Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:25])([CH3:24])[C@@H:11]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[CH:12]=C)(=[O:7])=[O:6].O=O.[O:28]=[O+][O-].CSC>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:25])[C@@H:11]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)[CH:12]=[O:28])(=[O:6])=[O:7]
Reactant: C=C[C@H](OCc1ccc(OC)cc1)C(C)(C)COS(=O)(=O)CCCCl
Reactant: O=[O+][O-]
Agent: O=O
Solvent: CSC
Solvent: ClCCl
Product: COc1ccc(CO[C@@H](C=O)C(C)(C)COS(=O)(=O)CCCCl)cc1
Yield: 66 %

Procedure:
Following the general procedure for the preparation of aldehydes from alkenes of Description 11, (3S)-3-[(4-methoxyphenyl)methoxy]-2,2-dimethylpent-4-enyl (3-chloropropyl)sulfonate (13a) (3.0 g, 7.7 mmol) dissolved in 100 mL of dichloromethane (DCM) was treated with a mixture of oxygen and ozone (O2/O3). Upon completion of the reaction, 2 mL (1.69 g, 27.2 mmol) of dimethyl sulfide (DMS) was added. After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:2) as eluent to provide 2.0 g (66% yield) of the title compound (13b) as a colorless oil. Rf=0.49 (EtOAc/Hxn=1:2). 1H NMR (400 MHz, CDCl3): δ=1.08 (s, 6H), 2.27-2.33 (m, 2H), 3.24-3.28 (m, 2H), 3.53 (d, J=2.4 Hz, 1H), 3.65-3.68 (m, 2H), 3.82 (s, 3H), 4.00 (d, J=9.2 Hz, 1H), 4.13 (d, J=9.2 Hz, 1H), 4.44 (d, J=11.2 Hz, 1H), 4.60 (d, J=11.2 Hz, 1H), 6.88 (d, J=8.4 Hz, 2H), 7.26 (d, J=8.4 Hz, 2H), 9.69 (d, J=2.4 Hz, 1H) ppm. MS (ESI) m/z 415.11 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([CH2:15][CH2:14][CH2:13][CH2:12]3)[C:7](=O)[NH:8]2)=[CH:4][CH:3]=1.CO>C1COCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([CH2:15][CH2:14][CH2:13][CH2:12]3)[CH2:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Nc2cc(Cl)ccc2C12CCCC2
Solvent: C1CCOC1
Solvent: CO
Product: Clc1ccc2c(c1)NCC21CCCC1
Temperature: 20 °C
Reaction time: 0.2 h
Yield: 88 %

Procedure:
A solution of borane-dimethyl sulfide complex in THF (2 M, 3.75 mL) was added to 6′ chloro-spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one under nitrogen and the resulting solution stirred at 20° C. for 0.2 h then at reflux for 1 h. The mixture was cooled then MeOH (3 mL) was added slowly (caution,) and reflux resumed for 1 h. Excess solvent was evaporated in vacuo and chromatography of the residue (SiO2; gradient elution with 0-40% Et2O in petrol) gave the title compound (0.335 g, 88%). MS: [M+H]+=208.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:11]([CH3:34])([CH3:33])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]([CH3:32])([C:28](OC)=[O:29])[CH3:27])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)(OC)=[O:8].[NH4+].[Cl-].Cl>O1CCCC1.C(OCC)(=O)C>[OH:8][CH2:7][C:11]([CH3:34])([CH3:33])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]([CH3:32])([CH3:27])[CH2:28][OH:29])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)C(C)(C)Cc1ccc(-c2ccc(CC(C)(C)C(=O)OC)cc2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(CO)Cc1ccc(-c2ccc(CC(C)(C)CO)cc2)cc1
Reaction time: 8 h
Yield: 58.6 %

