Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)(O)[O-].[Na+].[ClH:6].[NH2:7][CH2:8][CH2:9][C:10]1[CH:17]=[CH:16][C:14]([OH:15])=[C:12]([OH:13])[CH:11]=1.[CH2:18]1[O:26][C:25]2[CH:24]=[CH:23][C:22]([CH2:27][CH2:28][C:29](=O)[CH3:30])=[CH:21][C:20]=2[O:19]1>[Pt]=O.C(O)C>[ClH:6].[CH2:18]1[O:26][C:25]2[CH:24]=[CH:23][C:22]([CH2:27][CH2:28][CH:29]([NH:7][CH2:8][CH2:9][C:10]3[CH:17]=[CH:16][C:14]([OH:15])=[C:12]([OH:13])[CH:11]=3)[CH3:30])=[CH:21][C:20]=2[O:19]1
Reactant: CC(=O)CCc1ccc2c(c1)OCO2
Reactant: NCCc1ccc(O)c(O)c1
Agent: O=[Pt]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Product: CC(CCc1ccc2c(c1)OCO2)NCCc1ccc(O)c(O)c1

Procedure:
In 10 ml. of a saturated solution of sodium bicarbonate is dissolved 1.0 g. (0.00526 mole) dopamine hydrochloride. A solution of 4-[3,4-(methylenedioxy) phenyl]butan-2-one (1.10 g., 0.00526 mole) in 10 ml. ethanol is added to the above sodium bicarbonate solution. A white precipitate develops. The slurry is charged with 0.1 g. platinum oxide and hydrogenated for three hours at 20 psi. The solids are filtered and the solution concentrated. The residue is triturated with ethanol, refiltered and again concentrated. The oily residue is treated with ethereal hydrochloric acid and the so-formed solids collected and crystallized from methanol-isopropanol to give N-[4-(3,4-methylenedioxyphenyl)-but-2-yl]-β-(3,4-dihydroxyphenyl) ethylamine hydrochloride as a white solid, m.p. 204°-206°.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([Cl:10])[C:3]=1[NH2:4].[CH3:11][NH:12][C:13]([NH:15][C:16]#[N:17])=[NH:14].Cl>C(O)CCC>[ClH:1].[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([Cl:10])[C:3]=1[NH:4][C:16]([NH:15][C:13]([NH:12][CH3:11])=[NH:14])=[NH:17]
Reactant: CNC(=N)NC#N
Reactant: Nc1c(Cl)cc(Cl)cc1Cl
Agent: Cl
Solvent: CCCCO
Product: CNC(=N)NC(=N)Nc1c(Cl)cc(Cl)cc1Cl

Procedure:
To 20 g (0.1 mole) of 2,4,6-trichloroaniline and 12.6 g (0.1 mole) of 1-methyl-3-cyanoguanidine in 10 ml (0.1 mole) of concentrated hydrochloric acid is added 125 ml of n-butanol. The reaction mixture is refluxed for 17 hours, cooled and the alcohol evaporated off. The residue is extracted with ether after making it alkaline with 40% sodium hydroxide. The ether extract is dried over potassium carbonate and evaporated. The residue is dissolved in methanol, the pH adjusted to about 7, charcoal filtered and evaporated. The residue is triturated with ether and the solid that forms is recrystallized from water to obtain 1-(2,4,6-trichlorophenyl)-5-methylbiguanide hydrochloride.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:5]=[C:4]([NH:19][CH:20]2[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]2)[N:3]=1.[CH2:30]([NH2:33])[CH2:31][NH2:32].[OH-].[Na+]>C1(C)C(C)=CC=CC=1>[CH3:26][C:24]1([CH3:27])[CH2:25][CH:20]([NH:19][C:4]2[N:5]=[C:6]([NH:8][CH:9]3[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]3)[N:7]=[C:2]([NH:32][CH2:31][CH2:30][NH:33][C:2]3[N:3]=[C:4]([NH:19][CH:20]4[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]4)[N:5]=[C:6]([NH:8][CH:9]4[CH2:10][C:11]([CH3:18])([CH3:17])[NH:12][C:13]([CH3:16])([CH3:15])[CH2:14]4)[N:7]=3)[N:3]=2)[CH2:21][C:22]([CH3:29])([CH3:28])[NH:23]1
Reactant: CC1(C)CC(Nc2nc(Cl)nc(NC3CC(C)(C)NC(C)(C)C3)n2)CC(C)(C)N1
Reactant: NCCN
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: CC1(C)CC(Nc2nc(NCCNc3nc(NC4CC(C)(C)NC(C)(C)C4)nc(NC4CC(C)(C)NC(C)(C)C4)n3)nc(NC3CC(C)(C)NC(C)(C)C3)n2)CC(C)(C)N1

