Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[CH:19][CH:20]=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1.Cl.[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][Cl:27].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O>[ClH:27].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:26][CH2:25][N:24]([CH3:28])[CH3:23])[C:12]3[CH:18]=[CH:19][CH:20]=[CH:21][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc([C@@H]2Sc3ccccc3NC(=O)[C@@H]2O)cc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Yield: 92.8 %

Procedure:
A mixture of 30.1 g of cis-(+)-2-(4-methoxyphenyl)-3-hydroxy-2,3-dihydro-1,5-benzothiazepine-4(5H)-one, 18.7 g of 2-(dimethylamino)ethyl chloride hydrochloride, 33.0 g of potassium carbonate and 240 ml of ethyl acetate is refluxed for 30 minutes under stirring. Then, 5 ml of water are added to the mixture, and the aqueous mixture is further refluxed for 6 hours under stirring. After cooling the reaction mixture, said mixture is washed with water. The ethyl acetate layer is separated and washed with water. The ethyl acetate layer is then evaporated under reduced pressure to remove ethyl acetate. The residue is dissolved in ethanol. After cooling the solution, said solution is acidified with 10% HCl/ethanol and then stirred at a temperature below 10° C. for 5 hours. The crystalline precipitates are collected by filtration, washed with ethanol and then dried. 37.9 g of cis-(+)-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepine-4(5H)-one hydrochloride are thereby obtained. Yield: 92.7%
Reaction SMILES: C(O)C.[C:4]([N:7]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14](=[O:24])[C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=2)[CH2:9][CH2:8]1)(=[O:6])[CH3:5].[BH4-].[Na+]>ClCCl.O>[C:4]([N:7]1[CH2:12][CH2:11][CH:10]([CH2:13][CH:14]([OH:24])[C:15]2[CH:16]=[CH:17][C:18]([N:21]([CH3:22])[CH3:23])=[CH:19][CH:20]=2)[CH2:9][CH2:8]1)(=[O:6])[CH3:5]
Reactant: CC(=O)N1CCC(CC(=O)c2ccc(N(C)C)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: CC(=O)N1CCC(CC(O)c2ccc(N(C)C)cc2)CC1

Procedure:
In a solvent mixture of 60 ml of ethanol and 30 ml of water was dissolved 2.93 g of 1-acetyl-4-(4-dimethylaminobenzoylmethyl)piperidine prepared in Example 39, and at room temperature, 1 g of sodium borohydride was gradually added. The reaction mixture was diluted with dichloromethane and water for distribution and the dichloromethane layer was dried over anhydrous magnesium sulfate. The solvent was then distilled off and the oily residue was purified by silica gel column chromatography (eluent: ethyl acetate) to give a pale yellow solid melting at 119°-120° C.
Reaction SMILES: O.[C:2]([OH:6])(=[O:5])[CH:3]=O.[NH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[N:8]1.[C:16](=[O:26])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH2:17]>C1(C)C=CC=CC=1>[N:7]1([CH:3]([NH:17][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:26])[C:2]([OH:6])=[O:5])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[N:8]1
Reactant: NC(=O)OCc1ccccc1
Reactant: O=CC(=O)O
Reactant: c1ccc2[nH]nnc2c1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(NC(C(=O)O)n1nnc2ccccc21)OCc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of glyoxylic acid monohydrate (4.60 g), benzotriazole (5.95 g) and benzyl carbamate (7.55 g) was heated to reflux in toluene (100 ml) for 18 h, under Dean-Stark conditions. The mixture was then allowed to cool to room temperature, and the resulting precipitate collected by filtration. This was then recrystallised from diethyl ether giving an off-white solid (11.66 g)
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].[CH2:6]([Si:8]([CH2:12][CH3:13])([CH2:10][CH3:11])Cl)[CH3:7].Cl>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.CC1C=CC(C)=CC=1>[CH2:1]([O:5][Si:8]([CH2:12][CH3:13])([CH2:10][CH3:11])[CH2:6][CH3:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCO
Reactant: CC[Si](Cl)(CC)CC
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccc(C)cc1
Product: CCCCO[Si](CC)(CC)CC

