 9H), 5.87 ppm (d,J=12 Hz, 1H), 6.80 ppm (d,J=12 Hz, 1H) and 7.03 ppm (m, 5H).
Reaction SMILES: [C:1]([O-:5])(=O)[CH:2]=[CH2:3].[NH2:6][CH2:7][CH2:8][N:9]([CH2:13][CH2:14][NH2:15])[CH2:10][CH2:11][NH2:12].Cl>O>[CH2:7]([NH2:6])[CH2:8][N:9]([CH2:13][CH2:14][NH2:15])[CH2:10][CH2:11][NH2:12].[C:1]([NH2:6])(=[O:5])[CH:2]=[CH2:3]
Reactant: C=CC(=O)[O-]
Agent: Cl
Agent: NCCN(CCN)CCN
Solvent: O
Product: C=CC(N)=O
Reaction time: 96 h

Procedure:
Poly(NHS-acrylate) (4.4 g) was suspended in a solution containing water (100 mL) and tris(2-aminoethyl)amine (30 mL) which had been adjusted to pH 9 with concentrated HCl. After 4 days of stirring, the solid was filtered off, and the wash repeated. The solid was then rinsed briefly with water twice, isopropanol once, and dried in a vacuum oven at about room temperature to yield 3.4 g.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[CH:28][C:23]=2[O:22][CH2:21]1>>[ClH:19].[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][N:30]3[CH2:31][CH2:32][N:33]([S:16]([C:14]4[S:15][C:11]([C:5]5[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=5[CH3:10])=[CH:12][CH:13]=4)(=[O:18])=[O:17])[CH2:34][CH2:35]3)=[CH:28][C:23]=2[O:22][CH2:21]1
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(S(=O)(=O)N3CCN(Cc4ccc5c(c4)OCO5)CC3)s2)c(C)[nH]c1=O
Product: Cl
Yield: 61 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with 1-benzo[1,3]dioxol-5-ylmethyl-piperazine as described in Steps 5 and 6, Example 24 to give the title compound as a yellow glass (61% yield). LC/MS: RT 2.33 min, m/e 502 (M+H); 1H NMR (δ, ppm): 11.88 (1H, s), 10.79 (1H, s), 7.66 (1H, d), 7.36 (1H, s), 7.32 (1H, d), 7.16 (1H, s), 6.98 (2H, s), 6.05 (2H, s), 4.24 (2H, s), 3.69-3.77 (2H, m), 3.37-3.40 (2H, m), 3.14-3.17 (2H, m), 2.86-2.94 (2H, m), 2.40 (2H, q), 2.33 (3H, s), 1.10 (3H, t).
Reaction SMILES: Cl[C:2](=[N:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:16]([NH:19][NH2:20])(=O)[CH3:17]>C(#N)C>[CH3:17][C:16]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:20][N:19]=1
Reactant: CCOC(=O)C(Cl)=Nc1ccccc1C
Reactant: CC(=O)NN
Solvent: CC#N
Product: CCOC(=O)c1nnc(C)n1-c1ccccc1C

Procedure:
The suspension of 10B and acetohydrazide in acetonitrile was refluxed for 2 hours. The solvent was removed. The crude product was purified by flash column (Rf: 0.2, 50% EtOAc/Hexanes). MS (m/z) 246 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:7]([CH3:19])=[C:6]2[CH2:20][C:21]([NH:23]N)=[O:22].CCOC(C)=O.CO.CCOC(C)=O>[Ni].CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:7]([CH3:19])=[C:6]2[CH2:20][C:21]([NH2:23])=[O:22]
Reactant: COc1ccc2c(c1)c(CC(=O)NN)c(C)n2Cc1ccccn1
Agent: [Ni]
Solvent: CCO
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)c(CC(N)=O)c(C)n2Cc1ccccn1
Yield: 28.2 %

Procedure:
Using the procedure in Example 6, Part C, 200 mg (0.62 mmol) of 5-methoxy-2-methyl-1-[(2-pyridyl)methyl]-1H-indole-3-acetic acid hydrazide and approximately 1 gram of Raney nickel in 10 mL of EtOH were reacted to give after chromatographing twice on silica eluting with EtOAc followed by 5% MeOH/EtOAc, 54 mg (28% yield) of 5-methoxy-2-methyl-1-[(2-pyridyl)methyl]-1H-indole-3-acetamide, as a semi-solid material.