Procedure:
To a solution of 5.94 g of lithium aluminum hydride in 1500 ml of dry tetrahydrofuran, 30 g of 4,4'-bis(2-carbomethoxy-2-methylpropyl)biphenyl was slowly added. The reaction mixture thickened on stirring overnight. Then there was added 150 ml of ethyl acetate, 60 ml of saturated aqueous NH4Cl and 150 ml of concentrated HCl. After thorough mixing, the solid and liquid were separated by filtration. The filtrate was evaporated to dryness and the residue recrystallized from benzene to obtain 15 g of 4,4'-bis(3-hydroxy-2,2-dimethylpropyl)biphenyl. The solid from the above filtration was slurried with 50 ml of H2O, 10 ml of concentrated HCl and 50 ml of benzene and the mixture was heated at reflux for 1 hr. The benzene layer was separated, dried with MgSO4 at 80° C, filtered hot and then cooled to precipitate an additional 10 g of 4,4'-bis(3-hydroxy-2,2-dimethylpropyl)biphenyl, m.p. 168°-170° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:33])([CH3:32])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]2)[CH:9]=1.NC1N2N=CC=C2N=C(C2CCCC(=[O:50])C2)C=1.NC1N2N=CC=C2N=C(C2CCC(=O)CC2)C=1>>[CH3:30][Si:28]([CH3:29])([CH3:31])[CH2:27][CH2:26][O:25][CH2:24][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:33])[CH3:32])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:22][CH2:21][CH2:20][C:19](=[O:50])[CH2:18]2)[CH:9]=1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCC(=O)CC2)nc2ccnn12
Reactant: Nc1cc(C2CCCC(=O)C2)nc2ccnn12
Agent: Nc1cc(C2CCC(=O)CC2)nc2ccnn12
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCCC(=O)C2)nc2ccnn12

Procedure:
3-(7-(Bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexanone was synthesized in a manner similar to the synthesis of 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexanone, but 3-(7-aminopyrazolo[1,5-a]pyrimidin-5-yl)cyclohexanone substituted for 4-(7-aminopyrazolo[1,5-a]pyrimidin-5-yl)cyclohexanone.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)=O.Cl.[OH:18][NH2:19]>N1C=CC=CC=1>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)=[N:19][OH:18]
Reactant: NO
Reactant: COc1cccc(C(=O)c2sccc2Br)c1
Agent: Cl
Solvent: c1ccncc1
Product: COc1cccc(C(=NO)c2sccc2Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
A mixture prepared from 7 g of (3-bromothien-2-yl) (3-methoxyphenyl)methanone, 3.09 g of hydroxyamine hydrochloride and 40 ml of pyridine was stirred at room temperature overnight and thereafter heated at 100°-115° C. for 4 hours. The mixture was then quenched with water, the organics were extracted into ether, and the ether solution was washed with 3N hydrochloric acid and water and dried over anhydrous magnesium sulfate. Evaporation of the ether left a residue which crystallized upon standing overnight. The crude solid was passed through a column (alumina packed in hexane) with 15% ether/hexane used as an eluent. The solid was recrystallized from ether/hexane to give a crystalline product (6.4 g, m.p. 100°-103° C).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[C:18]1([S:24][CH2:25][CH2:26][NH2:27])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:27][CH2:26][CH2:25][S:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: NCCSc1ccccc1
Solvent: COCCOC
Product: N#Cc1c(NCCSc2ccccc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile and 2-aminoethyl phenyl sulfide in DME. ES-MS m/e (%): 338 (M+H+, 100).
Reaction SMILES: [C:1](Cl)(=[O:12])[O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.ClCCl.[C:17]([O:26][CH3:27])(=[O:25])[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[OH:20].N1C=CC=CC=1>C(OCC)(=O)C>[N+:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][C:1]([O:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[C:17]([O:26][CH3:27])=[O:25])=[O:12])=[CH:4][CH:5]=1)([O-:11])=[O:10]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)c1ccccc1O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)c1ccccc1OC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 120.7 %