Procedure:
42.3 (0.1 mole) of 2-chloro-4,6-bis(2,2,6,6-tetramethyl-4-piperidylamino)-1,3,5-triazine (prepared according to example 2A), 3 g (0.05 moles) of ethylenediamine, 4 g of sodium hydroxide and 150 ml of xylene were boiled for 16 hours under stirring.
Reaction SMILES: C[O:2][C:3](=[O:24])[CH:4]([O:22][CH3:23])[O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([C:16]#[C:17][Si](C)(C)C)=[CH:9]2.[OH-].[Na+].C(OCC)(=O)C.O>C(O)C>[C:16]([C:10]1[CH:11]=[N:12][C:13]2[C:8]([CH:9]=1)=[CH:7][C:6]([O:5][CH:4]([O:22][CH3:23])[C:3]([OH:24])=[O:2])=[CH:15][CH:14]=2)#[CH:17]
Reactant: COC(=O)C(OC)Oc1ccc2ncc(C#C[Si](C)(C)C)cc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: C#Cc1cnc2ccc(OC(OC)C(=O)O)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.2 %

Procedure:
To a solution of methoxy-(3-trimethylsilanylethynyl-quinolin-6-yloxy)-acetic acid methyl ester (1.99 g) in ethanol (14 mL) was added a solution of sodium hydroxide 2N (4 mL) at 0° C. The reaction mixture was stirred at room temperature for 1 hour. Ethyl acetate and water were added. The mixture was stirred. The two layers were separated. The aqueous layer was acidified at pH 1 with HCl 2N. Then it was extracted with ethyl acetate (twice). The organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure to give (3-ethynyl-quinolin-6-yloxy)-metoxy-acetic acid (1.15 g) as an orange solid.
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[C:16]2[NH:15][C:14](=O)[CH2:13][N:12]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=3[CH3:26])[C:11]=2[N:10]=[C:9]([CH3:27])[CH:8]=1)[CH2:4][CH3:5])[CH3:2].CSC.B>C1COCC1>[CH2:1]([CH:3]([O:6][C:7]1[C:16]2[NH:15][CH2:14][CH2:13][N:12]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=3[CH3:26])[C:11]=2[N:10]=[C:9]([CH3:27])[CH:8]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Oc1cc(C)nc2c1NC(=O)CN2c1c(C)cc(C)cc1C
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: CCC(CC)Oc1cc(C)nc2c1NCCN2c1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 117.5 %

