Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9]3[C:15]4=[C:16]([NH:20][C:21]5[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]6[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=6)=[C:23]([Cl:35])[CH:22]=5)[N:17]=[CH:18][N:19]=[C:14]4[S:13][C:10]=32)=[N:5]1.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[Cl:35][C:23]1[CH:22]=[C:21]([NH:20][C:16]2[N:17]=[CH:18][N:19]=[C:14]3[S:13][C:10]4[C:11]5[C:6]([CH2:7][CH2:8][C:9]=4[C:15]=23)=[N:5][N:4]([CH2:3][CH2:2][N:40]2[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]2)[CH:12]=5)[CH:26]=[CH:25][C:24]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1
Reactant: CN1CCNCC1
Reactant: Clc1cc(Nc2ncnc3sc4c(c23)CCc2nn(CCBr)cc2-4)ccc1OCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(CCn2cc3c(n2)CCc2c-3sc3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)CC1
Temperature: 60 °C
Reaction time: 4 h
Yield: 34.1 %

Procedure:
To a stirring solution of 2-(2-bromoethyl)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-4,5-dihydro-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-6-amine (100 mg, 0.16 mmol) in DMF (4 mL) were sequentially added 1-methyl-piperazine (0.023 mL, 0.24 mmol), sodium iodide (23.8 mg, 0.16 mmol), and sodium carbonate (33.6 mg, 0.32 mmol). The mixture was stirred at 60° C. for 4 h, after which time the contents were allowed to cool to rt and the solvent removed under reduced pressure. The crude product was purified via reverse phase HPLC to afford the desired product (32 mg, 34%) as a white solid. 1H-NMR (DMSO-d6) δ 8.58 (d, 1H), 8.40 (s, 1H), 8.36 (s, 1H), 7.93 (s, 1H), 7.83 (dd, 1H), 7.78 (s, 1H), 7.47-7.59 (m, 2H), 7.31 (dd, 1H), 7.19 (d, 1H), 5.25 (s, 2H), 4.12 (t, 2H), 3.35 (t, 2H), 2.85 (t, 2H), 2.63 (t, 2H), 2.35-2.45 (br s, 4H), 2.22-2.32 (br s, 4H), 2.12 (s, 3H); LCMS RT=2.18 min; [M+H]+=587.4.
Reaction SMILES: O.O.Cl.[F:4][C:5]([F:16])([F:15])[C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[NH:11])=[CH:8][CH:7]=1.C(Cl)Cl.[Cl:20][C:21]([SH:24])(Cl)Cl.[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[Cl:20][C:21]1[S:24][N:12]=[C:10]([C:9]2[CH:13]=[CH:14][C:6]([C:5]([F:15])([F:16])[F:4])=[CH:7][CH:8]=2)[N:11]=1
Reactant: N=C(N)c1ccc(C(F)(F)F)cc1
Reactant: SC(Cl)(Cl)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: FC(F)(F)c1ccc(-c2nsc(Cl)n2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(trifluoromethyl)benzamidine hydrochloride dihydrate (5.0 g), water (50 mL), methylene chloride (100 mL), benzyltriethylammonium chloride (0.44 g), and perchloromethyl mercaptan (2.1 mL) was prepared at room temperature and then cooled to 0° C. A solution of sodium hydroxide (3.07 g) in water (50 mL) was added via an addition funnel while maintaining the temperature below 10° C. The reaction was left to stir overnight at room temperature. The mixture was transferred to a separatory funnel and the two layers were separated. The organic layer was washed with saturated sodium bicarbonate, dried (MgSO4), filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (hexane as eluent) to afford 3.7 g of the title compound of Step H as a white powder. 1H NMR (CDCl3): δ 8.36 (d,2H), 7.73 (d,2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[I:17])[CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClCCl.[O-2].[O-2].[Mn+4]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[I:17])[CH:12]=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ccc(I)c(OCc2ccccc2)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1ccc(I)c(OCc2ccccc2)c1
Reaction time: 6 h
Yield: 91.1 %

