Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH2:11][CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])[NH:9][N:8]=1.[C:19]([O:23][C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1[S:38][C:37]([C:39](O)=[O:40])=[CH:36][CH:35]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20].CCN=C=NCCCN(C)C>C(Cl)Cl>[OH:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH:10]1[N:9]([C:39]([C:37]2[S:38][C:34]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[CH2:27][NH:26][C:24](=[O:25])[O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:35][CH:36]=2)=[O:40])[N:8]=[C:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)[CH2:11]1
Reactant: Oc1ccccc1C1CC(c2cnccn2)=NN1
Reactant: CC(C)(C)OC(=O)NCc1ccccc1-c1ccc(C(=O)O)s1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1ccccc1-c1ccc(C(=O)N2N=C(c3cnccn3)CC2c2ccccc2O)s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 22.4 %

Procedure:
A solution of 2-(3-pyrazin-2-yl-4,5-dihydro-1H-pyrazol-5-yl)phenol (0.10 g, 4.2 mmol), 5-(2-([(tert-butoxycarbonyl)amino]methyl)phenyl)thiophene-2-carboxylic acid (0.134 g, 4.02 mmol), and EDCI (0.116 g, 6.06 mmol) in DCM (4 mL) was allowed to stir at rt for 6 h. The reaction was quenched by the addition of water and the organic and aqueous solutions were separated. The aqueous solution was extracted with EtOAc. The organic solutions were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give tert-butyl [2-(5-{[5-(2-hydroxyphenyl)-3-pyrazin-2-yl-4,5-dihydro-1H-pyrazol-1-yl]carbonyl}-2-thienyl)benzyl]carbamate (0.50 g, 23%). LCMS: (FA) ES+ 556.2.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:9][N:8]([C:10](=[O:22])[CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][NH:17][C@@H:16]([CH3:20])[C:15]2=[O:21])[CH2:7][CH2:6][C:3]21[CH2:5][CH2:4]2.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][C:25]=1[O:33][C:34]([F:37])([F:36])[F:35]>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][CH2:11][C:10]([N:8]3[CH2:7][CH2:6][C:3]4([CH2:5][CH2:4]4)[C@H:2]([OH:1])[CH2:9]3)=[O:22])[C:15](=[O:21])[C@@H:16]2[CH3:20])=[O:32])=[CH:26][C:25]=1[O:33][C:34]([F:35])([F:37])[F:36]
Reactant: C[C@@H]1NCCN(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)C1=O
Reactant: O=C=Nc1ccc(Cl)c(OC(F)(F)F)c1
Product: C[C@H]1C(=O)N(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)CCN1C(=O)Nc1ccc(Cl)c(OC(F)(F)F)c1
Yield: 67 %

Procedure:
In analogy to the procedure described in Example 30, (S)-1-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-4-oxo-butyl]-3-methyl-piperazin-2-one (intermediate 13) and 1-chloro-4-isocyanato-2-trifluoromethoxy-benzene (intermediate 18) gave the titled compound in 67% yield as light brown foam. MS: 547.19 (MH+, 1Cl).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][OH:5].[H-].[Na+].Cl[C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([F:19])=[CH:12][N:11]=1.O>O1CCCC1>[CH3:1][O:2][C:3](=[O:6])[CH2:4][O:5][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([F:19])=[CH:12][N:11]=1
Reactant: COC(=O)CO
Reactant: O=[N+]([O-])c1cc(F)cnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)COc1ncc(F)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 66 %