Procedure:
Under ice-cooling, 1.0 g of 4-nitrophenyl chlorocarbonate was added portionwise to a 10 ml dichloromethane mixture of 1.3 g methyl salicylate and 0.54 ml pyridine, and stirred at room temperature for 3Hours. The reaction solution was diluted with ethyl acetate and washed with saturated sodium bicarbonate aqueous solution and saturated brine in that order, and then the organic layer was dried with anhydrous magnesium sulfate. This was concentrated under a reduced pressure, and the thus obtained residue was mixed with hexane and ethyl acetate and subjected to decantation, thereby obtaining 1.9 g of methyl 2-{[(4-nitrophenoxy)carbonyl]oxy}benzoate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]([O:10]C(C)(C)C)=[O:9])=[C:4]([C:17]2[CH:18]=[N:19][C:20](S(CCC)(=O)=O)=[N:21][CH:22]=2)[CH:3]=1.Cl.[CH3:30][NH2:31]>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([C:17]2[CH:22]=[N:21][C:20]([NH:31][CH3:30])=[N:19][CH:18]=2)[CH:3]=1
Reactant: CN
Reactant: CCCS(=O)(=O)c1ncc(-c2cc(Cl)ccc2OCC(=O)OC(C)(C)C)cn1
Agent: Cl
Product: CNc1ncc(-c2cc(Cl)ccc2OCC(=O)O)cn1

Procedure:
The title compound was prepared from the product of example 20 step (iv) and methylamine hydrochloride by the method of example 20 step (v).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([NH:5][C@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@H:9]([OH:16])[CH2:8][CH2:7]1)=[O:4].N1C=CN=C1.CN(C=O)C.[C:29]([Si:33](Cl)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([CH3:32])([CH3:31])[CH3:30]>CCOC(C)=O>[Si:33]([O:16][C@H:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@H:6]([NH:5][C:3](=[O:4])[C:2]([F:17])([F:18])[F:1])[CH2:7][CH2:8]1)([C:29]([CH3:32])([CH3:31])[CH3:30])([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C(N[C@@H]1CC[C@@H](O)c2ccccc21)C(F)(F)F
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](O[C@@H]1CC[C@@H](NC(=O)C(F)(F)F)c2ccccc21)(c1ccccc1)c1ccccc1
Yield: 94.7 %

Procedure:
To a 250 ml round bottom flask containing 2.2 g (8.49 mmol) of 2,2,2-trifluoro-N-((1R,4R)-4-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)acetamide and 1.73 g (25.48 mmol) of imidazole was added 35 ml of DMF, and stirring was started. To this solution was added 4.67 g (16.99 mmol) of t-butylchlorodiphenylsilane. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with 150 ml EtOAc, and washed with 20 ml distilled water. The organic phase was dried over MgSO4 and concentrated in vacuo and purified by column chromatography (eluting with 1:1 DCM:Hex), to give 4.0 g (95%) of the titled compound.
Reaction SMILES: [C:1]([CH:4]([C:10]([O:12]CC)=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=O)[CH3:2].Cl.[NH2:16][NH2:17]>CCO>[CH2:8]([O:7][C:5]([C:4]1[C:10](=[O:12])[NH:16][NH:17][C:1]=1[CH3:2])=[O:6])[CH3:9]
Reactant: NN
Reactant: CCOC(=O)C(C(C)=O)C(=O)OCC
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(C)[nH][nH]c1=O
Temperature: 25 °C