Procedure:
A solution of 125 g (370 mmol) of 3-benzyloxy-4-iodobenzyl alcohol and 160 g (1.84 mol) of manganese dioxide in 750 ml of dichloromethane is stirred at room temperature for 18 hours. Since the reaction is not complete, a further 160 g (1.84 mol) of manganese dioxide are added and the medium is stirred for 6 hours. The reaction medium is filtered through Celite and the filtrate is then concentrated under vacuum. 114 g (92%) of 3-benzyloxy-4-iodobenzaldehyde are obtained in the form of a yellow oil.
Reaction SMILES: C[O:2][CH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]([NH:10]C(=O)OC(C)(C)C)[CH:5]=1.B(Br)(Br)Br>C(Cl)Cl>[NH2:10][C:6]1[N:7]=[CH:8][N:9]=[C:4]([CH2:3][OH:2])[CH:5]=1
Reactant: COCc1cc(NC(=O)OC(C)(C)C)ncn1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nc1cc(CO)ncn1
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl 6-(methoxymethyl)pyrimidin-4-ylcarbamate (100 mg, 0.42 mmole) in CH2Cl2 (2 mL) was added BBr3 (2.1 mL, 1M solution in CH2Cl2, 2.1 mmole) dropwise at −20° C. After 1.5 hours, the mixture was quenched with MeOH and concentrated. The solid was taken up in MeOH and concentrated (2×) and dried in vacuo to give the title compound as a tan solid. 1H-NMR (300 MHz, d6-DMSO) δ 8.63 (s, 1H), 6.64 (s, 1H), 4.50 (s, 2H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:24]=[CH:23][C:8]2[N:9]([CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[C:10]([CH2:12][CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[N:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+]>CO>[CH:13]1([CH2:12][C:10]2[N:9]([CH:18]([CH2:19][CH3:20])[CH2:21][CH3:22])[C:8]3[CH:23]=[CH:24][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=3[N:11]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCC(CC)n1c(CC2CCCC2)nc2cc(C(=O)OC)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(CC)n1c(CC2CCCC2)nc2cc(C(=O)O)ccc21
Temperature: 140 °C
Yield: 65 %

Procedure:
To 3.22 g of -Cyclopentylmethyl-1-(1-ethyl-propyl)-1H-benzoimidazole-5-carboxylic acid methyl ester 5 ml of methanol and 7 ml of 2 M aqueous sodium hydroxide solution were added and the reaction was heated in a microwave reactor to 140° C. for 1 h. The methanol was removed by distillation and the mixture was adjusted to pH 5 by the addition of 2M aqueous hydrochloric acid. The precipitated product was collected by filtration, washed with water and dried in vacuo. 2.22 g (65%) of Cyclopentylmethyl-1-(1-ethyl-propyl)-1H-benzoimidazole-5-carboxylic acid were obtained as light-brown solid.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].C1(C)C=CC=CC=1.Cl[C:17]1[O:18][C:19]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:20]([C:22]([F:25])([F:24])[F:23])[N:21]=1.C(N(CC)CC)C>>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][C:17]1[O:18][C:19]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:20]([C:22]([F:24])([F:23])[F:25])[N:21]=1)[CH3:3]
Reactant: CCOC(=O)c1oc(Cl)nc1C(F)(F)F
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)CNc1nc(C(F)(F)F)c(C(=O)OCC)o1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
By the procedure of Example 15, 4.19 g (0.03 mol) of glycine ethyl ester hydrochloride was added to a mixture of 100 ml toluene containing 4.87 g (0.02 mol) of ethyl 2-chloro-4-trifluoromethyl-5-oxazolecarboxylate and 6.07 g (0.06 mol) of triethylamine. The reaction mixture was stirred at ambient temperature for 48 hours. The product was separated and then recrystallized from methylcyclohexane to yield 3.55 g of a yellow powder product (m.p.=62°-63° C.) identified in Table I.
Reaction SMILES: N([O-])=O.[Na+].O.Cl.[CH2:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[NH:21][NH:22][C:23]([C:26]2[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=2)=[N:24][N:25]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)Cl>[CH2:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[N:21]=[N:22][C:23]([C:26]2[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=2)=[N:24][N:25]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Cc1cccc(C2=NN=C(c3ccccc3Cc3ccccc3)NN2)c1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1cccc(-c2nnc(-c3ccccc3Cc3ccccc3)nn2)c1
Temperature: 0 °C
Yield: 99.5 %