Procedure:
Hydroxy-acetic acid methyl ester (0.96 g, 10.7 mmol) was dissolved in 2 ml of anhydrous tetrahydrofuran under nitrogen atmosphere, and sodium hydride (0.42 g, 10.7 mmol) was added thereto at room temperature. After stirring for 30 minutes, 2-chloro-5-fluoro-3-nitro-pyridine (1.57 g, 8.89 mmol) dissolved in 15 ml of anhydrous tetrahydrofuran was added dropwise at room temperature, and the reaction mixture was stirred at room temperature for 18 hours. After completion of the reaction by adding water, the mixture was extracted with dichloromethane, and the combined organic layer was washed with water and saturated saline solution, dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of n-hexane:ethyl acetate=9:1. The fractions containing the product were collected and evaporated to obtain (5-fluoro-3-nitro-pyridin-2-yloxy)-acetic acid methyl ester as yellow liquid (1.35 g, 66%).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][C:17]1([CH3:32])[C@@H:19](/[CH:20]=[CH:21]\[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C@H:18]1[C:29]([OH:31])=[O:30].[O:33]([C:40]1[N:45]=[C:44]([CH:46](O)[CH3:47])[CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:16][C:17]1([CH3:32])[C@@H:19](/[CH:20]=[CH:21]\[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[C@H:18]1[C:29]([O:31][CH:46]([C:44]1[CH:43]=[CH:42][CH:41]=[C:40]([O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:45]=1)[CH3:47])=[O:30]
Reactant: CC(O)c1cccc(Oc2ccccc2)n1
Reactant: CC(C)(C)OC(=O)/C=C\[C@H]1[C@@H](C(=O)O)C1(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(OC(=O)[C@@H]1[C@H](/C=C\C(=O)OC(C)(C)C)C1(C)C)c1cccc(Oc2ccccc2)n1
Temperature: 20 °C
Reaction time: 4 h
Yield: 85.3 %

Procedure:
A solution of 55.7 g of dicyclohexylcarbodiimide, 2.6 g of 4-dimethylamino-pyridine and 450 ml of methylene chloride were added over 25 minutes at 0° C. to a mixture of 65 g of (1R,cis,Z)2,2-dimethyl-3-[3-oxo-3-tert.-butoxy-1-propenyl]-cyclopropane-carboxylic acid, 70 g of (RS)1-(6-phenoxy-2-pyridyl)-ethanol and 650 ml of methylene chloride and the mixture was stirred at 20° C. for 4 hours and was vaccum filtered. The filtrate was evaporated to dryness and the residue was chromatographed over silica gel. Elution with and 100-4 n-hexane-ethyl acetate mixture yielded 101 g of (RS)1-(6-phenoxy-2-pyridyl)-ethyl(1R,cis,Z)2,2-dimethyl-3-[3-oxo-3-tert.-butoxy-1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+64° (c=1% in toluene).
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:9][C:8]1([NH:19][C:20]([O:22][CH3:23])=[O:21])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)(=O)=O.[C-:24]#[N:25].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CS(C)=O>[C:24]([CH2:6][CH:7]1[CH2:9][C:8]1([NH:19][C:20](=[O:21])[O:22][CH3:23])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)#[N:25]
Reactant: [C-]#N
Reactant: COC(=O)NC1(c2cccc([N+](=O)[O-])c2)CC1COS(C)(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)NC1(c2cccc([N+](=O)[O-])c2)CC1CC#N
Temperature: 23 °C
Reaction time: 18 h
Yield: 63.8 %

Procedure:
A mixture of ((1RS,2SR)-2-(methoxycarbonylamino)-2-(3-nitrophenyl)cyclopropyl)methyl methanesulfonate (intermediate B8a) (4.53 g, 13.2 mmol, Eq: 1.00), potassium cyanide (1.11 g, 17.1 mmol, Eq: 1.3) and tetrabutylammonium iodide (486 mg, 1.32 mmol, Eq: 0.1) in DMSO (13 ml) was stirred at 23° C. for 18 h. Poured into ice water, extracted with EtOAc, washed organic layer with brine, reextracted combined aqueous layer with EtOAc, dried combined organic layer over Na2SO4. Removal of the solvent in vacuum left a dark brown oil (8370-1/1; HPLC 1.775 min 60%, 2.070 min 27%, 2.262 min 13%). The crude material was purified by flash chromatography (silica gel, 50 g, 0% to 60% EtOAc in heptane) to give the methyl (1SR,2SR)-2-(cyanomethyl)-1-(3-nitrophenyl)cyclopropylcarbamate (2.318 g, 8.42 mmol, 64.0% yield) as a yellow gum. MS (ISP): m/z=276.1 [(M+H)+].
Reaction SMILES: [CH3:1][N:2]([CH3:18])[S:3]([NH:6][C:7](=[O:17])[C:8]1[CH:13]=[C:12]([F:14])[C:11]([CH3:15])=[CH:10][C:9]=1[F:16])(=[O:5])=[O:4].[Br:19]N1C(=O)CCC1=O>ClCCCl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:19][CH2:15][C:11]1[C:12]([F:14])=[CH:13][C:8]([C:7]([NH:6][S:3]([N:2]([CH3:1])[CH3:18])(=[O:5])=[O:4])=[O:17])=[C:9]([F:16])[CH:10]=1
Reactant: Cc1cc(F)c(C(=O)NS(=O)(=O)N(C)C)cc1F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCCl
Product: CN(C)S(=O)(=O)NC(=O)c1cc(F)c(CBr)cc1F
Temperature: 25 °C

