Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.C([Li])CCC.Cl[C:16]([O:18][CH3:19])=[O:17].O>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:16]([O:18][CH3:19])=[O:17])=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(F)cc1
Reactant: COC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C#Cc1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 66.3 %

Procedure:
A solution of 4-fluorophenylacetylene (2.86 mL, 3.00 g, 24.97 mmol) in tetrahydrofuran at −78° C. was treated with a solution of n-butyllithium in hexanes (2.29 M, 12.0 mL, 27.5 mmol) followed by stirring at −78° C. for 45 minutes. The solution was then treated rapidly with methyl chloroformate (2.12 mL, 2.60 g, 27.5 mmol) followed by stirring at −78° C. for 30 minutes and warming to room temperature for 18 hours. The mixture was treated with water and concentrated in vacuo to remove tetrahydrofuran. The residue was dissolved in ethyl acetate and washed with water and saturated sodium chloride solution. Drying (Na2SO4) and concentration in vacuo afforded a yellow solid, which was chromatographed over a 340 g silica gel cartridge, eluting with 15-50% dichloromethane in hexanes. These procedures afforded the product (2.95 g, 66%) as an off-white fluffy solid.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[F:11][C:12]1[C:32]([F:33])=[CH:31][C:15]2[N:16]3[C:20]([CH2:21][C:22](=[O:24])[NH:23][C:14]=2[CH:13]=1)=[N:19][N:18]=[C:17]3[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[CH2:34]([N:41]([CH:46]([CH3:48])[CH3:47])[C:42](=[O:45])[CH2:43]Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C=O)C>[CH2:34]([N:41]([CH:46]([CH3:48])[CH3:47])[C:42](=[O:45])[CH2:43][N:23]1[C:22](=[O:24])[CH2:21][C:20]2[N:16]([C:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:18][N:19]=2)[C:15]2[CH:31]=[C:32]([F:33])[C:12]([F:11])=[CH:13][C:14]1=2)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C1Cc2nnc(-c3ccccc3)n2-c2cc(F)c(F)cc2N1
Reactant: CC(C)N(Cc1ccccc1)C(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)N(Cc1ccccc1)C(=O)CN1C(=O)Cc2nnc(-c3ccccc3)n2-c2cc(F)c(F)cc21
Temperature: 0 °C
Reaction time: 0.58 h

Procedure:
To a solution of KHMDS (0.5 M in THF, 16.6 mL, 8.33 mmol) at 0° C. was added 8,9-difluoro-1-phenyl-4H,6H-2,3,6,10b-tetraaza-benzo[e]azulen-5-one (Preparation 4(C) (2.0 g, 6.4 mmol) in DMF (20 mL). The reaction was stirred at 0° C. for 35 minutes, was cooled to −10° C., and a solution of N-benzyl-2-bromo-N-isopropyl-acetamide (Preparation 1 (C) (1.9 g, 7.0 mmol) in DMF (20 mL) was added. The reaction was stirred at −10C for 2 hours and at room temperature for 24 hours. The reaction was quenched with a pH 6.8 buffer and the aqueous solution was washed with EtOAc (3×). The combined organic solutions were washed with brine (4×), dried (Na2SO4), filtered and concentrated. Purification by medium pressure chromatography eluting with a solvent gradient (CH2Cl2 to 3% MeOH in CH2Cl2) provided 2.01 g of N-benzyl-2-(8,9-difluoro-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-N-isopropyl-acetamide. 1H NMR (CD2Cl2) δ 7.60-7.17 (m, 11H), 6.75 (q, 1H), 4.85-4.38 (m, 4H), 4.10 (q, 1H), 3.60 (q, 1H), 3.41 (s, 1H), 1.21 (q, 3H), 1.13 (q, 3H); MS 502.4 (M+1), 500.3 (M−1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:10][C:11](=[O:24])/[CH:12]=[CH:13]/[C:14]3[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=3)[CH:8]=2)[CH:3]=[N:2]1.C1COCC1.[N:30]([CH3:33])=[C:31]=[O:32]>CCOC(C)=O>[C:20]([C:17]1[CH:16]=[CH:15][C:14](/[CH:13]=[CH:12]/[C:11]([NH:10][C:7]2[CH:8]=[C:9]3[C:4]([CH:3]=[N:2][N:1]3[C:31](=[O:32])[NH:30][CH3:33])=[CH:5][CH:6]=2)=[O:24])=[CH:19][CH:18]=1)([CH3:21])([CH3:23])[CH3:22]
Reactant: CN=C=O
Reactant: CC(C)(C)c1ccc(/C=C/C(=O)Nc2ccc3cn[nH]c3c2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=O)n1ncc2ccc(NC(=O)/C=C/c3ccc(C(C)(C)C)cc3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a round-bottomed flask, equipped with a magnetic stir bar, was added (2E)-N-(1H-indazol-6-yl)-3-[4-(tert-butyl)phenyl]prop-2-enamide, Example 155, (61 mg, 0.19 mmol), THF (8 mL) and isocyanatomethane (54 mg, 0.96 mmol, Carbolabs). The reaction mixture was stirred at room temperature for 8 h. The reaction mixture was diluted with EtOAc (10 mL), washed with water (8 mL), dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (40:20:1 hexane:EtOAc:MeOH) provided the title product as an off-white solid. MP 208-209° C. MS (ESI, pos. ion) m/z: 377 (M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([OH:12])=[C:7]([C:13](OCC)=[O:14])[C:6](=[O:18])[C:5]2([CH2:20][CH3:21])[CH3:19].[ClH:22].[NH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(N(C(C)C)C(C)C)C>O1CCOCC1>[Cl:22][C:11]1[CH:10]=[C:9]2[C:4](=[CH:3][CH:2]=1)[C:5]([CH2:20][CH3:21])([CH3:19])[C:6](=[O:18])[C:7]([C:13]([NH:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:14])=[C:8]2[OH:12]
Reactant: CCOC(=O)C1=C(O)c2ccc(Cl)cc2C(C)(CC)C1=O
Reactant: Cl
Reactant: CC(C)(C)OC(=O)CN
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCC1(C)C(=O)C(C(=O)NCC(=O)OC(C)(C)C)=C(O)c2cc(Cl)ccc21
Temperature: 95 °C
Reaction time: 4 h
Yield: 55.9 %