Procedure:
0.1 moles of n-butanol, 0.15 moles of triethylchlorosilane and 0.0005 moles of triethylbenzyl ammonium chloride in 50 ml of p-xylene were heated under reflux (80°-110° C.). When the evolution of HCl had ceased, the product was worked up by fractional distillation at reduced pressure.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=[O:7].[CH2:11]([N:18]1[C:23](=[O:24])[CH:22]2[CH2:25][CH2:26][CH:19]1[CH2:20][CH2:21]2)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:11]([N:18]1[C:23](=[O:24])[CH:22]2[CH2:25][CH2:26][CH:19]1[C:20](=[O:7])[CH2:21]2)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1C2CCC(CC2)N1Cc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=C1CC2CCC1N(Cc1ccccc1)C2=O
Temperature: 25 °C
Yield: 92 %

Procedure:
A solution of dimethyl sulphoxide (2.34 g) in dichloromethane (5 ml) was added to a cooled (-60° C.) solution of oxalyl chloride (1.78 g) in dichloromethane (5 ml) and after 2 minutes the mixture was treated with a solution of 2-benzyl-2-azabicyclo[2.2.2]octan-3-one (2.31 g--commercially available) in dichloromethane (10 ml), stirred at -60° C. for 30 minutes, treated with triethylamine (5.05 g), allowed to warm up to room temperature, quenched with water and extracted into dichloromethane. The dichloromethane extracts were dried over sodium sulphate and evaporated. The residue was purified by chromatography on silica using hexane plus 50% ethyl acetate as eluant. Appropriate fractions were combined and evaporated to give the desired compound (2.10 g, 92%) as a colourless oil which was used directly in Preparation 3 without characterisation or further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[F:11][C:12]([F:16])([F:15])[CH2:13][OH:14].[OH-].[K+].Cl>CS(C)=O>[F:11][C:12]([F:16])([F:15])[CH2:13][O:14][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: OCC(F)(F)F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=C(O)c1ccc(OCC(F)(F)F)nc1
Reaction time: 18 h
Yield: 81.9 %

Procedure:
A mixture of 6-chloropyridine-3-carboxylic acid (6.0 g, 38.1 mmol), 2,2,2-trifluoroethanol (8.2 mL, 114.2 mmol) and potassium hydroxide (10.7 g, 190.4 mmol) in DMSO (50 mL) was stirred at 120 C for 18 h and left standing at room temperature for 2 days. A further 2 equivalents of potassium hydroxide and 1.5 equivalent of 2,2,2-trifluoroethanol were added and the reaction mixture was stirred at 120 C for 18 h. The mixture was acidified with a concentrated aqueous solution of HCl until a cream precipitate appeared. The precipitate was collected by filtration, washed with a 1N aqueous solution of HCl before being dissolved in EtOAc, washed 3 times with a 1N aqueous solution of HCl and 3 times with brine. The organic phase was dried over sodium sulfate, filtered and concentrated under vacuum to afford the title compound as a cream solid (6.9 g, 82%). Method C HPLC-MS: MH+ requires m/z=222 Found: m/z=222, Rt=1.24 min (98%).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)=[C:4]([CH3:16])[CH:3]=1.C(OC([N:24]1[CH2:28][C@H:27]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH2:26][C@H:25]1[C:37](O)=[O:38])=O)(C)(C)C>>[F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:13]=[CH:12][C:10]([NH:11][C:37]([C@@H:25]3[CH2:26][C@@H:27]([CH2:29][C:30]4[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=4)[CH2:28][NH:24]3)=[O:38])=[CH:9][CH:8]=2)=[C:4]([CH3:16])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](Cc2ccc(F)cc2)C[C@H]1C(=O)O
Reactant: Cc1cc(F)ccc1Oc1ccc(N)cc1
Product: Cc1cc(F)ccc1Oc1ccc(NC(=O)[C@@H]2C[C@@H](Cc3ccc(F)cc3)CN2)cc1
Yield: 93 %