Procedure:
A mixture of N-[(dimethylamino)sulfonyl]-2,5-difluoro-4-methylbenzamide (Preparation 2, 0.50 g, 1.80 mmol), N-bromosuccinimide (freshly recrystallised and dried, 0.42 g, 2.34 mmol) and azobisisobutyronitrile (14.8 mg, 0.09 mmol) in 1,2-dichloroethane (15 mL) was heated under reflux with stirring whilst being irradiated with light from a 100 watt lamp. After 6 hours more N-bromosuccinimide (300 mg, 1.69 mmol) and azobisisobutyronitrile (10 mg, 0.06 mmol) were added and the mixture heated for a further 4 hours. An additional amount of N-bromosuccinimide (100 mg, 0.56 mmol) was then added and the mixture heated under reflux for a further 4 hours. The reaction mixture was cooled to room temperature and evaporated in vacuo to leave a pale yellow oil (0.54 g). Purification by silica gel column chromatography eluting with ethyl acetate/heptane 0:100-1:4 afforded the title compound (0.176 g, 27%) as a colourless oil which solidified on standing.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:20][O:21][CH:22]([C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=2)[C:23]([O:25]C)=[O:24])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].O>CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:20][O:21][CH:22]([C:27]2[CH:32]=[C:31]([C:33]([F:35])([F:34])[F:36])[CH:30]=[C:29]([C:37]([F:40])([F:38])[F:39])[CH:28]=2)[C:23]([OH:25])=[O:24])([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(OCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(COC(C(=O)O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 2-[1(-tert-butoxycarbonyl4-phenylpiperidin4-yl)methoxy]-2-(3,5-bis(trifluoromethyl)phenyl)acetate (11 g, 0.019 mol) in methanol (100 ml) at 0° C. was added potassium hydroxide (3.2 g, 5.7 mmol), followed by water (3 ml). The homogeneous solution was stirred at 0° C. for 1 hour. The methanol was removed in vacuo and pH4 buffer (100 ml) added to the residue. The product was extracted into diethyl ether (2×100 ml), the combined ethereal solutions dried (MgSO4), filtered and evaporated in vacuo. The resulting white foam was used without further purification.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([N:22]1[CH2:21][C@@H:20]([CH3:25])[N:16]2[C:17]3[CH:18]=[CH:19][C:11]([O:10][CH:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[CH:12][C:13]=3[CH:14]=[C:15]2[C:23]1=[O:24])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CNC2=O)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CN(Cc3ccccc3)C2=O)CC1
Yield: 58 %