Procedure:
A mixture of ethyl 6-chloro-4-ethyl-1-hydroxy-4-methyl-3-oxo-naphthalene-2-carboxylate (0.5 g, 2 mmol), and tert-butyl 2-aminoacetate hydrochloride (0.4 g, 2 mmol) in 5 mL dioxane, was treated with N-ethyl-N-isopropylpropan-2-amine (0.6 g, 5 mmol). The resulting mixture was warmed to 95° C. and stirred for 4 hours, M+Na=416, M−1=392. The mixture was then cooled to room temperature and concentrated in vacuo. The crude product was purified by column chromatography eluting with 10-20% EtOAc/hexane to give 0.44 g of the title compound as a white yellow solid. MS m/e=416 (M+Na)+.
Reaction SMILES: [C:1](=[O:23])([O:3][CH2:4][CH:5]1[C:17]2([OH:19])[O:18][N:12]([CH2:13][CH:14]3[CH:16]2[NH:15]3)[C:11]2[C:6]1=[C:7]([OH:22])[CH:8]=[C:9]([CH:20]=O)[CH:10]=2)[NH2:2].Cl.[CH3:25][O:26][NH2:27].C(=O)(O)[O-].[Na+]>CO>[C:1](=[O:23])([O:3][CH2:4][CH:5]1[C:17]2([OH:19])[O:18][N:12]([CH2:13][CH:14]3[CH:16]2[NH:15]3)[C:11]2[C:6]1=[C:7]([OH:22])[CH:8]=[C:9]([CH:20]=[N:27][O:26][CH3:25])[CH:10]=2)[NH2:2]
Reactant: CON
Reactant: NC(=O)OCC1c2c(O)cc(C=O)cc2N2CC3NC3C1(O)O2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CON=Cc1cc(O)c2c(c1)N1CC3NC3C(O)(O1)C2COC(N)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73.4 %