Procedure:
To a stirred solution of diethyl acetylmalonate (20 g, 89.0 mmol) in EtOH (180 ml) is added hydrazine mono-hydrochloride (7.54 g, 107.0 mmol, 1.2 eq.) in one portion at RT. The reaction mixture is heated at reflux for 3 h then filtered hot. The filtrate is cooled to RT and concentrated under reduced pressure. The resulting crude residue is purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, DCM/[DCM/MeOH 9:1] 95:5→1:9]) to yield the title compound as a white solid. TLC: RF=0.21 (DCM/MeOH 92.5:7.5); HPLC: AtRet=0.75; MS: m/z 171.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 1.24 (t, J 7.1, 3H), 2.30 (s, 3H), 4.15 (q, J 7.1, 2H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:6]=1[CH2:7][N:8]1[C:12](=[O:13])[CH2:11][CH:10]([C:14]([O:16][CH3:17])=[O:15])[CH2:9]1.[CH3:24]I>C1COCC1.O>[CH3:3][O:4][C:5]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:6]=1[CH2:7][N:8]1[C:12](=[O:13])[CH2:11][C:10]([CH3:24])([C:14]([O:16][CH3:17])=[O:15])[CH2:9]1
Reactant: COC(=O)C1CC(=O)N(Cc2ccc(OC)cc2OC)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C1(C)CC(=O)N(Cc2ccc(OC)cc2OC)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydride (327 mg, 13.6 mmol) ws added to a solution of methyl 1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carboxylate (2.0 g, 6.8 mmol) in THF (50 mL) at 0° C. The mixture was stirred at room temperature for 2 hours. Then the mixture was added methyl iodide (4.8 g, 34 mmol) dropwise at 0° C. The mixture was stirred at room temperature for 16 hours and then was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue purified by chromatography on silica gel (ethyl acetate/petroleum ether) to give methyl 1-(2,4-dimethoxybenzyl)-3-methyl-5-oxopyrrolidine-3-carboxylate. MS ESI calc'd. for C16H22NO5 [M+H]+ 308. found 308. 1H NMR (400 MHz, CD3OD): δ 7.11 (d, J=8.8 Hz, 1H), 6.56 (s, 1H), 6.50 (d, J=8.8 Hz, 1H), 4.39 (s, 2H), 3.82 (s, 3H), 3.80 (s, 3H), 3.68 (s, 3H), 3.64 (d, J=16.8 Hz, 1H), 3.10 (d, J=16.8 Hz, 1H), 2.93 (d, J=16.8 Hz, 1H), 2.32 (d, J=16.8 Hz, 1H), 1.33 (s, 3H).
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:13]2[C:8](=[C:9]([F:14])[CH:10]=[CH:11][CH:12]=2)[N:7]=[CH:6][CH:5]=1.[CH3:15][CH:16]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][OH:26])=[CH:20][CH:19]=1)[CH3:17]>CN(C=O)C.O>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[N:7]=[CH:6][CH:5]=[C:4]2[O:26][CH2:25][CH2:24][C:21]1[CH:22]=[CH:23][C:18]([CH:16]([CH3:17])[CH3:15])=[CH:19][CH:20]=1
Reactant: Fc1cccc2c(Cl)ccnc12
Reactant: CC(C)c1ccc(CCO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1ccc(CCOc2ccnc3c(F)cccc23)cc1
Reaction time: 8 h
Yield: 40.8 %

Procedure:
To a suspension of 0.96 g of sodium hydride in 10 mL of dry DMF was added 3.6 g of 4-chloro-8-fluoroquinoline. The mixture was cooled in an ice/water bath, and 3.3 g of 2-[4-(1-methylethyl)phenyl]ethyl alcohol was added. The mixture was stirred overnight, then diluted with ice and water. The pH was adjusted to 7, then the product was extracted into CH2Cl2. The CH2Cl2 layer was separated, filtered, and evaporated in vacuo. An azeotrope with xylene was formed to facilitate removal of residual DMF. The residue was chromatographically purified on a silica gel column, eluting with CH2Cl2, →5% EtOAc/CH2Cl2 →10% EtOAc/CH2Cl2. The fractions containing product were combined and evaporated to give an oil, which crystallized on adding ether. Recrystallization yielded 2.5 g of title product. M.P. 56°-60° C.
Reaction SMILES: C[O:2][C:3](=O)[C:4](=[CH:9][NH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([NH:21][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])[CH:19]=2)[N:14]=[CH:13][N:12]=1)[C:5]([O:7][CH3:8])=[O:6]>C1(OC2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)Cl.CO>[O:2]=[C:3]1[N:12]2[CH:13]=[N:14][C:15]3[CH:16]=[CH:17][C:18]([NH:21][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])=[CH:19][C:20]=3[C:11]2=[N:10][CH:9]=[C:4]1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)C(=CNc1ncnc2ccc(NC(=O)C(C)C)cc12)C(=O)OC
Solvent: CO
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cnc2c3cc(NC(=O)C(C)C)ccc3ncn2c1=O
Temperature: 255 °C
Reaction time: 0.25 h
Yield: 76.2 %