Procedure:
The title compound was synthesized in analogy to example 17, from (R)-8-(1-isopropyl-piperidin-4-yloxy)-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 8), sodium hydride and benzyl bromide, to give the desired product as a light yellow solid (58%).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][C@@H:27]4[CH2:32][CH2:31][NH:30][CH2:29][C@H:28]4[OH:33])=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][C@@H:27]4[CH2:32][CH2:31][N:30]([C:34](=[O:37])[CH2:35][CH3:36])[CH2:29][C@H:28]4[OH:33])=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1
Reactant: CCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ccnc2c1C(=O)N[C@@H]1CCNC[C@H]1O
Agent: Cl
Product: CCC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)ccc4OCC4CC4)ccnc23)[C@H](O)C1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-fluorophenyl]-N-[(3R*,4R*)-3-hydroxypiperidin-4-yl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f10) and commercially propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][CH2:7][CH2:8][CH2:9][N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20])=[O:2].[CH2:24](O)[CH2:25][OH:26]>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:2]1[CH2:24][CH2:25][O:26][CH:1]1[C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][CH2:7][CH2:8][CH2:9][N:10]1[C:11](=[O:20])[C:12]2=[CH:19][CH:18]=[CH:17][CH:16]=[C:13]2[C:14]1=[O:15]
Reactant: OCCO
Reactant: O=Cc1cccc(OCCCN2C(=O)c3ccccc3C2=O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: O=C1c2ccccc2C(=O)N1CCCOc1cccc(C2OCCO2)c1
Yield: 112.6 %

Procedure:
To a solution of N-[3-(3-formylphenoxy)propyl]phthalimide (92.8 g, 0.3 mole), ethylene glycol (44 mL, 0.8 mole) in benzene (1.5 L) was added 3 g of p-toluenesulfonic acid and the mixture was refluxed under a Dean-Stark trap for 14 hours. The cooled mixture was extracted with 100 mL of saturated aqueous sodium bicarbonate and then with 200 mL of saturated aqueous sodium chloride. The organic phase was dried and evaporated under reduced pressure to give 119.4 g of the title compound which crystallized on standing.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH2:1]([O:8][C:9]1[C:14]2[N:15]=[C:16]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CNCCN1
Reactant: O=S1CCN(c2nc(Cl)nc3c(OCc4ccccc4)ncnc23)CC1
Product: O=S1CCN(c2nc(N3CCNCC3)nc3c(OCc4ccccc4)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 1 from 8-benzyloxy-2-chloro-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 227°-229° C.) and piperazine.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C[Al](C)C.[F:14][C:15]1[CH:24]=[C:23]2[C:18]([C:19]([OH:30])=[C:20]([C:25](OCC)=[O:26])[CH:21]=[N:22]2)=[CH:17][CH:16]=1.Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:25]([C:20]2[CH:21]=[N:22][C:23]3[C:18]([C:19]=2[OH:30])=[CH:17][CH:16]=[C:15]([F:14])[CH:24]=3)=[O:26])=[CH:4][CH:3]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2cc(F)ccc2c1O
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2cc(F)ccc2c1O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a 0° C. solution of 4-chlorobenzylamine (0.52 mL) in 5 mL of toluene is added 2.13 mL of a 2.0 M solution of trimethylaluminum in toluene. The solution is stirred for 5 min at 0° C. and then a suspension of 0.50 g of ethyl 7-fluoro-4-hydroxy-3-quinolinecarboxylate (J. Med. Chem., 20, 1001 (1977)) in 5 mL of toluene is added. The solution is stirred at 0° C. for an additional 10 min and then it is stirred 18 h at 90° C. The mixture is cooled to 25° C. and it is poured onto a mixture of a large excess of 3 M hydrochloric acid and ice. After stirring the mixture vigorously for 30 min it is filtered. The solid is dissolved in 50 mL of warm glacial acetic acid and distilled water is added to the resulting solution until it is cloudy. The mixture is then allowed to stand for several hours at 5° C. Filtration of this mixture gives the desired amide as 150 mg of a solid.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.CS(C)=O.[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O>[CH2:30]([NH:37][CH2:12][C@@H:13]1[O:18][C:17]2[CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:16]=2[O:15][CH2:14]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3ccc([N+](=O)[O-])cc3O2)cc1
Reactant: NCc1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc2c(c1)O[C@@H](CNCc1ccccc1)CO2
Temperature: 90 °C
Reaction time: 18 h