Procedure:
To a solution of 4-formyl-6,9-dihydroxy-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (100 mg) in methanol (5 ml) were added O-methylhydroxylamine hydrochloride (105 mg) and sodium bicarbonate (106 mg). The mixture was stirred for 1.5 hours at ambient temperature and evaporated in vacuo. The residue was subjected to preparative thin layer chromatography, which was developed with a mixture of chloroform and methanol (4:1, v/v) to afford 6,9-dihydroxy-4-methoxyiminomethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (80 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[N:16]([O-])=[O:17].[Na+]>C(O)(=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:15])[C:9](=[N:16][OH:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)c1ccc(Br)cc1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(=NO)C(=O)c1ccc(Br)cc1
Temperature: 1 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
Crude ethyl 3-(4-bromophenyl)-3-oxopropanoate (24.5 g, 0.0884 mol) is dissolved in acetic acid (250 mL) at 23° C. under nitrogen, and water (60 mL) is added. The mixture is cooled to 1° C., and a solution of sodium nitrite (7.63 g, 0.111 mol) in water (60 mL) is added dropwise while maintaining the reaction temperature between 1 to 3° C. The mixture is allowed to stir at 1° C. for 3 hours. Water (100 mL) is added dropwise to the cooled reaction mixture to precipitate the product. The cold (about 5° C.) mixture is suction filtered and the collected solids are rinsed with cold 1:1 (v/v) HOAc/water (50 mL), followed by water (2×50 mL). The solids are suction dried overnight to give 18.3 g of crude title compound.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.[OH-].[K+].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1>CC(C)=O.O>[I:1][C:2]1[C:10]2[C:5](=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:22][C:21]2[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[N:3]=1
Reactant: O=[N+]([O-])c1cccc2c(I)n[nH]c12
Reactant: COc1ccc(CCl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(Cn2nc(I)c3cccc([N+](=O)[O-])c32)cc1
Reaction time: 2 h
Yield: 90.4 %

Procedure:
3-Iodo-7-nitro-1H-indazole (2.50 g, 8.65 mmol) obtained in Step 1 was dissolved in acetone (50 mL), and thereto potassium hydroxide (0.73 g, 12.97 mmol) and 4-methoxybenzylchloride (1.63 g, 10.38 mmol) were added in drops at 0° C. The mixture was stirred for 2 hours. At the end of reaction, the mixture was diluted with water, and extracted with ethylacetate. The extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The solvent was removed under reduced pressure and the residue was separated by column chromatography to give 3-iodo-7-nitro-1-(4-methoxybenzyl)-1H-indazole (3.2 g, Yield 91%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[CH2:10][Cl:11])[CH:6]=[CH:7][CH:8]=1.[CH3:21][NH:22][CH3:23]>>[ClH:11].[CH3:21][N:22]([CH2:10][C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[CH3:23]
Reactant: CNC
Reactant: COc1cccc(C=C(CCl)c2cccc(OC)c2)c1
Product: COc1cccc(C=C(CN(C)C)c2cccc(OC)c2)c1
Product: Cl

Procedure:
By substituting equivalent quantities of 2,3-di(3-methoxyphenyl)allyl chloride and dimethylamine in the procedure of Example 3, there is produced N,N-dimethyl-2,3-di(3-methoxyphenyl)allylamine hydrochloride.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:38])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([OH:31])[N:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:45]([O:47][C:48](=[O:51])[CH2:49]Br)[CH3:46]>CN(C=O)C.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:38])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:49][C:48]([O:47][CH2:45][CH3:46])=[O:51])[N:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)n(-c3ccccc3)n2)CC1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N2CCN(C(=O)OCC)CC2)nn1-c1ccccc1
Temperature: 100 °C

Procedure:
To a solution of 60 mg of 4-{(S)-4-tert-Butoxycarbonyl-2-[(5-hydroxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester in 20 ml of DMF, 73 mg of cesium carbonate and 38 mg of Bromo-acetic acid ethyl ester was added and heated to 100° C. for 4 h. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was used in the subsequent reaction.
Reaction SMILES: O1CCCC1.C([N-]C(C)C)(C)C.[Li+].[Cl:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[Cl:25])[N:21]=[C:20]([O:26][CH3:27])[C:19]([O:28][CH3:29])=[N:18]2.[B:30](OC)([O:33]C)[O:31]C.Cl>O1CCCC1.O>[Cl:25][C:24]1[C:15]([Cl:14])=[CH:16][C:17]2[N:18]=[C:19]([O:28][CH3:29])[C:20]([O:26][CH3:27])=[N:21][C:22]=2[C:23]=1[B:30]([OH:33])[OH:31]
Reactant: COB(OC)OC
Reactant: COc1nc2cc(Cl)c(Cl)cc2nc1OC
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1nc2cc(Cl)c(Cl)c(B(O)O)c2nc1OC
Reaction time: 1 h
Yield: 26.1 %