Procedure:
A mixture of dimethyl[[6-(2-methylpropionamido)-4-quinazolinylamino]methylene]propanedioate (8.4 g) in diphenyl ether (42 ml) was stirred at 255° C. for 15 minutes. The reaction mixture was cooled to ambient temperature to give crystals which were filtered off, washed with hexane and dried. There were obtained 6.9 g of the crude crystals. The crude crystals were dissolved in a mixture of chloroform and methanol (4:1) under heating. Insoluble materials were removed by filtration. The filtrate was concentrated under reduced pressure to about 150 ml. After cooling, there was obtained crystalline methyl 4-oxo-10-(2-methylpropionamido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylate (5.85 g).
Reaction SMILES: N12CCCN=C1CCCCC2.Cl[C:13]1[N:18]=[C:17]([O:19][CH3:20])[C:16]([N+:21]([O-:23])=[O:22])=[C:15]([O:24][CH3:25])[N:14]=1.Cl.[F:27][C:28]([F:40])([F:39])[C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[CH2:35][NH:34][CH2:33][CH2:32]2>CN(C=O)C>[CH3:25][O:24][C:15]1[C:16]([N+:21]([O-:23])=[O:22])=[C:17]([O:19][CH3:20])[N:18]=[C:13]([N:34]2[CH2:33][CH2:32][C:31]3[C:36](=[CH:37][CH:38]=[C:29]([C:28]([F:27])([F:40])[F:39])[CH:30]=3)[CH2:35]2)[N:14]=1
Reactant: COc1nc(Cl)nc(OC)c1[N+](=O)[O-]
Reactant: FC(F)(F)c1ccc2c(c1)CCNC2
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COc1nc(N2CCc3cc(C(F)(F)F)ccc3C2)nc(OC)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 99 %

Procedure:
1,8-diazabicyclo[5.4.0]undec-7-ene (0.669 g, 4.4 mmol) was added to a mixture of 4a (0.438 g, 2 mmol) and 6-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (0.487 g, 2.05 mmol) in DMF (5 ml) at 0° C. over 5 minutes. The mixture was stirred for an additional 5 minutes at room temperature. The mixture was washed with brine, extracted with ethyl acetate and chromatographed to yield 5b (0.76 g, 1.98 mmol, 99%).
Reaction SMILES: [Mg].II.Br[C:5]([CH3:7])=[CH2:6].[CH3:8][C:9]1[CH2:10][CH2:11][CH:12]2[C:18]=1[CH2:17][CH2:16][C:15](=[O:19])[CH2:14][C:13]2=[CH2:20]>O1CCCC1>[OH:19][C:15]1([C:5]([CH3:7])=[CH2:6])[CH2:16][CH2:17][C:18]2[CH:12]([CH2:11][CH2:10][C:9]=2[CH3:8])[C:13](=[CH2:20])[CH2:14]1
Reactant: C=C1CC(=O)CCC2=C(C)CCC12
Reactant: C=C(C)Br
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: C=C1CC(O)(C(=C)C)CCC2=C(C)CCC12
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a Grignard solution, prepared from 1 g of magnesium chips activated with 1 g of iodine, 5 ml of 2-bromopropene and about 100 ml of tetrahydrofuran, were added over 10 minutes 1.76 g of 1-methyl-4-methylene-6-oxo-2,3,3a,4,5,6,7,8-octahydroazulene. The mixture was stirred vigorously for 30 minutes, cooled to 0° and treated with excess ice-cold ammonium chloride solution. The mixture was then extracted with ether, the organic extract washed with carbonate solution and water, dried over magnesium sulphate an concentrated under reduced pressure. The crude product (2.6 g), which was obtained in the form of a yello oil, was distilled under high vacuum and yielded 1.6 g (yield 76%) of pure 6-hydroxy-6-isopropenyl-1-methyl-4-methylen-2,3,3a,4,5,6,7,8-octahydroazulene; b.p.0.1 ca 100° IR(film): νmax = 3550, 3090, 1640, 1450/40, 1378, 1330, 1220, 1165, 1105, 1065, 1038, 900/895, 780 cm-1. The compound has a woody, slightly camphorous, somewhat spicy odour.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:7][CH2:8][O:9][CH:10]([OH:12])[CH3:11].[OH-].[Na+]>CO>[C:1]([NH:5][CH2:7][CH2:8][O:9][CH:10]([OH:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: CC(O)OCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(O)OCCNC(C)(C)C
Temperature: 150 °C