Procedure:
Proceeding as in Reference 6, but substituting 4-(4-fluoro-2-methylphenoxy)aniline and (2S,4R)-1-(tert-butoxycarbonyl)-4-(4-fluorobenzyl)pyrrolidine-2-carboxylic acid, gave (2S,4R)—N-(4-(4-fluoro-2-methylphenoxy)phenyl)-4-(4-fluorobenzyl)pyrrolidine-2-carboxamide (359 mg, 93%).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[N:30]=[CH:29][N:28]=[C:27]3[C:23]=2[N:24]=[CH:25][N:26]3[CH3:31])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(OCC)(=O)C.O>CN(C)C=O>[C:9]([O:13][C:14]([N:16]1[CH2:17][CH2:18][N:19]([C:22]2[N:30]=[CH:29][N:28]=[C:27]3[C:23]=2[N:24]=[C:25]([Cl:1])[N:26]3[CH3:31])[CH2:20][CH2:21]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1cnc2c(N3CCN(C(=O)OC(C)(C)C)CC3)ncnc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1c(Cl)nc2c(N3CCN(C(=O)OC(C)(C)C)CC3)ncnc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 65.8 %

Procedure:
N-chlorosuccinimide (1.25 g) was added to a solution of 4-(9-methyl-9H-purin-6-yl)-piperazine-1-carboxylic acid t-butyl ester (2.70 g) in N,N-dimethylformamide (30 mL), and this was stirred at room temperature for 20 hours. Ethyl acetate (200 mL) and water (50 mL) were added, the organic layer was washed twice with 50 mL of water and then once with 50 mL of saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The organic layer was filtered and then concentrated under reduced pressure. The residue was purified by silica gel chromatography, and the ethyl acetate:hexane 4:1 fraction gave the title compound (1.97 g).
Reaction SMILES: C(OCC)(=O)C.[N+:7]([C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[CH:12][C:11]=1[CH:20]1[CH2:25][CH2:24][O:23][C:21]1=[O:22])([O-])=O.[H][H]>[Pt]=O.C(O)C>[CH3:19][O:18][C:13]1[CH:12]=[C:11]2[C:10](=[CH:15][C:14]=1[O:16][CH3:17])[NH:7][C:21](=[O:22])[CH:20]2[CH2:25][CH2:24][OH:23]
Reactant: COc1cc(C2CCOC2=O)c([N+](=O)[O-])cc1OC
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc2c(cc1OC)C(CCO)C(=O)N2
Yield: 99.1 %

Procedure:
An ethyl acetate solution containing 2.0 g of α-(2-nitro-4,5-dimethoxyphenyl)-butyrolactone and 500 mg of platinum oxide was stirred in a 2.0 atm. hydrogen gas atmosphere. Ethanol was added to the reaction mixture, followed by filtration. The solvent was evaporated to yield 1.76 g of the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:27])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])=[CH:16][N:15]=2)=[CH:8][S:7][CH:6]=1)=[O:4].[OH-].[Na+].C1COCC1.Cl>C(O)C.O>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:11]([NH:10][C:9]2[C:5]([C:3]([OH:4])=[O:2])=[CH:6][S:7][CH:8]=2)=[O:27])=[N:15][CH:16]=1
Reactant: COC(=O)c1cscc1NC(=O)COc1ccc(-c2ccccc2Cl)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: O=C(COc1ccc(-c2ccccc2Cl)cn1)Nc1cscc1C(=O)O
Temperature: 25 °C
Yield: 66.9 %