Procedure:
A mixture of 8-(1-ethyl-propoxy)-6-methyl-4-(2,4,6-trimethyl-phenyl)-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (13 mg, 0.0354 mmol) and 2M borane dimethylsulfide complex (BH3.DMS) (0.044 ml, 0.0884 mmol) in 2 ml of dry THF was heated at reflux for 2 hours. The mixture was quenched with 0.2 ml of methanol and 0.2 ml of concentrated hydrochloric acid (HCl) and the resulting mixture was stirred at room temperature for 2 hours, and then concentrated to dryness. The residue was quenched with water, neutralized with saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated to give 14.7 mg of the title compound as a brown crystals. The crystals were purified through silica gel column chromatography using 10% ethyl acetate in hexane as eluent to give 9 mg of the title compound as a colorless oil. 1H NMR (CDCl3) δ 6.93(s,2H), 6.02(s,1H), 4.18(m,1H), 3.62(m,2H), 3.44(m,2H), 2.31(s,3H), 2.12(s,9H), 1.71(m,4H), 0.98(t,6H)ppm.
Reaction SMILES: [C:1]([O:23][CH:24]1[CH2:29][C:28]([CH3:31])([CH3:30])[N:27]([OH:32])[C:26]([CH3:34])([CH3:33])[CH2:25]1)(=[O:22])[C:2]1[C:3](=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:4]([O:6][CH:7]1[CH2:12][C:11]([CH3:14])([CH3:13])[N:10]([OH:15])[C:9]([CH3:17])([CH3:16])[CH2:8]1)=[O:5].[CH2:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH3:36].[O-]O>O.[Mo](=O)(=O)=O>[C:4]([O:6][CH:7]1[CH2:12][C:11]([CH3:13])([CH3:14])[N:10]([O:15][CH:35]([CH3:36])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:9]([CH3:17])([CH3:16])[CH2:8]1)(=[O:5])[C:3]1[C:2](=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:1]([O:23][CH:24]1[CH2:29][C:28]([CH3:31])([CH3:30])[N:27]([O:32][CH:35]([CH3:36])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:26]([CH3:34])([CH3:33])[CH2:25]1)=[O:22]
Reactant: CCc1ccccc1
Reactant: CC1(C)CC(OC(=O)c2ccccc2C(=O)OC2CC(C)(C)N(O)C(C)(C)C2)CC(C)(C)N1O
Agent: O=[Mo](=O)=O
Agent: [O-]O
Solvent: O
Product: CC(ON1C(C)(C)CC(OC(=O)c2ccccc2C(=O)OC2CC(C)(C)N(OC(C)c3ccccc3)C(C)(C)C2)CC1(C)C)c1ccccc1
Temperature: 110 °C
Yield: 88 %

Procedure:
The compound is prepared from 40.0 g of di-(1-oxyl-2,2,6,6-tetramethylpiperidin-4-yl) phthalate, 200 ml of ethylbenzene, and 2.0 g of molybdenum trioxide which are heated to 110° C. (nitrogen atmosphere). Thereafter, 65 g of 70% t-butyl hydroxperoxide in water is added dropwise over one hour. The reaction mixture is refluxed for 3 hours after the hydroperoxide addition is complete. The crude product is chromatographed on silica gel (9:1 hexane:ethyl acetate) to give 51.0 g (88% yield) of a soft glassy product.
Reaction SMILES: C1(C([O:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([Cl:17])=[CH:12][C:11]=2[C:18](=[O:20])[CH3:19])=O)CCCCC1.[OH-:21].[K+].Cl>N1C=CC=CC=1>[Cl:17][C:13]1[CH:14]=[C:15]([CH3:16])[C:10]([OH:9])=[C:11]([C:18](=[O:20])[CH2:19][C:18]([CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:10]2)=[O:21])[CH:12]=1
Reactant: [OH-]
Reactant: CC(=O)c1cc(Cl)cc(C)c1OC(=O)C1CCCCC1
Agent: Cl
Agent: [K+]
Solvent: c1ccncc1
Product: Cc1cc(Cl)cc(C(=O)CC(=O)C2CCCCC2)c1O
Temperature: 50 °C
Reaction time: 1 h
Yield: 154.2 %

