Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH3:17])[C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[F:18][C:19]([F:33])([F:32])[C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH:23]=O.O>CO>[F:18][C:19]([F:32])([F:33])[C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:27]=1)[CH2:23][NH:1][C@@H:2]([CH3:17])[C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4]
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C[C@H](N)[C@H](O)c1ccc(O)c(NS(C)(=O)=O)c1
Solvent: CO
Solvent: O
Product: C[C@H](NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H](O)c1ccc(O)c(NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.2 %

Procedure:
To a solution of the amine (4) (107 mg, 0.41 mmol) and 3,5-bis(trifluoromethyl)benzaldehyde (90 μL, 0.54 mmol) in methanol (4 mL) was added borane-pyridine complex (130 μL, 1.24 mmol) at 40° C. and the resulting mixture was stirred for 1.5 hours. The reaction mixture was cooled to room temperature and water was added thereto, followed by extraction with a mixed solvent (ethyl acetate:methanol=10:1) and subsequent washing of the organic layer with saturated brine. The organic layer was dried and concentrated and the obtained crude product was purified by amine silica gel column chromatography (eluent; chloroform:methanol=7:1) to obtain the desired amine (6) as a white solid (132 mg, Yield: 66%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]2[C:8](=[O:16])[C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[S:11][CH:4]2[CH2:3]1.[C:17]1([Li])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CCOCC>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]2[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([OH:16])[C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[S:11][CH:4]2[CH2:3]1
Reactant: [Li]c1ccccc1
Reactant: CN1CCC2C(=O)c3ccccc3SC2C1
Solvent: O
Solvent: CCOCC
Product: CN1CCC2C(C1)Sc1ccccc1C2(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.4 %

Procedure:
40 g of 1,2,3,4,4a,10a-hexahydro-2-methyl-5H-[1]-benzothiopyrano[2,3-c]pyridin-5-one were dissolved in 2 liters of dry ether and the solution obtaining was cooled to 5° C. in an ice bath while 220 ml (2 moles) of phenyl lithium were added dropwise thereto over 30 minutes with the temperature held below 0° C. When the addition was complete, the ice bath was removed and the solution thus obtained was stirred at room temperature for 30 minutes. 3 liters of water were added dropwise thereto and the resultant suspension was stirred vigorously for 2 hours and then was filtered. The product was washed with water and ether and was dried to obtain 20.5 g of 2-methyl-5-phenyl-1,3,4,4a,5,10a-hexahydro-2H[1]benzothiopyrano[2,3-c]pyridin-5-ol (37% yield) melting at 176°-181° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([NH2:12])[C:8]([NH2:11])=[CH:9][CH:10]=1)=[O:4].N1C=CC=CC=1.[C:19]([C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>C(#N)C>[C:19]([C:23]1[CH:24]=[CH:25][C:26]([C:27]([NH:12][C:7]2[C:8]([NH2:11])=[CH:9][CH:10]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=2)=[O:28])=[CH:30][CH:31]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: COC(=O)c1ccc(N)c(N)c1
Solvent: c1ccncc1
Solvent: CC#N
Product: COC(=O)c1ccc(N)c(NC(=O)c2ccc(C(C)(C)C)cc2)c1
Reaction time: 3 h

Procedure:
To a stirring solution of 4-methoxycarbonyl-1,2-benzenediamine (8.5 g, 51 mmol) and pyridine (4.1 mL, 51 mmol) in acetonitrile (225 mL) at 0° C. was added via an addition funnel a solution of 4-t-butylbenzoyl chloride (10 g, 51 mmol) in acetonitrile (25 mL). After 3 h, the mixture was concentrated to a volume of about 20 mL in vacuo and then diluted with ethyl acetate (300 mL) and water (100 mL). The phases were separated and the organic phase was washed twice with 1 M citric acid, once with brine, twice with satd aq NaHCO3 and once again with brine. The organic phase was then dried with MgSO4, filtered and partially concentrated in vacuo. After standing for 48 h, the resulting precipitate was filtered, washed with ethyl acetate and dried in vacuo to give 8.2 g (48%) of off white solid. By a similar procedure, a second crop of 2.6 g (16%) was isolated from the mother liquor.
Reaction SMILES: [C:1](Cl)(=O)C(Cl)=O.[CH:7]1[C:17]2[CH:16]=[CH:15][C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[C:12](=[CH:22][C:23]([OH:25])=[O:24])[C:11]=2[CH:10]=[CH:9][CH:8]=1>C1C=CC=CC=1>[CH3:1][O:24][C:23](=[O:25])[CH:22]=[C:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:17]=2[CH:16]=[CH:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]1=2
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C=C1c2ccccc2C=Cc2ccccc21
Solvent: c1ccccc1
Product: COC(=O)C=C1c2ccccc2C=Cc2ccccc21