Procedure:
To a suspension of 4-{2-[5-(2-chloro-phenyl)-pyridin-2-yloxy]-acetylamino}-thiophene-3-carboxylic acid methyl ester (79 mg) in ethanol (10 mL) was added a solution of sodium hydroxide (1M, 0.392 mL) and THF (8 mL) and the reaction mixture was stirred at room temperature over night. After such time the reaction mixture was acidified by addition of a solution of hydrochloric acid (1N, 0.395 mL) and then water was added. The precipitate was isolated by filtration, washed with water and dried in vacuo to yield 4-{2-[5-(2-chloro-phenyl)-pyridin-2-yloxy]-acetylamino}-thiophene-3-carboxylic acid (51 mg, 67%).
Reaction SMILES: [C:1]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=O)[C:2]1[C:3](=CC=CC=1)[OH:4].[CH2:19]([C:27](C1C=CC=CC=1)=[C:28](OC)C([O-])=O)[CH2:20][CH2:21][CH2:22]CCCC.O1[SiH2]O[SiH2]O[SiH2]O[SiH2]O[SiH2]1>>[CH3:28][CH2:27][CH2:19][CH2:20][CH2:21][CH2:22][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:10][CH2:1][CH2:2][CH2:3][OH:4]
Reactant: CCCCCCCCOC(=O)c1ccccc1O
Reactant: CCCCCCCCC(=C(OC)C(=O)[O-])c1ccccc1
Agent: O1[SiH2]O[SiH2]O[SiH2]O[SiH2]O[SiH2]1
Product: CCCCCCCCCCCCCCOCCCO

Procedure:
2% C12-C15 alkyl benzoate (Finsolv TN from Finetex); 5% octyl salicylate (Escalol 587 from ISP); 7.5% octylmethoxycinnamate (Escalol 557 from ISP); 8.2% phenyltrimethicone; 13.3% cyclopentasiloxane; 18% siliconized polyamide; and 1% fragrance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH:11][C:12]1[N:17]=[C:16]([CH3:18])[N:15]=[C:14]([C:19]2[CH:20]=[C:21]([C:25]([CH3:29])([CH3:28])[C:26]#[N:27])[CH:22]=[CH:23][CH:24]=2)[CH:13]=1.[N:30]([Sn](CCCC)(CCCC)CCCC)=[N+:31]=[N-:32]>FC(F)(F)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH:11][C:12]1[CH:13]=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([CH3:29])([C:26]3[N:30]=[N:31][NH:32][N:27]=3)[CH3:28])[CH:20]=2)[N:15]=[C:16]([CH3:18])[N:17]=1
Reactant: Cc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C(C)(C)C#N)c2)n1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: FC(F)(F)c1ccccc1
Product: Cc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C(C)(C)c3nn[nH]n3)c2)n1
Temperature: 180 °C

Procedure:
To a solution of 2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methyl-pyrimidin-4-yl}-phenyl)-2-methyl-propionitrile [50 mg, 0.11 mmol, Intermediate (67)] in α,α,α-trifluorotoluene (2 mL) is added azidotributyltin (0.251 mL, 0.88 mmol) and heated in microwave oven at 180° C. for 1.5 hours. Reaction mixture is concentrated and purified via silica gel chromatography eluting with 20 to 100% EtOAc in heptane to give [2-(2,4-dichloro-phenyl)-ethyl]-(2-methyl-6-{3-[1-methyl-1-(2H-tetrazol-5-yl)-ethyl]-phenyl}-pyrimidin-4-yl)-amine as a solid, which is treated with 1M hydrogen chloride in ether affording [2-(2,4-dichloro-phenyl)-ethyl]-(2-methyl-6-{3-[1-methyl-1-(2H-tetrazol-5-yl)-ethyl]-phenyl}-pyrimidin-4-yl)-amine hydrochloride [47 mg, 80%, Example 47] as a solid. LC/MS: RT=2.47 minutes, MS: 484 (M+H). 1H NMR [300 MHz, (CD3)2SO]: □8.64 (1H, br s), 7.3-7.8 (7H, m), 6.56 (1H, s), 3.98 (3H, s), 3.64 (2H, m), 3 (2H, m), 1.8 (6H, s). IC50=0.4 nM
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH:6]1[O:8][CH2:7]1.[NH:13]1[CH2:18][CH2:17][CH:16]([N:19]2[CH2:24][CH2:23][CH2:22][NH:21][C:20]2=[O:25])[CH2:15][CH2:14]1>C(O)C>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH:6]([OH:8])[CH2:7][N:13]1[CH2:18][CH2:17][CH:16]([N:19]2[CH2:24][CH2:23][CH2:22][NH:21][C:20]2=[O:25])[CH2:15][CH2:14]1
Reactant: Clc1ccccc1OCC1CO1
Reactant: O=C1NCCCN1C1CCNCC1
Solvent: CCO
Product: O=C1NCCCN1C1CCN(CC(O)COc2ccccc2Cl)CC1