Procedure:
Lithium diisopropylamide mono(tetrahydrofuran) (1.5M in cyclohexane, 6.18 mL, 9.26 mmol) was added to a stirred suspension of 6,7-dichloro-2,3-dimethoxyquinoxaline (Preparation 1, 2.0 g, 7.72 mmol) in dry tetrahydrofuran (150 mL) at −78° C., under nitrogen. After 1 hour at −78° C., trimethyl borate (1.47 mL, 2.0 g, 19.3 mmol) was added. The solution was stirred for a further 1 hour and then left to reach room temperature over 18 hours. Water (50 mL) was added, the solution was acidified to pH 1 with 2M aqueous hydrochloric acid solution and extracted with dichloromethane (3×150 mL). The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, by gradient elution using dichloromethane:methanol (100:0 changing to 99:1, by volume) as the eluent to afford 6,7-dichloro-2,3-dimethoxyquinoxaline-5-boronic acid (0.610 g, 26%) as a light brown solid.
Reaction SMILES: [K+].Cl[CH:3]([CH:7]=O)[C:4]([O-:6])=[O:5].[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][N:11]=1.S(=O)(=O)(O)O.[CH2:22](O)[CH3:23]>>[Br:16][C:13]1[CH:14]=[CH:15][C:10]2[N:11]([C:3]([C:4]([O:6][CH2:22][CH3:23])=[O:5])=[CH:7][N:9]=2)[CH:12]=1
Reactant: CCO
Reactant: O=CC(Cl)C(=O)[O-]
Reactant: Nc1ccc(Br)cn1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)c1cnc2ccc(Br)cn12
Temperature: 25 °C
Yield: 48 %

Procedure:
To a suspension of 2-chloro-3-oxopropanoate potassium salt (6.3 g, 33 mmol) (prepared according to Ikemoto, T. et al., Tetrahedron 2000, 56, 7915-7921) and 2-amino-5-bromopyridine (1.93 g, 11.1 mmol) in ethanol (150 mL) was added concentrated sulfuric acid (1.1 g) and the reaction mixture was heated at reflux for 16 h, allowed to cool to ambient temperature and concentrated in vacuo. The residue was partitioned between ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate (100 mL) and the aqueous phase was extracted with ethyl acetate (2×50 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with a 0-50% gradient of ethyl acetate in hexanes to afford ethyl 6-bromoimidazo[1,2-a]pyridine-3-carboxylate as a yellow solid in 48% yield (1.45 g): 1H NMR (300 MHz, CDCl3) δ9.48-9.42 (m, 1H), 8.26-8.19 (m, 1H), 7.63-7.55 (m, 1H), 7.49-7.40 (m, 1H), 4.45-4.31 (m, 2H), 1.44-1.31 (m, 3H); MS (ES+) m/z 268.9 (M+1), 270.9 (M+1).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH3:8][N:9]([CH3:13])[CH2:10][CH2:11][NH2:12].O1CCOCC1>C(C(C)=O)C>[CH3:8][N:9]([CH3:13])[CH2:10][CH2:11][NH:12][C:1](=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5]
Reactant: O=C1CCC(=O)O1
Reactant: CN(C)CCN
Solvent: CCC(C)=O
Solvent: C1COCCO1
Product: CN(C)CCNC(=O)CCC(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1.4 g of succinic anhydride and then 1.5 cm3 of 2-dimethylaminoethylamine are added to 15 cm3 of dioxane. After stirring for 18 hours at room temperature, the solvent is evaporated under reduced pressure (2.7 kPa) at 20° C., to give a residue which is taken up hot in 40 cm3 of methyl ethyl ketone. After cooling, the solubilized fraction is removed. The residual gum is crystallized hot from 15 cm3 of acetone. After filtration, the solid is rinsed with a minimum of acetone and then with diethyl ether, and dried under reduced pressure (2.7 kPa) at 20° C. to give 2.03 g of N-(2-dimethylaminoethyl)succinamic acid in the form of a white solid melting at 155° C.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][O:4][CH2:3]1.[C:7]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])[NH:8][NH2:9]>CO>[O:4]1[CH2:5][CH2:6][C:2](=[N:9][NH:8][C:7]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NN=C1CCOC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 113.1 %

Procedure:
3-oxotetrahydrofuran (10.38 g) was dissolved in methanol (200 mL), and t-butyl carbazate (17.53 g) was added to the solution. The mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated to give the title compound (27.3 g). 1H-NMR (400 MHz, CDCl3) δ (ppm): 1.52 (s, 9H), 2.46 (t, J=6.9 Hz, al), 4.10 (t, J=6.9 Hz, 2H), 4.33 (s, 2H).
Reaction SMILES: [CH3:1][C@H:2]([CH2:9]CCS([O-])(=O)=O)[CH2:3][CH2:4]S([O-])(=O)=O.[NH2:16][C@@H:17]([CH3:20])[CH2:18][OH:19]>C(Cl)Cl.C([O-])([O-])=O.[K+].[K+].O>[CH3:1][C@@H:2]1[CH2:3][CH2:4][N:16]([C@@H:17]([CH3:20])[CH2:18][OH:19])[CH2:9]1
Reactant: C[C@H](CCCS(=O)(=O)[O-])CCS(=O)(=O)[O-]
Reactant: C[C@H](N)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: C[C@@H]1CCN([C@@H](C)CO)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.8 %