Procedure:
A 3 L three necked flask equipped with a heating mantle, thermocouple and mechanical stirrer is charged with [7-nitro-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (356.8 g, 0.977 mol), DMSO (1 L) and benzylamine (261.7 g, 2.44 mol). The slurry is heated to maintain an internal temperature of 90° C. Heating is continued for 18 h, and then the solution is allowed to cool to 30° C. over 2 h. Water (400 mL) is added over 15 min. then seed crystals (˜100 mg) are added resulting in rapid formation of a precipitate. The slurry is stirred for 30 min prior to additional water (2 L) being added over 1.5 h. The slurry is stirred for 4 h, the solids are collected by vacuum filtration, washed with water (2 L) and suction dried under nitrogen giving the title compound (302.87 g, 103%) as a yellow powder (94% ee). Yield is high due to trapped water, m.p. 98° C. (dried sample). LCMS (Basic Method): 2.05 min, 301 (M+H)+. 1H NMR (300 MHz, DMSO-d6) δ 7.77-7.70 (m, 1H), 7.47-7.18 (m, 6H), 7.10-7.06 (m, 1H), 4.47 (dd, J=2.5, 11.5 Hz, 1H), 4.37-4.29 (m, 1H), 4.15 (dd, J=7.1, 11.5 Hz, 1H), 3.73 (s, 2H), 2.82-2.70 (m, 2H), 2.43 (br s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:17](N)=[C:16](Cl)[N:15]=[C:14](C(C)C)[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:23]([NH2:25])[CH3:24]>C(O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([NH:25][CH2:23][CH3:24])[N:15]=[C:14]([NH:1][CH:2]([CH3:7])[CH3:3])[N:13]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)c1nc(Cl)c(N)c(NS(=O)(=O)c2ccc(N)cc2)n1
Reactant: CCN
Solvent: CCO
Product: CCNc1cc(NS(=O)(=O)c2ccc(N)cc2)nc(NC(C)C)n1
Temperature: 130 °C
Reaction time: 4 h
Yield: 85.7 %

Procedure:
0.1 g (0.000293 mol) of 4-amino-N-(6-chloro-2-isopropyl-amino-pyrimidin-4-yl)-benzenesulfonamide was dissolved in 20 ml of ethanol, treated with 1.93 ml (0.0293 mol) of ethylamine and stirred in an autoclave at 130° C. for 4 hours. The reaction mixture was freed from solvent, the residue was suspended in 5 ml of ethanol and treated in an ultrasound bath for 15 min. The precipitate was filtered off, dissolved in 10 ml of 0.1N NaOH and filtered. The filtrate was adjusted to pH 6 with 0.1N HCl. The precipitate was filtered off under suction, washed with water and dried. There was obtained 0.044 g (43%) of 4-amino-N-(6-ethylamino-2-isopropylamino-pyrimidin-4-yl)-benzenesulfonamide as white crystals; m.p.: 266-267° C.
Reaction SMILES: [CH2:1]([S:3][CH:4]1[N:7]([CH:8](O)[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[O:10])[C:6](=[O:23])[CH:5]1[CH2:24][CH2:25][O:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1)=[O:28])[CH3:2].N1C(C)=CC=CC=1C.S(Cl)([Cl:50])=O>O1CCCC1>[CH2:1]([S:3][CH:4]1[N:7]([CH:8]([Cl:50])[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[O:10])[C:6](=[O:23])[CH:5]1[CH2:24][CH2:25][O:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1)=[O:28])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCSC1C(CCOC(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)N1C(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Product: CCSC1C(CCOC(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)N1C(Cl)C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of 11.3 g p-nitrobenzyl 2(4-ethylthio-3-p-nitrobenzyloxycarbonyloxyethyl-2-oxo-1-azetidinyl)-2-hyroxyacetate and 3.02 ml 2,6-lutidine in 175 ml anhydrous tetrahydrofuran was cooled to 0° C. under a nitrogen atmosphere. Thionyl chloride (1.75 ml) was added dropwise and the resulting mixture was stirred at 0° C. for 20 min. The mixture was filtered through Supercel and the filtrate was concentrated in vacuo. The concentrate was dissolved in methylene chloride and the resulting solution was washed successively with 200 ml 1N aqueous hydrochloric acid, 200 ml saturated aqueous sodium bicarbonate solution and 200 ml saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo to an oil (11.6 g) of the title compound. The NMR spectrum of the title compound in deuterochloroform showed peaks at 1.04-1.6 (c, 6H); 2.6 (m, 2H); 3.4 (m, 1H); 4.8-5.4 (c, 6H); 5.85, 5.9, 5.98, 6.1 (s, 1H); 7.5 (m, 4H); 8.2 (m, 4H) ppm.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[Br:14]Br>C(O)(=O)C.C(OCC)(=O)C>[Br:14][C:3]1[C:4]2[CH:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[CH:7]=[CH:6][C:5]=2[S:1][CH:2]=1
Reactant: COC(=O)c1ccc2sccc2c1
Reactant: BrBr
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1ccc2scc(Br)c2c1
Reaction time: 2 h
Yield: 85.3 %