Procedure:
A solution of 9.2 g of 1-(o-chloro-phenoxy)-2,3-epoxypropane and 9.15 g of 1-(4-piperidyl)-2-oxo-hexahydro-pyrimidine in 7 ml of abs. ethanol is heated for 5 hours to 95° C and then evaporated in vacuo. The residue is recrystallised from chloroform/petroleum ether to yield the 1-[3-(o-chloro-phenoxy)-2-hydroxypropyl]-4-(2-oxo-hexahydro-1-pyrimidinyl)-piperidine, which melts at 150°-153° C.
Reaction SMILES: [CH2:1]([S-:3])[CH3:2].[Na+].[C:5]([O:9][C:10]([N:12]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28](Cl)[CH:27]=3)(=[O:25])=[O:24])=[CH:19][C:18]=2[O:33][CH3:34])[CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].O>CN(C=O)C>[C:5]([O:9][C:10]([N:12]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([S:3][CH2:1][CH3:2])[CH:27]=3)(=[O:25])=[O:24])=[CH:19][C:18]=2[O:33][CH3:34])[CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].[C:5]([O:9][C:10]([N:12]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([S:3][CH2:1][CH3:2])[CH:27]=3)(=[O:24])=[O:25])=[CH:19][C:18]=2[OH:33])[CH2:13]1)=[O:11])([CH3:6])([CH3:8])[CH3:7]
Reactant: COc1cc(S(=O)(=O)c2cccc(Cl)c2)ccc1C1CCN(C(=O)OC(C)(C)C)C1
Reactant: CC[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1cccc(S(=O)(=O)c2ccc(C3CCN(C(=O)OC(C)(C)C)C3)c(O)c2)c1
Product: CCSc1cccc(S(=O)(=O)c2ccc(C3CCN(C(=O)OC(C)(C)C)C3)c(OC)c2)c1
Temperature: 100 °C