Procedure:
2-Acetyl-4-chloro-6-methylphenyl cyclohexanecarboxylate (12 g, 0.0408 mole) was dissolved in pyridine (60 ml) and to the solution was added KOH powder (3 g, 0.0536 mole) with stirring at 50° C. The stirring was continued for 1 hour. The reaction mixture was cooled and poured into diluted hydrochloric acid and extracted with hexane-ethyl acetate (2:1). The extract was washed with water and dried (MgSO4). The solvent was distilled off under reduced pressure. The residue was treated with cold methanol to obtain the title compound (9.27 g) as crystals, yield 77.3%. The crystals were recrystallized from ethyl acetate and hexane to obtained prisms, m.p. 76°-77° C.
Reaction SMILES: CS[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:6]=2[N:7]=1.[CH3:15][N:16]([CH3:22])[C@@H:17]1[CH2:21][CH2:20][NH:19][CH2:18]1>C1(C)C=CC=CC=1>[CH3:15][N:16]([CH3:22])[CH:17]1[CH2:21][CH2:20][N:19]([C:3]2[O:4][C:5]3[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:6]=3[N:7]=2)[CH2:18]1
Reactant: CN(C)[C@@H]1CCNC1
Reactant: CSc1nc2cc([N+](=O)[O-])ccc2o1
Solvent: Cc1ccccc1
Product: CN(C)C1CCN(c2nc3cc([N+](=O)[O-])ccc3o2)C1
Yield: 45 %

Procedure:
Suspend 2-methylsulfanyl-5-nitro-benzooxazole (1.68 g, 7.99 mmol) in toluene (8 mL). Add (3R)-(+)-3-(dimethylamino)pyrrolidine (1.8 mL) and heat to 70° C. overnight. Cool the reaction to room temperature, dilute with toluene (10 mL) and filter. Wash the product with toluene (5 mL) and hexane (10 mL). Dry on the filter flask for 30 min to afford the title compound (1.00 g, 45%). 1H NMR (400 MHz, DMSO-d6): δ 8.03 (d, 1H, J=2.2 Hz), 7.94 (dd, 1H, J=8.6, 2.4 Hz), 7.62 (d, 1H, J=8.8 Hz), 3.81 (dd, 1H, J=10.1, 7.0 Hz), 3.75 (m, 1H), 3.57 (dt, 1H, J=10.0, 7.2 Hz), 3.34 (m, 1H), 2.86 (m, 1H), 2.21-2.13 (m, 7H), 1.87 (m, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3]1=[O:11].[OH-].[Na+].Br[CH2:15][CH2:16][CH2:17][Cl:18]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C>[Cl:18][CH2:17][CH2:16][CH2:15][N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:2]([CH3:1])[C:3]1=[O:11]
Reactant: ClCCCBr
Reactant: Cn1c(=O)[nH]c2ccccc21
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Product: Cn1c(=O)n(CCCCl)c2ccccc21
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 47 parts of 1,3-dihydro-1-methyl-2H-benzimidazol-2-one, 5 parts of N,N,N-triethylbenzenemethanaminium chloride and 375 parts of a sodium hydroxide solution 50% are added 96 parts of 1-bromo-3-chloropropane at 60° C. The whole is heated to 70° C. and stirring is continued for 1 hour at 70° C. The reaction mixture is poured onto crushed ice and the product is extracted with methylbenzene. The extract is washed with water, dried, filtered and evaporated, yielding 80 parts of 1-(3-chloropropyl)-1,3-dihydro-3-methyl-2H-benzimidazol-2-one as an oily residue.
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][C:4]([C:7]([N:11]2[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:13][CH2:12]2)([C:9]#N)[CH3:8])=[CH:3][CH:2]=1.C[Mg]Br.[Cl-].[NH4+]>O1CCCC1.C(OCC)C>[C:1]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:2]=[CH:3][C:4]([C:7]([N:11]2[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:13][CH2:12]2)([CH3:8])[CH3:9])=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NCC1CCN(C(C)(C#N)c2ccc(-c3ccccc3)cc2)CC1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NCC1CCN(C(C)(C)c2ccc(-c3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.1 %