Procedure:
(R)-2-Methylbutane-1,4-diyldimethanesulfonate (37.5 g, 0.144 mol, from step 2 of Intermediate 11) was added to neat (S)-2-aminopropan-1-ol (54.8 g, 0.730 mol). The mixture was stirred in a room temperature water bath to minimize the exotherm. After 24 h, the reaction was diluted with DCM (150 mL), sat'd K2CO3 solution (150 mL), and just enough water (60 mL) to dissolve the resulting ppt. The organic layer was separated, and the aqueous layer was extracted with DCM (150 mL). The organic layers were combined, dried (Na2SO4), filtered, concentrated, and purified by silica gel chromatography (10:7; ethyl acetate:hexanes→10:7:2:1; ethyl acetate:hexanes:methanol:triethylamine) to give (S)-2-((R)-3-methylpyrrolidin-1-yl)propan-1-ol (17.9 g) as a pale yellow oil. 1H NMR (400 MHz, DMSO-d6): δ 4.33 (t, 1H), 3.48 (m, 1H), 3.18 (m, 1H), 2.79 (dd, 1H), 2.58 (m, 1H), 2.48 (m, 1H), 2.26 (m, 1H), 2.08 (m, 1H), 2.01 (dd, 1H), 1.88 (m, 1H), 1.20 (m, 1H), 0.98 (d, 3H), 0.96 (d, 3H); LCMS: 144.3 (M+H)+.
Reaction SMILES: [CH3:1][CH2:2][C@@:3]1([OH:59])[CH2:21][N:19]2[CH2:20][C@H:5]([CH2:6][C@:7]([C:55]([O:57][CH3:58])=[O:56])([C:22]3[CH:23]=[C:24]4[C@:32]56[C@@H:36]7[C@:37]([CH2:52][CH3:53])([C@@H:41]([O:48][C:49]([CH3:51])=[O:50])[C@:42]([OH:47])([C:43]([O:45][CH3:46])=[O:44])[C@@H:31]5[N:30]([CH3:54])[C:25]4=[CH:26][C:27]=3[O:28][CH3:29])[CH:38]=[CH:39][CH2:40][N:35]7[CH2:34][CH2:33]6)[C:8]3[NH:16][C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[C:9]=3[CH2:17][CH2:18]2)[CH2:4]1.OS(O)(=O)=O.[Br:65]N1C(=O)CCC1=O.[F:73][C:74]([F:79])([F:78])[C:75]([OH:77])=[O:76]>>[CH3:1][CH2:2][C@@:3]1([OH:59])[CH2:21][N:19]2[CH2:20][C@@H:5]([CH2:6][C@:7]([C:55]([O:57][CH3:58])=[O:56])([C:22]3[CH:23]=[C:24]4[C@:32]56[C@@H:36]7[C@:37]([CH2:52][CH3:53])([C@@H:41]([O:48][C:49]([CH3:51])=[O:50])[C@:42]([OH:47])([C:43]([O:45][CH3:46])=[O:44])[C@@H:31]5[N:30]([CH3:54])[C:25]4=[CH:26][C:27]=3[O:28][CH3:29])[CH:38]=[CH:39][CH2:40][N:35]7[CH2:34][CH2:33]6)[C:8]3[NH:16][C:15]4[C:14]([Br:65])=[CH:13][CH:12]=[CH:11][C:10]=4[C:9]=3[CH2:17][CH2:18]2)[CH2:4]1.[F:73][C:74]([F:79])([F:78])[C:75]([O-:77])=[O:76]
Reactant: CC[C@]1(O)C[C@@H]2CN(CCc3c([nH]c4ccccc34)[C@@](C(=O)OC)(c3cc4c(cc3OC)N(C)[C@H]3[C@@](O)(C(=O)OC)[C@H](OC(C)=O)[C@]5(CC)C=CCN6CC[C@]43[C@@H]65)C2)C1
Reactant: O=C(O)C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Product: CC[C@]1(O)C[C@H]2CN(CCc3c([nH]c4c(Br)cccc34)[C@@](C(=O)OC)(c3cc4c(cc3OC)N(C)[C@H]3[C@@](O)(C(=O)OC)[C@H](OC(C)=O)[C@]5(CC)C=CCN6CC[C@]43[C@@H]65)C2)C1
Product: O=C([O-])C(F)(F)F
Reaction time: 18 h
Yield: 69 %