Procedure:
Oxalyl chloride (2.665 g., 1.79 ml., 0.021 mole) is added to a suspension of (5H-dibenzo[a,d]cyclohepten-5-ylidene)acetic acid (5.000 g., 0.020 mole) in dry benzene (70 ml.). An exothermic reaction occurs and the solid gradually dissolves. After solution is complete, the mixture is refluxed for one hour, then concentrated in vacuo to give an amber oil which crystallizes on storage at ambient temperature. The yield of crude ester melting at 83.5°-84.5° C. (uncorr.) is 5.210 g. (99.31%). Recrystallization of the material from methanol affords colorless rods melting at 86.0°-86.5° C. (uncorr.) in a yield of 3.508 g. (66.86%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.[C:17]1([CH:23]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:24][CH:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][NH2:34])[CH2:27][CH2:26]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)C(C)C)C.C(=O)([O-])O.[Na+]>C(O)CCC>[C:35]1([CH:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:24][CH:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][NH:34][C:2]3[CH:3]=[CH:4][C:5]4[N:6]([N:8]=[C:9]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)[N:10]=4)[N:7]=3)[CH2:27][CH2:26]2)[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: Clc1ccc2nc(-c3ccccc3)nn2n1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(-c2nc3ccc(NCCCN4CCC(OC(c5ccccc5)c5ccccc5)CC4)nn3n2)cc1
Temperature: 0 °C
Yield: 37.6 %

Procedure:
365 mg of 6-chloro-2-phenyl[1,2,4]triazolo[1,5-b]pyridazine and 0.513 g of 4-(diphenylmethoxy)-1-piperidinepropanamine were suspended in 8 ml of n-butanol; 0.54 ml of N-ethyldiisopropylamine was added, followed by heating and refluxing for 19 hours. Ice water and sodium hydrogen carbonate were added, followed by extraction with ethyl acetate; the extract was washed with saturated saline and dried with magnesium sulfate. After the dry product was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (50:5:1). The desired fraction was collected and concentrated; the resulting crystal was recrystallized from ethyl acetate to yield 308 mg of the title compound.
Reaction SMILES: O.[CH2:2]([NH2:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:12]([CH2:16][CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21])([O:14]C)=[O:13].[OH-].[Na+]>CCOCC>[CH2:2]([NH:11][C:20](=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][C:12]([OH:14])=[O:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: COC(=O)CCCCC(=O)Cl
Reactant: CCCCCCCCCN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CCCCCCCCCNC(=O)CCCCC(=O)O

Procedure:
A two liter beaker fitted with a mechanical stirrer, ice bath, and pH electrode, was charged with 700 mL of water and 89.4 g (0.624 mol) of nonylamine in 200 mL of ether. To this stirred mixture was added dropwise over a 30 minute period a solution of the above 5-carbomethoxyvaleryl chloride in 100 mL of ether. Concurrent with addition of the ether solution was added 50% sodium hydroxide solution at a rate such as to keep the pH of the aqueous layer between 10 and 12. Following addition of the acid chloride and sodium hydroxide the reaction mixture was added to a two L separatory funnel and extracted with 300 mL methylene chloride. The methylene chloride layer was separated, washed with 300 mL saturated sodium chloride solution, and dried over magnesium sulfate. Removal of the methylene chloride on a rotary evaporator yielded a yellow oil which solidified upon standing. Recrystallization from hexane afforded the methylester of 6-nonylamino-6-oxocaproic acid as colorless crystals, mp 56°-57° C., weight 155.1 g. Upon cooling to -15° C. the filtrate deposited an additional 11.0 of product. Total yield was 166.1 g (93%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[CH3:10][Si:11]([CH3:27])([CH3:26])[C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17]2.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:10][Si:11]([CH3:26])([CH3:27])[C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[N:19]([CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[CH:3]=1)[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17]2
Reactant: CCOC(=O)c1cc2cccc([Si](C)(C)C)c2[nH]1
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc2cccc([Si](C)(C)C)c2n1Cc1cccc(F)c1
Yield: 63.2 %