Procedure:
A solution of 6N NaNO2 in water (1 mL, 5.876 mmol) was added dropwise to conc. HCl (0.7 mL, 7.05 mmol). The resulting nitrous gases were bubbled through a suspension of 22 (200 mg, 0.588 mmol) in CH2Cl2 cooled to 0° C. for 1 hr. The solvent was removed in vacuo. The purple residue was purified by flash column chromatography (2% EtOAc in n-hexane) to give 3-(2-Benzyl-phenyl)-6-m-tolyl-[1,2,4,5] tetrazine 23 (198 mg, 0.585 mmol, 100% yield). m.p. 90-91° C.; HRMS (MALDI-FTMS) calcd for C22H18N4+H+: 339.1604, found 339.1597.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]([CH3:21])([C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:20])[NH:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:8][CH:7]=1)[CH3:5].C(OC(N1CCC(NC(=O)C2C=CC(C(C(OC)=O)(C)C)=CC=2)CC1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.[CH2:59]([O:61][C:62]1[CH:63]=[C:64]([CH:67]=[CH:68][C:69]=1[O:70][CH3:71])[CH:65]=O)[CH3:60].C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>ClCCl.C(O)C.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:22])[C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:12](=[O:20])[NH:13][CH:14]2[CH2:15][CH2:16][N:17]([CH2:65][C:64]3[CH:67]=[CH:68][C:69]([O:70][CH3:71])=[C:62]([O:61][CH2:59][CH3:60])[CH:63]=3)[CH2:18][CH2:19]2)=[CH:10][CH:11]=1)([CH3:5])[CH3:21]
Reactant: CCOc1cc(C=O)ccc1OC
Reactant: COC(=O)C(C)(C)c1ccc(C(=O)NC2CCNCC2)cc1
Agent: COC(=O)C(C)(C)c1ccc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc(CN2CCC(NC(=O)c3ccc(C(C)(C)C(=O)OC)cc3)CC2)ccc1OC

Procedure:
In analogy to the procedure described in example 50k), 2-methyl-2-[4-(piperidin-4-ylcarbamoyl)-phenyl]-propionic acid methyl ester [prepared from 4-[4-(1-methoxycarbonyl-1-methyl-ethyl)-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester by treatment with TFA in dichloromethane in analogy to the preparation described in example 50i)] was reacted with 3-ethoxy-4-methoxybenzaldehyde, sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as colorless foam. MS: 469.3 (MH+).
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][NH2:4].[C:11]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](=O)[CH3:29])=[CH:23][CH:22]=1)([O:13]CC1C=CC=CC=1)=[O:12]>C1C=CC=CC=1>[C:11]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH:28]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:29])=[CH:23][CH:22]=1)([OH:13])=[O:12]
Reactant: CC(=O)Cc1ccc(C(=O)OCc2ccccc2)cc1
Reactant: NCC(O)c1ccccc1
Solvent: c1ccccc1
Product: CC(Cc1ccc(C(=O)O)cc1)NCC(O)c1ccccc1
Reaction time: 8 h

Procedure:
2-Hydroxy-2-phenylethanamine (0.68 g) and 1-(4-carbobenzyloxyphenyl)-propan-2-one (1.34 g) were refluxed in benzene (50 ml) in a Dean and Stark apparatus for 2 hours. The solvent was removed, tetrahydrofuran (50 ml), benzene (10 ml) and water (3 ml) were added followed by sodium borohydride (0.9 g). The reaction mixture was left at room temperature overnight. The solvent was removed under reduced pressure and the residue partitioned between water and ether. The layers were separated and the organic layer dried (MgSO4). Removal of the solvent gave the title compound as the benzyl ester (1.67 g). This was dissolved in ethanol amd hydrogenated at 75 psi and 50° for 4 hours. Filtration and evaporation of the solvent gave the title compound mp 180°-190° (ethyl acetate-methanol), τ(TFA-d)8.5 (3H, d, J=7 Hz), 5.85-7.45 (5H, m), 4.72 (1H, broad), 2.6 (7H, m), 1.8 (2H, d, J=8 Hz). τ(d6DMSO+D2O+NaOD) 9.05 (3H, d, J=7 Hz), 6.9-7.7 (5H, m), 2.85 (2H, d, J=8 Hz), 2.7 (5H, s), 2.17 (2H, d, J=8 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][C:15](=[O:18])[N:14]([C@H:19]([C:30]([O:32]C)=[O:31])[CH2:20][CH2:21][O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+:35]>O1CCCC1.CO>[CH2:23]([O:22][CH2:21][CH2:20][C@@H:19]([N:14]1[C:15](=[O:18])[CH2:16][CH2:17][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12][CH2:13]1)[C:30]([O-:32])=[O:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Li+:35]
Reactant: COC(=O)[C@H](CCOCc1ccccc1)N1CCN(C(=O)OCc2ccccc2)CCC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C([O-])[C@@H](CCOCc1ccccc1)N1CCN(C(=O)OCc2ccccc2)CCC1=O
Reaction time: 3 h
Yield: 98.8 %