Procedure:
To a solution of methyl 1-benzothiophene-5-carboxylate (5.15 g, 26.8 mmol) in acetic acid (50 mL) was added dropwise bromine (2.06 mL, 40.2 mmol) at room temperature, and the resulting mixture was stirred for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M aqueous sodium sulfite solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1), and crystallized from hexane/ethyl acetate to give the title compound (6.20 g, yield 85%) as colorless crystals.
Reaction SMILES: [BH4-].[Na+].[NH2:3][C:4]1[N:9]=[C:8]([CH3:10])[C:7]([CH:11]=[O:12])=[C:6]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:5]=1>CO>[NH2:3][C:4]1[N:9]=[C:8]([CH3:10])[C:7]([CH2:11][OH:12])=[C:6]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:5]=1
Reactant: CCCCCNc1nc(N)nc(C)c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCCNc1nc(N)nc(C)c1CO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium borohydride (0.6 g) was added to a solution of the product from step (ii) (2 g) in MeOH (30 ml) at 0-5° C. The mixture was warmed to rt, stirred for 3 h then the solvent evaporated under reduced pressure. The residue was partitioned between EtOAc and brine, the organics separated, dried and evaporated under reduced pressure to afford the subtitle compound, 1.78 g.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]#[N:15])=[CH:12][N:11]=[C:10]([NH:16][C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][N:21]=[CH:20]4)[N:9]=2)=[CH:4][N:3]=1.[CH3:26][N:27]([CH3:33])[C@@H:28]1[CH2:32][CH2:31][NH:30][CH2:29]1>>[C:14]([C:13]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:30]3[CH2:31][CH2:32][C@@H:28]([N:27]([CH3:33])[CH3:26])[CH2:29]3)=[N:3][CH:4]=2)=[N:9][C:10]([NH:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][N:21]=[CH:20]3)=[N:11][CH:12]=1)#[N:15]
Reactant: CN(C)[C@@H]1CCNC1
Reactant: N#Cc1cnc(Nc2ccc3[nH]ncc3c2)nc1-c1ccc(Cl)nc1
Product: CN(C)[C@@H]1CCN(c2ccc(-c3nc(Nc4ccc5[nH]ncc5c4)ncc3C#N)cn2)C1

Procedure:
4-(2-Chloropyridin-5-yl)-5-cyano-N-(indazol-5-yl)pyrimidine-2-amine (522 mg, 1.5 mmol) and 3-(R)-dimethylaminopyrrolidine were heated together at 140° in a sealed flask for 2 h. On cooling the reaction mixture was triturated with water to give a brown solid which was collected and subjected to column chromatography (silica gel; 1% triethylamine-10% methanol-89% dichloromethane) to give the title compound (417 mg) as a yellow solid m.p.249-250°. δH (d6DMSO) 13.00 (1H, br s), 10.32 (1H, s), 8.81 (2H, d, J 9.2 Hz), 8.15-8.12 (2H, m), 8.04 (1H, s), 7.59 (1H, m), 7.52 (1H, d, J 9.8 Hz), 6.63 (1H, d, J 9.0 Hz), 3.77-3.67 (2H, m), 3.41-3.24 (2H, m), 2.82 (1H, br m), 2.22 (6H, s), 2.21 (1H, m) and 1.84 (1H, m).