Procedure:
0.42 ml (3.44 mmol) of 3-fluorobenzyl bromide is added, slowly at ambient temperature, to a suspension of 0.75 g (2.87 mmol) of ethyl 7-trimethylsilyl-1H-indole-2-carboxylate, obtained according to the protocol described in stage 5.1, and of 1.18 g (8.61 mmol) of potassium carbonate in 50 ml of dry acetonitrile, maintained under an inert atmosphere. The reaction mixture is stirred at reflux for 18 h. After this period of time, the cooled suspension is filtered through a frit and then rinsed with acetonitrile. The reaction crude obtained after evaporation of the filtrate under reduced pressure is purified by flash chromatography on a silica gel column, elution being carried out with a gradient of 10 to 50% of dichloromethane in heptane. 0.67 g of the expected ethyl 7-trimethylsilyl-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylate is thus isolated.
Reaction SMILES: [FH:1].N[C:3]1[C:4]([O:10][C:11]2[CH:23]=[CH:22][C:14]([O:15][CH:16]([CH3:21])[C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=2)=[N:5][CH:6]=[C:7]([Cl:9])[CH:8]=1.[N+]([O-])([O-])=O.[Na+]>>[Cl:9][C:7]1[CH:8]=[C:3]([F:1])[C:4]([O:10][C:11]2[CH:23]=[CH:22][C:14]([O:15][CH:16]([CH3:21])[C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=2)=[N:5][CH:6]=1
Reactant: F
Reactant: COC(=O)C(C)Oc1ccc(Oc2ncc(Cl)cc2N)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Product: COC(=O)C(C)Oc1ccc(Oc2ncc(Cl)cc2F)cc1
Temperature: 55 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
A vessel is charged with 400 g (20 moles) of hydrogen fluoride and 167.4 g (0.518 mole) of methyl 2-[4-(3-amino-5-chloropyridin-2-yloxy)phenoxy]propionate are added in portions at a temperature from -8° to 0° C. 37.3 g (0.540 mole) of sodium nitrate are added over one hour and the mixture is stirred for two hours before it is slowly heated in an autoclave to 55° C. Excess hydrogen fluoride is removed by distillation and the residue is taken up in a mixture of 200 ml of methylene chloride and ice-water and the solution is neutralised with concentrated ammonia. The neutralised solution is extracted three times with methylene chloride and the organic extracts are washed with water, dried and concentrated by evaporation, affording 81.0 g (48% of theory) of methyl 2-[4-(5-chloro-3-fluoropyridin-2-yloxy)phenoxy]propionate with a melting point of 63°-64°.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[OH:28][CH2:29][CH2:30][N:31]([CH2:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1)[CH3:32]>>[OH:28][CH2:29][CH2:30][N:31]([CH2:33][C:34]1[CH:35]=[CH:36][C:37]([NH:38]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:39][CH:40]=1)[CH3:32]
Reactant: CN(CCO)Cc1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN(C)CCO)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-((N-(2-hydroxy-ethyl)-N-methyl-amino)-methyl)-aniline Rf value: 0.5 (aluminium oxide, methylene chloride/ethanol=40:1) C27H27N3O4
Reaction SMILES: [F:1][C:2]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[C:5]([NH2:13])=[CH:4][CH:3]=1.[C:14]([O:18][C:19]([NH:21][C@@H:22]([CH3:26])[C:23](O)=[O:24])=[O:20])([CH3:17])([CH3:16])[CH3:15].C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:14]([O:18][C:19](=[O:20])[NH:21][C@H:22]([C:23](=[O:24])[NH:13][C:5]1[C:6]2[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[C:2]([F:1])=[CH:3][CH:4]=1)[CH3:26])([CH3:15])([CH3:16])[CH3:17]
Reactant: Nc1ccc(F)c2c1NCCCC2
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)c2c1NCCCC2
Temperature: 0 °C
Yield: 71 %