Procedure:
A solution of 2.01 g (4.40 mmol) of 4-((S)-3-benzyloxy-1-methoxycarbonyl-propyl)-5-oxo-[1,4]diazepane-1-carboxylic acid benzyl ester in 12 ml of tetrahydrofuran/methanol (1:1) was treated at 0° C. with 4.43 ml (4.40 mmol) of 1 M aq. lithium hydroxide solution, and kept 3 h at this temperature. The reaction was evaporated, dissolved in acetonitrile and evaporated again (3×) to give 1.94 g (98%) of the titled compound as light yellow foam. MS: 439.2 (M−H−).
Reaction SMILES: [C:1]([NH:9][NH:10][C:11](=[S:14])[NH:12][CH3:13])(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Cl>O>[CH3:13][N:12]1[C:1]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)=[N:9][NH:10][C:11]1=[S:14]
Reactant: CNC(=S)NNC(=O)c1ccncc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cn1c(-c2ccncc2)n[nH]c1=S
Temperature: 70 °C
Yield: 97.5 %

Procedure:
To a mechanically stirred suspension of 2-isonicotinoyl-N-methylhydrazinecarbothioamide (610 g) in water (5.0 L) was added sodium bicarbonate (390 g) at r.t. The reaction mixture was thereafter slowly heated to 70° C. over 2 h, and maintained at that temperature for another 3.5 h before cooling (ice-bath) to 17° C., followed by adjusting the pH to 3 by slow addition (over 90 min) of concentrated hydrochloric acid (ca. 470 mL). Subsequent filtration of the reaction mixture, followed by washing the collected solid with dilute hydrochloric acid (0.1 N, 2×1.0 L), gave a wet cake that was dried at 100 mbar under a gentle stream of air for 1.5 days to yield 544 g of the title compound.
Reaction SMILES: [N:1]1([C:6]2[CH:40]=[CH:39][C:9]([CH2:10][C:11]3[C:12](Cl)=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:22]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)([C:24]3[N:28]([CH3:29])[CH:27]=[N:26][CH:25]=3)[OH:23])=[CH:16][C:15]=4[CH3:37])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[NH:41]1[CH2:44][CH2:43][CH2:42]1>CN(C=O)C>[N:41]1([C:12]2[C:11]([CH2:10][C:9]3[CH:39]=[CH:40][C:6]([N:1]4[CH:5]=[CH:4][CH:3]=[N:2]4)=[CH:7][CH:8]=3)=[C:20]([Cl:21])[C:19]3[C:14](=[C:15]([CH3:37])[CH:16]=[C:17]([C:22]([C:30]4[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=4)([C:24]4[N:28]([CH3:29])[CH:27]=[N:26][CH:25]=4)[OH:23])[CH:18]=3)[N:13]=2)[CH2:44][CH2:43][CH2:42]1
Reactant: C1CNC1
Reactant: Cc1cc(C(O)(c2ccc(Cl)cc2)c2cncn2C)cc2c(Cl)c(Cc3ccc(-n4cccn4)cc3)c(Cl)nc12
Solvent: CN(C)C=O
Product: Cc1cc(C(O)(c2ccc(Cl)cc2)c2cncn2C)cc2c(Cl)c(Cc3ccc(-n4cccn4)cc3)c(N3CCC3)nc12
Temperature: 100 °C