Procedure:
A solution of 45.63 g (0.625 mole) of tertiary-butylamine and 31 g (0.25 mole) of 2-chloroethoxyethanol in 100 ml of methanol was charged to a 300 ml steel autoclave and heated under autogenous pressure for 1 hour at 150° C. The reactor was cooled and the contents removed. To the homogeneous solution was added 11 g (0.275 mole) of NaOH pellets and the reaction refluxed for 0.5-1 hour, cooled, filtered, vacuum stripped, and distilled. The yield was 31.4 g (78%).
Reaction SMILES: O=C1CCC(=O)N1[O:8][C:9](=O)[CH2:10][CH2:11][C@H:12]([NH:20][C:21](=[O:47])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[NH2:49][C@H:50]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:51][CH2:52][C:53](=[O:55])[OH:54].CCN(C(C)C)C(C)C>C1COCC1.O>[C:59]([O:58][C:56](=[O:57])[C@@H:50]([NH:49][C:9](=[O:8])[CH2:10][CH2:11][CH:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[NH:20][C:21](=[O:47])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:41])[CH2:51][CH2:52][C:53]([OH:54])=[O:55])([CH3:62])([CH3:61])[CH3:60]
Reactant: CC(C)(C)OC(=O)[C@@H](N)CCC(=O)O
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)N[C@@H](CCC(=O)ON1C(=O)CCC1=O)C(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)NC(CCC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 1.5 h
Yield: 61 %

Procedure:
To a solution of (S)-2-(19-tert-butoxycarbonylnonadecanoylamino)pentanedioic acid 1-tert-butyl ester 5-(2,5-dioxopyrrolidin-1-yl)ester (prepared similarly as described in WO 2005/012347) (4.1 g) in THF (100 ml) was added a solution of H-Glu-OtBu (1.47 g) in water (20 ml). pH was adjusted to 8 with DIPEA. The mixture was concentrated after stirring for 1.5 h. The residue was recrystallized from DCM to give the title compound as a white solid (2.81 g, 61%).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([F:32])=[C:6]2[C:10]([C:11](=[O:31])[C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:24]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[N:23]=[N:22][N:21]=4)[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:7]=12.C([Sn](CCCC)(CCCC)[C:38]1[CH:42]=[C:41]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[NH:40][N:39]=1)CCC>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:32][C:5]1[CH:4]=[N:3][C:2]([C:38]2[CH:42]=[C:41]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[NH:40][N:39]=2)=[C:7]2[NH:8][CH:9]=[C:10]([C:11](=[O:31])[C:12](=[O:13])[N:14]3[CH2:15][CH2:16][N:17]([C:20]4[N:24]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:23]=[N:22][N:21]=4)[CH2:18][CH2:19]3)[C:6]=12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C(=O)OCC)[nH]n1
Reactant: O=C(C(=O)N1CCN(c2nnnn2-c2ccccc2)CC1)c1c[nH]c2c(Br)ncc(F)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(-c2ncc(F)c3c(C(=O)C(=O)N4CCN(c5nnnn5-c5ccccc5)CC4)c[nH]c23)n[nH]1
Temperature: 100 °C

Procedure:
To a sealed tube containing 1-(7-bromo-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (Compound B-1) (1.24 g, 2.48 mmol) in 1,4-dioxane (20 mL) was added ethyl 3-(tributylstannyl)-1H-pyrazole-5-carboxylate (1.12 g, 2.61 mmol) and Pd(PPh3)4(0.87 g, 0.75 mmol). The mixture was flushed with N2, and was sealed and heated to 100° C. After 14 h of heating, the mixture was cooled to rt, was diluted with MeOH, and was filtered through a pad of celite to remove any solids. The solution was concentrated under reduced pressure, and was re-dissolved in DMF. The DMF solution was loaded on the prep HPLC for purification. After purification, the title product was isolated as an off-white solid (0.901 g). LCMS: m/e 559.6 (M+H)+, ret time 2.283 min (method 2). 1H NMR (500 MHz, DMSO-D6) δ ppm 14.52 (s, 1 H) 12.35 (s, 1 H) 8.26-8.41 (m, 2 H) 7.36-7.76 (m, 6 H) 4.29-4.47 (m, J=6.71 Hz, 2 H) 3.09-3.80 (m, 8 H) 1.36 (s, 3 H).