Procedure:
To an ice-cooled mixture of 6-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-9-ylamine=(195 mg, 1.0826 mmol), (S)-2-tert-butoxycarbonylaminopropionic acid (225 mg, 1.19 mmol) and HOAt (147 mg, 1.083 mmol) in DCM (10 mL) was added EDCI HCl (249 mg, 1.3 mmol). The reaction mixture was stirred in the ice bath for 2 h, then diluted with DCM, washed with aqueous Na2CO3 and then water. The organic layer was dried (Na2SO4) and then concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 20-50% EtOAc in cyclohexane) affording the title compound as a pink gum (270.6 mg, 71%). LCMS (Method J): RT 3.26 min [M+H]+ 352
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:11])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[CH3:12][C:13]([CH3:18])([CH3:17])[C:14](Cl)=[O:15]>N1C=CC=CC=1>[CH3:12][C:13]([CH3:18])([CH3:17])[C:14]([NH:1][C:2]1[NH:3][C:4](=[O:11])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1)=[O:15]
Reactant: Nc1nc2[nH]ccc2c(=O)[nH]1
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1nc2[nH]ccc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
A solution of 2-amino-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one (186 g, 1.23 mol) in pyridine (2 L) was treated with trimethylacetyl chloride (475 g, 3.94 mol, 485 mL, 3.2 eq) at 90° C. for 2 h, to give a mixture of N(2)-monoacylated and N(2), N(7)-bisacylated material. The solvent was evaporated and the residue was taken up in aqueous ammonia (37% NH3, 310 mL) and MeOH (2 L), and stirred at rt for 30 min, to selectively cleave the N(7)-pivaloyl group. The solid was collected by filtration, washed with water (500 mL×5), and dried on high vacuum to give the title compound as a solid (193 g). Concentration of the mother liquor provided additional solid material, which was collected, washed with water (50 mL×5), and dried (77 g). The combined yield was 93% (HPLC purity 98.6% ). tR: 4.57 min. 1H-NMR (DMSO-d6) δ 12.00, (br. s, 1H), 7.40 (br. s, 1H), 6.96 (q, 1H), 6.40 (q, 1H), 1.24 (s, 9H).
Reaction SMILES: BrC1SC(N[C:8](=[O:10])C)=NN=1.[NH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21]2[N:25]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:24]3[CH:34]=[CH:35][CH:36]=[CH:37][C:23]=3[N:22]=2)[CH2:16][CH2:15]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[F:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][N:25]2[C:24]3[CH:34]=[CH:35][CH:36]=[CH:37][C:23]=3[N:22]=[C:21]2[NH:20][CH:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][NH:11][CH:8]=[O:10])[CH2:15][CH2:16]2)=[CH:28][CH:29]=1
Reactant: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: CC(=O)Nc1nnc(Br)s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=CNCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reaction time: 8 h