Procedure:
To a solution of the compound prepared in Example 363 (0.112 g) in tetrahydrofuran (3 mL) at 0° C. was added a 3.0 M solution of methylmagnesium bromide in diethyl ether (0.27 mL), and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was poured onto cold saturated ammonium chloride, and the mixture was extracted with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexanes:triethylamine=80:20:1) to obtain the title compound (0.035 g) having the following physical data.
Reaction SMILES: Cl.[CH2:2]([NH2:13])[CH2:3][C:4]1[CH:12]=[CH:11][C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=1.C(N(CC)CC)C.[Cl:21][CH2:22][C:23](Cl)=[O:24]>C(Cl)Cl>[Cl:21][CH2:22][C:23]([NH:13][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=1)=[O:24]
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)NCCc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.5 %

Procedure:
To homopiperonylamine hydrochloride (2.14 g, 10.6 mmol) (a compound of formula (Y7)) in CH2Cl2 (20 mL) in an ice bath was added triethylamine (3.1 mL, 21 mmol) and chloroacetyl chloride (0.85 mL, 10 mmol) (a compound of formula (Y6)). After warming to ambient temperature and stirring for 16 hours, the reaction was partitioned with 1 N HCl. The organic layer was separated, washed with aqueous bicarbonate, dried (Na2SO4), and the solvent was removed in vacuo to give 1.8 g of 2-chloro-N-[2-(1,3-benzodioxol-5-yl)ethyl]acetamide, a compound of formula (Y8).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](O)=[O:8])[C:4]([CH3:10])=[N:3]1.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:20][CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[C:16]([CH:19]=1)[C:17]#[N:18].C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>O.CN(C)C=O>[C:17]([C:16]1[CH:19]=[C:12]([NH:11][C:7]([C:5]2[C:4]([CH3:10])=[N:3][N:2]([CH3:1])[CH:6]=2)=[O:8])[CH:13]=[CH:14][C:15]=1[O:20][CH2:21][C:22]([CH3:24])([CH3:23])[CH3:25])#[N:18]
Reactant: CC(C)(C)COc1ccc(N)cc1C#N
Reactant: Cc1nn(C)cc1C(=O)O
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1nn(C)cc1C(=O)Nc1ccc(OCC(C)(C)C)c(C#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.8 %

Procedure:
1,3-Dimethylpyrazole-4-carboxylic acid (0.6 g), 5-amino-2-neopentyloxybenzonitrile (0.9 g), triethylamine (1.0 g) and diethyl cyanophosphate (1.0 g) were added to dimethylformamide (10 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. n-Hexane was added to the residue to allow crystallization. The crystals were recrystallized from hydrous methanol to give the title compound (0.5 g), melting point: 193–194° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11]([OH:13])=O.[CH3:14][N:15]1[CH2:20][CH2:19][CH:18]([NH:21][CH3:22])[CH2:17][CH2:16]1>ClCCl>[CH3:22][N:21]([CH:18]1[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]1)[C:11]([C:7]1[C:6]2[C:10](=[C:2]([Br:1])[CH:3]=[CH:4][CH:5]=2)[NH:9][CH:8]=1)=[O:13]
Reactant: CNC1CCN(C)CC1
Reactant: O=C(O)c1c[nH]c2c(Br)cccc12
Solvent: ClCCl
Product: CN1CCC(N(C)C(=O)c2c[nH]c3c(Br)cccc23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.6 %