Procedure:
Sodium ethanethiolate (0.698 g, 8.304 mmol) was added to a solution of 3-[4-(3-chloro-benzenesulfonyl)-2-methoxy-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (1.251 g, 2.768 mmol) in DMF (10 mL) and the mixture was heated at 100° C. for 48 hours. The reaction mixture was cooled to room temperature and water was added. The resulting mixture was extracted with EtOAc, and the combined organic extracts were washed with water brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified via flash chromatography (hexane/EtOAc/AcOH, 70/30/1) to give 3-[4-(3-ethylsulfanyl-benzenesulfonyl)-2-methoxy-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester as a first fraction, and 3-[4-(3-ethylsulfanyl-benzenesulfonyl)-2-hydroxy-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester as a second fraction.
Reaction SMILES: Cl.[CH3:2][O:3][N:4]1[C:8](=[O:9])[CH2:7][C:6]2([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[C:5]1=[O:15].C(N(CC)CC)C.[CH3:23][N:24]=[C:25]=[O:26]>O>[CH3:2][O:3][N:4]1[C:8](=[O:9])[CH2:7][C:6]2([CH2:14][CH2:13][N:12]([C:25](=[O:26])[NH:24][CH3:23])[CH2:11][CH2:10]2)[C:5]1=[O:15]
Reactant: CN=C=O
Reactant: CON1C(=O)CC2(CCNCC2)C1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CNC(=O)N1CCC2(CC1)CC(=O)N(OC)C2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-methoxy-2,8-diazaspiro[4,5]decane-1,3-dione hydrochloride (1.5 g) in water (20 ml) was added triethylamine (1 ml), followed by methyl isocyanate (1 ml), and this was followed by stirring at room temperature for 30 minutes. The water was then evaporated off under reduced pressure. The residue was directly subjected to silica gel column chromatography (eluent; chloroform-acetone-methanol=10:3:2 (v/v)), and the solvent for the solution containing the desired product was evaporated off under reduced pressure to obtain 1.4 g of a colorless oily compound.
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH3:10][NH2:11].[OH-].[Na+].[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>CC#N.O>[Cl:3][C:2]1[N:1]=[C:8]([N:18]2[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]2)[N:7]=[C:5]([NH:11][CH3:10])[N:4]=1
Reactant: CN
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CN1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CNc1nc(Cl)nc(N2CCN(C)CC2)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A mixture of cyanuric chloride (3.86 g, 20.9 mmol, 1 equivalent) in CH3CN/H2O (1/1, 200 ml) was cooled to 0° C. Methylamine solution in water (40% (w), 1.83 ml, 20.9 mmol, 1 equivalent) was added, followed by 1N NaOH (20.9 ml, 20.9 mmol, 1 equivalent). The reaction mixture was stirred at 0° C. for 15 min and LCMS showed the reaction had completed. At 0° C., N-methylpiperazine (2.3 ml, 20.9 mmol, 1 equivalent) was added, followed by 1N NaOH (4.2 ml, 0.2 equivalents). The solution turned to clear. The solvent was evaporated to give the crude product which was further purified with silica gel chromatography (eluant 70% B, solvent B is 10% MeOH in DCM with 1% Et3N) to give the product (1.8 g). 1H NMR (CDCl3, 400 MHz): δ2.33 (s, 3H), 2.44 (br, 4H), 2.95&2.96 (3H), 3.86 (br, 4H), 5.1&5.7 (br, 1H).
Reaction SMILES: Cl(O)(=O)(=O)=O.[CH3:6][O:7][C:8]1[N:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C@H:22]3[O:31][C@H:25]4[O:26]C(C)(C)[O:28][C@H:24]4[C@H:23]3[CH2:32][CH2:33][N:34]3[C:39](=[O:40])[C:38]4[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=4[N:36]=[N:35]3)=[CH:16][CH:15]=2)=[CH:10][CH:9]=1>C(#N)C.C(OCC)(=O)C.O>[OH:28][C@@H:24]1[C@H:25]([OH:26])[O:31][C@H:22]([CH2:21][CH2:20][C:17]2[CH:18]=[CH:19][C:14]([C:11]3[CH:12]=[N:13][C:8]([O:7][CH3:6])=[CH:9][CH:10]=3)=[CH:15][CH:16]=2)[C@@H:23]1[CH2:32][CH2:33][N:34]1[C:39](=[O:40])[C:38]2[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=2[N:36]=[N:35]1
Reactant: COc1ccc(-c2ccc(CC[C@H]3O[C@H]4OC(C)(C)O[C@H]4[C@H]3CCn3nnc4ccccc4c3=O)cc2)cn1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: COc1ccc(-c2ccc(CC[C@H]3O[C@@H](O)[C@@H](O)[C@H]3CCn3nnc4ccccc4c3=O)cc2)cn1
Temperature: 55 °C