Procedure:
A mixture of 4.4 parts of N-(5-bromo-1,3,4-thiadiazol-2-yl)acetamide, 7.3 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-amine, 3.18 parts of sodium carbonate and 135 parts of N,N-dimethylformamide was stirred overnight at 80°-90° C. The reaction mixture was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of acetonitrile and 2,2'-oxybispropane, yielding 1.7 parts of N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]formamide; mp. 153.2° C. (intermediate 156).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:18]2[CH2:20][CH2:19]2)[NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([NH2:17])[CH3:16])[N:8]=1.C1COCC1.O.C([O-])(O)=O.[Na+].Cl[C:33]([O:35][CH3:36])=[O:34]>O>[Br:1][C:2]1[N:3]=[C:4]([CH:18]2[CH2:20][CH2:19]2)[NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([NH:17][C:33](=[O:34])[O:35][CH3:36])[CH3:16])[N:8]=1
Reactant: COC(=O)Cl
Reactant: C[C@H](N)CNc1nccc(-c2[nH]c(C3CC3)nc2Br)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)N[C@@H](C)CNc1nccc(-c2[nH]c(C3CC3)nc2Br)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
A mixture of (S)—N1-(4-(4-bromo-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-yl)propane-1,2-diamine (13.3 g, 27.3 mmol, assumed theoretical yield) in 1:1 THF-water (200 mL) was cooled to 0° C. and solid NaHCO3 (20.6 g, 245 mmol) was added in portions. Methyl chloroformate (3.74 mL, 27.3 mmol) was added dropwise over 20 minutes and stirred for an additional 30 minutes. LCMS of an aliquot indicated complete reaction. Water (300 mL) was added and the resulting mixture was extracted with EtOAc (3×500 mL). The EtOAc layer was washed with brine (2×1 L), dried (Na2SO4) and concentrated. The resulting solid was suspended in a mixture of EtOAc (7 mL) and ethyl ether (25 mL) and the resulting suspension was allowed to settle at 0° C. The solids were collected and washed with cold Et2O (20 mL) to afford (S)-methyl 1-(4-(4-bromo-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate (9.56 g, 24.1 mmol, 89%) as an off-white solid: LCMS(m/z) 395.1 (MH+), tR=0.61 minute; 1H NMR (400 MHz, CDCl3) δ 0.91-1.03 (m, 2H), 1.08-1.19 (m, 2H), 1.22 (d, J=6.6 Hz, 3H), 1.77 (br s, 1H), 2.13-2.26 (m, 1H), 2.70-2.90 (m, 1H), 3.70 (s, 3H), 3.90-4.03 (m, 1H), 4.18-4.32 (m, 1H), 4.46-4.86 (m, 1H), 5.48-5.60 (m, 1H), 7.46 (d, J=5.5 Hz, 1H), 8.24 (d, J=5.4 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[N:17][C:18]#[N:19])OC2C=CC=CC=2)[CH:5]=[CH:6][CH:7]=1.[CH3:20][C:21]1[C:29]2[C:28]([N:30]3[CH2:35][CH2:34][NH:33][C@@H:32]([CH3:36])[CH2:31]3)=[N:27][CH:26]=[N:25][C:24]=2[NH:23][CH:22]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([N:33]2[CH2:34][CH2:35][N:30]([C:28]3[C:29]4[C:21]([CH3:20])=[CH:22][NH:23][C:24]=4[N:25]=[CH:26][N:27]=3)[CH2:31][C@@H:32]2[CH3:36])=[N:17][C:18]#[N:19])[CH:5]=[CH:6][CH:7]=1
Reactant: N#CN=C(Nc1cccc(Cl)c1)Oc1ccccc1
Reactant: Cc1c[nH]c2ncnc(N3CCN[C@@H](C)C3)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1c[nH]c2ncnc(N3CCN(C(=NC#N)Nc4cccc(Cl)c4)[C@@H](C)C3)c12
Temperature: 85 °C
Yield: 46.5 %

Procedure:
The cyanocarbamimidate from step A (0.47 g, 1.7 mmol), (S)-5-methyl-4-(3-methylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine from Example 1, step B (0.40 g, 1.7 mmol), and N,N-diisopropylethylamine (1 ml) were added to acetonitrile (10 ml). The mixture was heated at 85° C. in a sealed pressure tube for 4 hours. The solvent was evaporated, and the residue was purified by flash chromatography (80 g SiO2, 0-5% MeOH:CH2Cl2, 50 min) to give (S)—N-(3-chlorophenyl)-N′-cyano-2-methyl-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboximidamide (0.32 g, 0.79 mmol, 46%).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([OH:6])[CH3:5].[C:19]([O-:22])(=[O:21])[CH3:20].[K+]>CN(C=O)C>[C:19]([O:22][CH2:2][CH2:3][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([OH:6])[CH3:5])(=[O:21])[CH3:20]
Reactant: CC(O)(CCCl)c1ccccc1-c1ccccc1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCCC(C)(O)c1ccccc1-c1ccccc1
Reaction time: 3 h