Procedure:
To a solution of 7-Bromo-1H-indole-3-carboxylic acid (A) (240 mg, 1 mmol) in dichloromethane (8 cm3) was added polystyrene-bound carbodiimide (1 g, loading 1.3 mmol/g, 1.3 mmol) followed by 1-methyl-4-(methylamino)piperidine (192 mg, 1.5 mmol) and the resulting suspension was gently shaken at room temperature for 16 h. The suspension was filtered and the resin washed with dichloromethane. The filtrate was then washed with saturated aqueous sodium bicarbonate solution, water before the organic portion was dried over magnesium sulfate, filtered and the filtrate evaporated under reduced pressure to give the title compound (B) (107.2 mg, 31%).
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[NH:6][C:7]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.[CH2:18](Br)[CH:19]=[CH2:20].[In].Cl>C1COCC1>[Cl:17][C:16]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]([OH:14])([CH2:20][CH:19]=[CH2:18])[C:10]([F:13])([F:11])[F:12])=[N:6][C:5]=2[CH:15]=1
Reactant: C=CCBr
Reactant: O=C(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Agent: Cl
Agent: [In]
Solvent: C1CCOC1
Product: C=CCC(O)(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F

Procedure:
1-(5,6-Dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (1.41 g; 4.99 mmol), allyl bromide (0.85 mL; 10.05 mmol) and indium (1.15 g; 10.05 mmol) were suspended in THF (50 mL) and 0.01 M HCl (150 mL) and stirred vigorously over 18 hours. The layers were separated and the aqueous layer was extracted with ethyl acetate (3×30 mL). The combined extracts were washed with brine (50 mL) and dried over Na2SO4. The resulting crude brown oil was purified by column chromatography (SiO2; 20% ethyl acetate/hexanes) to yield the title compound as a tan solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH:5]([CH2:8][OH:9])[N:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(N(CC)CC)C.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>ClCCl.CN(C)C1C=CN=CC=1>[OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH:5]([CH2:8][O:9][S:30]([C:27]2[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=2)(=[O:32])=[O:31])[N:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1C(CO)CCC1CO
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CCC(CO)N2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1,1-dimethylethyl 2,5-bis(hydroxymethyl)-1-pyrrolidinecarboxylate (commercially available, for example from J&W Pharmlab, 7.57 g, 32.7 mmol) in dichloromethane (200 mL) was added triethylamine (4.79 mL, 34.4 mmol), 4-dimethylaminopyridine (0.20 g, 1.64 mmol) and p-toluenesulfonyl chloride (6.55 g, 34.4 mmol). The reaction was stirred at room temperature for 18 hours. The reaction was diluted with DCM (200 mL) and the solution washed with water (200 mL). The organic layer was collected via a hydrophobic frit and the solvent removed under vacuum. The residue was purified by silica chromatography (Biotage SP4, eluting 30% EtOAc in iso-hexane (3 column volumes), a gradient from 30-50% (over 6 column volumes) then 50% EtOAc (3 column volumes)) to yield the title compound as a colourless gum (2.28 g).
Reaction SMILES: [C:1](=O)([O-:3])[O-:2].[Na+:5].[Na+].S(=O)=O.[S:10]([O-:13])([O-:12])=[O:11]>>[S:10]([O-:13])([O-:12])=[O:11].[Na+:5].[Na+:5].[C:1](=[O:3])=[O:2]
Reactant: O=C([O-])[O-]
Agent: O=S([O-])[O-]
Agent: O=S=O
Agent: [Na+]
Product: O=C=O

Procedure:
In a brief overview, a source 11 of sodium carbonate with a source 12 of sulfur dioxide are fed to the sulfite reactor 10 under conditions suitable to produce sodium sulfite with carbon dioxide as a by-product and generate a sodium sulfite liquor 14 which exits the sulfite reactor 10.
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:21][CH:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[CH:17]=[C:16]([C:29]#[C:30][C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[CH:15]=2)=[CH:9][C:8]=1[Cl:38])C.[OH-].[Na+].Cl>C(O)C>[Cl:38][C:8]1[CH:9]=[C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:21][CH:22]3[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]3)[CH:17]=[C:16]([C:29]#[C:30][C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[CH:15]=2)[CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:39])=[O:3]
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(Cl)cc3)cc(OCC3CCN(C)CC3)c2)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN1CCC(COc2cc(C#Cc3ccc(Cl)cc3)cc(Sc3ccc(OCC(=O)O)c(Cl)c3)c2)CC1
Reaction time: 16 h