Procedure:
A solution of vinblastine sulfate (0.5 g, 0.55 mmol) in trifluoroacetic acid (50 mL) under nitrogen was stirred at room temperature for 20 min. The flask was wrapped with foil to keep the reaction mixture in the dark and a solution of N-bromosuccinimide (103 mg, 0.58 mmol) in trifluoroacetic acid (25 mL) was added dropwise. After stirring for 18 h, the reaction mixture was concentrated under reduced pressure, diluted with dichloromethane, and poured into ice water. The aqueous layer was washed 3× with dichloromethane. The pH of the mixture was adjusted to 11-12 with 3% NH3 (aq). The organic layer was separated and the aqueous layer was extracted with dichloromethane (3×) and the combined organic layers were washed with water, dried (Na2SO4), and concentrated under reduced pressure. Purification by column chromatography (silica (deactivated by eluting with 10% triethylamine in hexane), EtOAc) gave a mixture of mono and dibromides (0.33 g, 65%). Purification by reversed phase chromatography (C18, acetonitrile/water, 0.05% trifluoroacetic acid) gave 12′-bromovinblastine as a trifluoroacetate (0.42 g, 69%). 1H NMR (300 MHz, CDCl3) δ 8.09 (s, 1H), 7.62 (d, J=2 Hz, 1H), 7.21 (dd, J=9, 2 Hz, 1H), 6.97 (d, J=9 Hz, 1H), 6.52 (s, 1H), 6.10 (s, 1H), 5.85 (dd, J=9, 4 Hz, 1H), 5.46 (s, 1H), 5.30 (d, J=9 Hz, 1H), 3.89 (m, 2H), 3.80 (s, 6H), 3.73 (s, 1H), 3.65 (m, 1H), 3.63 (s, 3H), 3.50-2.90 (m, 6H), 2.85 (m, 3H), 2.71 (s, 3H), 2.62 (s, 1H), 2.53-2.38 (m, 2H), 2.36-2.10 (m, 2H), 2.11 (s, 3H), 1.90-1.70 (m, 3H), 1.54-1.25 (m, 7H), 0.89 (t, J=7 Hz, 3H), 0.77 (t, J=7 Hz, 3H); ESI MS m/z 889, 891 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=2)=[CH:19][CH:18]=1)=[O:15]>>[F:31][C:30]([F:33])([F:32])[C:27]1[CH:28]=[CH:29][C:24]([O:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][C:14](=[O:15])[N:11]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:10][C:6]=3[C:7](=[O:8])[NH2:9])[CH3:12])=[CH:18][CH:19]=2)=[N:25][CH:26]=1
Reactant: CNc1ccc(Cl)cc1C(N)=O
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Product: CN(C(=O)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)c1ccc(Cl)cc1C(N)=O

Procedure:
The title product was prepared from 5-chloro-2-(methylamino)-benzamide and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate, preparative HPLC (method C) (31%, light yellow oil). HPLC-MS m/z=466.1 (M+1), Rt: 3.99 min.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:34])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([NH2:33])=[CH:14][C:15]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:16]=2[CH:32]=1)([CH3:3])[CH3:2].[C:35]([NH:38][C:39]1[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=1)(=[O:37])[CH3:36]>>[CH:1]([O:4][C:5](=[O:34])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([NH:33][S:45]([C:42]2[CH:41]=[CH:40][C:39]([NH:38][C:35](=[O:37])[CH3:36])=[CH:44][CH:43]=2)(=[O:47])=[O:46])=[CH:14][C:15]2[N:19]=[C:18]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:17]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:16]=2[CH:32]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)OC(=O)CCCCCOc1cc2c(cc1N)nc(-c1ccccc1)n2-c1ccccc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2cc3nc(-c4ccccc4)n(-c4ccccc4)c3cc2OCCCCCC(=O)OC(C)C)cc1

Procedure:
6-[(5-Amino-1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanoic acid isopropyl ester was reacted according to general operating instructions 13 with 4-(acetylamino)benzenesulfonic acid chloride.