Procedure:
2.6 g. of 1-chloro-3-p-biphenylyl-3-butanol (obtainable from p-biphenylylmagnesium bromide and 1-chloro-3-buranone) are dissolved in 20 ml. of DMF, 3 g. of anhydrous potassium acetate are added and the mixture is stirred for 3 hours at 60°. After standard working up, 1-acetoxy-3-p-biphenylyl-3-butanol is obtained.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=[C:2]([N:15]2[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1cc(F)ncc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ncc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 95.1 %

Procedure:
2-Fluoro-4-methyl-5-nitropyridine (0.8 g, 5.12 mmol), tert-butyl piperazine-1-carboxylate (1.05 g, 5.64 mmol) and potassium carbonate (0.85 g, 6.15 mmol) were taken up in acetonitrile (15 mL) and heated at 60° C. for 1.5 h. After this time, the reaction was quenched with water (20 mL) and extracted with EtOAc (2×30 mL). The organic layers were combined and dried over sodium sulphate, then concentrated in vacuo. The crude material was purified by column chromatography (silica gel: 100-200 mesh, 1:1 EtOAc/heptane) to give the title compound (1.57 g, 97%). LCMS (ES+) 323.1 (M+H)+, RT 1.71 minutes (method 4).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]([CH3:11])[CH2:9][N:8](CC3C=CC(OC)=CC=3)[C:4]=2[N:5]=[CH:6][N:7]=1.[C:21]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(O[K])(C)(C)C.C(OCC)(=O)C>CN1C(=O)CCC1>[C:24]([O:23][C:21]([N:28]1[CH2:33][CH2:32][N:31]([C:2]2[C:3]3[CH:10]([CH3:11])[CH2:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:30][CH2:29]1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: COc1ccc(CN2CC(C)c3c(Cl)ncnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(C)(C)O[K]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC1CNc2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 128 °C
Yield: 50 %

Procedure:
To a solution of 4-Chloro-7-(4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine (0.55 g, 1.88 mmol) in NMP (20 mL) were added 1-Boc-piperazine (1.0 g, 5.40 mmol) and tBuOK (0.21 g, 1.88 mmol). The mixture was heated to 128° C. for 30 hours. After cooling, the mixture was diluted by ethyl acetate (500 mL) and washed with water (5×150 mL). The organic phase was dried and concentrated. The residue was subject to column chromatography, eluted by hexane/ethyl acetate (1:1) to give 4-(5-Methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.30 g, 36%). 1H NMR (CDCl3, 400 MHz) δ 8.19 (s, 1H), 7.18 (d, J=8.4 Hz, 2H), 6.84 (d, J=8.4 Hz, 2H), 4.52 (dd, J=27.6 Hz, J=14.8 Hz, 2H), 3.79 (s, 3H), 3.58 (m, 12H), 3.34 (m 1H), 2.95 (m, 1H), 1.48 (s, 9H), 1.15 (d, J=6.8 Hz, 3H). MS (APCI+) [M+H]+440.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[NH2:8].[C:10]([O:14][C:15]([NH:17][C:18](=NC(OC(C)(C)C)=O)SC)=[O:16])([CH3:13])([CH3:12])[CH3:11]>CO.C(O)(=O)C>[C:10]([O:14][C:15](=[O:16])[NH:17][C:18]1[NH:8][C:7]2[CH:6]=[CH:5][C:4]([OH:9])=[CH:3][C:2]=2[N:1]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reactant: Nc1ccc(O)cc1N
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)Nc1nc2cc(O)ccc2[nH]1
Reaction time: 3 h
Yield: 61.8 %

Procedure:
5.75 g of 3,4-diaminophenol were combined with 15.5 g of 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea in 150 ml methanol and 22 ml acetic acid in a round bottom flask. The reaction mixture was heated to reflux with stirring for 3 hours. Solvents were then evaporated under reduce pressure yielding 7.13 g crude (5-hydroxy-1H-benzoimidazol-2-yl)-carbamic acid tert-butyl ester.