Procedure:
{2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(1-methyl-piperidin-4-ylmethoxy)phenylsulfanyl]-phenoxy}-acetic acid ethyl ester (60 mg; 0.10 mmol) was dissolved in ethanol (7 mL), and aqueous 1N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h, acidified with 1N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried, evaporated to dryness and purified by prep. HPLC (method B). Yield: 20 mg. HPLC-MS: m/z: 556.5 (M+); Rt: 2.10 min.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:30]=[CH:29][C:8]([C:9]([O:11][C@H:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([N:21]4[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[C:15]=3[C@H:14]([CH3:28])[CH2:13]2)=[O:10])=[CH:7][CH:6]=1)([O-:4])=[O:3].[C:31]([O:35][C:36]([N:38]([CH:51]([CH3:53])[CH3:52])[CH2:39][CH:40]([C:44]1[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=1)[C:41](O)=[O:42])=[O:37])([CH3:34])([CH3:33])[CH3:32].ClCCl.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[N+:2]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([O:11][C@H:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([N:21]4[CH2:27][CH2:26][CH2:25][N:24]([C:41](=[O:42])[C@@H:40]([C:44]5[CH:45]=[CH:46][C:47]([Cl:50])=[CH:48][CH:49]=5)[CH2:39][N:38]([C:36]([O:35][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:37])[CH:51]([CH3:52])[CH3:53])[CH2:23][CH2:22]4)[C:15]=3[C@H:14]([CH3:28])[CH2:13]2)=[O:10])=[CH:29][CH:30]=1)([O-:4])=[O:3]
Reactant: CC(C)N(CC(C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Reactant: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(N3CCCNCC3)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CC(C)N(C[C@@H](C(=O)N1CCCN(c2ncnc3c2[C@H](C)C[C@H]3OC(=O)c2ccc([N+](=O)[O-])cc2)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Yield: 49.5 %

Procedure:
(5R,7R)-4-(1,4-Diazepan-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl 4-nitrobenzoate hydrochloride (61 mg, 0.140 mmol) and 3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (48 mg, 0.140 mmol) were suspended in dichloromethane (5 mL) N,N-Diisopropylethylamine (54 mg, 0.420 mmol) was then added. HBTU (53 mg, 0.140 mmol) was added, and the resultant solution was stirred at ambient for 16 hours. After this time, the reaction mixture was quenched by the addition of saturated sodium carbonate solution and then extracted twice with dichloromethane. The combined organic portions were dried over sodium sulfate, filtered, and concentrated. The residue thus obtained was purified by silica gel chromatography to give (5R,7R)-4-(4-((S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoyl)-1,4-diazepan-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl 4-nitrobenzoate (50 mg, 50%). LCMS (APCI+) M+=721.1, Rt=4.51 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[C:15]([CH2:19][OH:20])[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]>ClCCl.[O-2].[O-2].[Mn+4]>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[C:15]([CH:19]=[O:20])[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1cccc(CO)c12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCOC(=O)c1cc2c(cn1)[nH]c1cccc(C=O)c12
Reaction time: 16 h
Yield: 50.4 %

Procedure:
5-Hydroxymethyl-beta-carboline-3-carboxylic acid ethyl ester (1.0 g) is stirred in dichloromethane (250 ml) with manganese dioxide (1.5 g) for 16 hours at room temperature (25° C.). After addition of more manganese dioxide (0.75 g) the reaction mixture is stirred for another 16 hours. Then after filtering of the undissolved portion it is evaporated, the residue is recrystallized twice from ethyl acetate. Thus, 0.5 g of 5-formyl-beta-carboline-3-carboxylic acid ethyl ester with a melting point of 273°-276° C. is obtained.