Procedure:
Perchloric acid (4.8 mL) was added to a solution of the compound obtained from step c above (8.1 g) in acetonitrile (50 mL) and water (8 mL) at room temperature. The reaction mixture was heated to 55° C. for 30 minutes. The reaction mixture was then quenched using sodium bicarbonate solution. The solvents were evaporated under reduced pressure. The residue thus obtained was taken up in ethyl acetate and water. The organic layer was separated, washed with water and brine solution, and dried over anhydrous sodium sulphate. The solvent was concentrated under reduced pressure to yield the title compound (8 g).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[CH:14]=[N:15][C:16]([CH2:19][NH:20][C:21](=[O:25])[CH2:22][O:23][CH3:24])=[CH:17][CH:18]=3)[CH:12]=[C:6]2[C:5]=1[NH:26][C@H:27]1[C@@H:31]([CH2:32][CH3:33])[CH2:30][N:29](C(OCC2C=CC=CC=2)=O)[CH2:28]1)(=[O:3])[NH2:2].[Si]([I:48])(C)(C)C>C(#N)C>[IH:48].[IH:48].[CH2:32]([C@H:31]1[CH2:30][NH:29][CH2:28][C@H:27]1[NH:26][C:5]1[C:6]2[N:7]([CH:10]=[C:11]([C:13]3[CH:14]=[N:15][C:16]([CH2:19][NH:20][C:21](=[O:25])[CH2:22][O:23][CH3:24])=[CH:17][CH:18]=3)[CH:12]=2)[N:8]=[CH:9][C:4]=1[C:1]([NH2:2])=[O:3])[CH3:33]
Reactant: CC[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3ccc(CNC(=O)COC)nc3)cc12
Reactant: C[Si](C)(C)I
Solvent: CC#N
Product: CC[C@H]1CNC[C@H]1Nc1c(C(N)=O)cnn2cc(-c3ccc(CNC(=O)COC)nc3)cc12
Product: I
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 97.4 %

Procedure:
To a suspension of (3S,4S)-benzyl 3-((3-carbamoyl-6-(6-((2-methoxyacetamido)methyl)pyridin-3-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-4-ethylpyrrolidine-1-carboxylate (22 mg, 0.038 mmol) in Acetonitrile (1 mL) at 0° C. was added TMS-I (0.013 mL, 0.094 mmol) and after stirring 15 minutes at 0° C., the cooling bath was removed. At 3.5 hr, SM remained by HPLC. The reaction mixture was recooled to 0° C. and additional TMS-I (0.013 mL, 0.094 mmol) was added. After stirring 15 minutes at 0° C., the cooling bath was removed and the reaction mixture was stirred 2 hr at rt. The reaction mixture was recooled to 0° C. and 0.5 ml of MeOH was added. Stirring at 0° C. was continued for 30 minutes. At this time, the volatiles were removed in vacuo to afford crude 4-(((3S,4S)-4-ethylpyrrolidin-3-yl)amino)-6-(6-((2-methoxyacetamido)methyl)pyridin-3-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide, dihydroiodide (26 mg, 0.037 mmol, 98% yield) as a brown solid. The material was used as is in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]([N:13]([CH3:15])[CH3:14])=[O:12])=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>CC#N>[CH3:15][N:13]([CH3:14])[C:11](=[O:12])[CH2:10][N:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(NCC(=O)N(C)C)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN(CC(=O)N(C)C)c1ccc(OC)cc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 85.6 %

Procedure:
To a stirred solution of 2-(4-methoxyphenylamino)-N,N-dimethylacetamide (19) (10.7 g, 51.2 mmol) in MeCN (80 mL) and DIPEA (13.4 ml, 77 mmol) was added ethyl bromoacetate (6.84 ml, 61.4 mmol) the reaction was stirred at 60° C. for 16 h. The volatiles were removed in vacuo, and the crude mixture was dissolved in EtOAc (150 mL), washed with 1M HCl (aq.) (150 mL), brine (150 mL), dried (MgSO4), filtered and solvents removed in vacuo to afford a purple oil. The residue was purified by silica gel chromatography (120 g, 60-100% EtOAc in isohexane) to afford ethyl 2-((2-(dimethylamino)-2-oxoethyl)(4-methoxyphenyl)amino)acetate (X) (12.9 g, 85%) as a purple oil: m/z 295.4 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 6.81-6.71 (m, 2H), 6.60-6.47 (m, 2H), 4.24-3.96 (m, 6H), 3.66 (s, 3H), 2.99 (br s, 3H), 2.83 (br s, 3H), 1.19 (t, J=7.1 Hz, 3H).