Procedure:
(3-(4-(1H-Pyrazol-1-yl)benzyl)-2,4-dichloro-8-methylquinolin-6-yl)(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanol (200 mg, 0.34 mmol, Intermediate 67), azetidine (194 mg, 3.40 mmol), and DMF (2 mL) were combined in a reaction tube, then sealed and heated to 100° C. and maintained at that temperature overnight. The reaction vessel was then cooled to room temperature and the solvent and excess azetidine were removed by reduced pressure distillation. The crude residue was taken up into EtOAc, then extracted twice with a saturated, aqueous NH4Cl solution. The organic phase was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified via reverse phase chromatography using acetonitrile with ammonium hydroxide in water as eluent to afford the title compound. MS (ESI): mass calcd. for C34H30Cl2N6O, 608.2. m/z found, 609.2 [M+H]+. 1H NMR (600 MHz, CDCl3) δ ppm 7.86 (d, J=2.1 Hz, 1H), 7.84 (d, J=2.4 Hz, 1H), 7.66 (d, J=1.7 Hz, 1H), 7.57-7.54 (m, 2H), 7.37 (dd, J=2.3, 1.1 Hz, 1H), 7.32-7.29 (m, 2H), 7.25 (d, J=8.5 Hz, 2H), 7.19-7.15 (m, 2H), 7.13 (s, 1H), 6.43-6.40 (m, 1H), 6.29 (d, J=1.2 Hz, 1H), 5.80-5.74 (m, 1H), 4.27 (s, 2H), 4.11 (t, J=7.5 Hz, 4H), 3.32 (s, 3H), 2.58 (s, 3H), 2.26-2.17 (m, 2H).
Reaction SMILES: Br[CH2:2][C@H:3]([CH3:21])[C@H:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1)[CH2:5][CH3:6].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:29][NH:30][CH3:31].O>CN(C)C=O>[CH2:5]([C@@H:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1)[C@@H:3]([CH3:21])[CH2:2][N:30]([CH3:31])[CH3:29])[CH3:6]
Reactant: CNC
Reactant: CC[C@@H](c1cccc(OCc2ccccc2)c1)[C@@H](C)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC[C@@H](c1cccc(OCc2ccccc2)c1)[C@@H](C)CN(C)C
Yield: 89 %

Procedure:
The product of Example 44 (2.7 g, 8 mmol) was dissolved in N,N-dimethylformamide, potassium carbonate (2.7 g, 20 mmol) and dimethylamine hydrochloride (0.7 g, 8 mmol) were added therein, and it was reacted at room temperature for 12 hours. After the reaction solution was poured into water, the aqueous phase was extracted with dichloromethane twice, then the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated through silica gel column chromatography to give target 2.1 g, yield: 89%.
Reaction SMILES: C([N:8]1[CH:12]=[C:11]([C:13]2[CH:17]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:15][N:14]=2)[N:10]=[CH:9]1)C1C=CC=CC=1.[H][H]>C(O)(=O)C.C(O)C.[Pd]>[NH:8]1[CH:12]=[C:11]([C:13]2[CH:17]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:15][N:14]=2)[N:10]=[CH:9]1
Reactant: [H][H]
Reactant: CCOC(=O)c1cc(-c2cn(Cc3ccccc3)cn2)n[nH]1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1cc(-c2c[nH]cn2)n[nH]1
Yield: 101.6 %

Procedure:
Ethyl 3-(1-benzyl-1H-imidazol-4-yl)-1H-pyrazole-5-carboxylate (8.77 mmol, 2.6 g) was dissolved in a mixture of acetic acid (10 ml) and ethanol (190 ml). The mixture was run through H-Cube (10% Pd/C CatCart (8.77 mmol) flow 1.5 ml/min, +80° C., Full hydrogen mode). The collected fractions were combined and evaporated. The acquired solid was stirred in toluene and evaporated. This was repeated once more. 1.837 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.33 (t, 3H), 4.35 (q, 2H), 7.38 (s, 1H), 8.07 (d, 1H), 9.14 (bs, 1H), 14.44 (bs, 1H). LC-MS: [M−1]=205.0.
Reaction SMILES: O([C:8]([NH:10][N:11]1[CH2:16][CH:15]=[CH:14][CH2:13][CH2:12]1)=[O:9])C1C=CC=CC=1.[NH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][N:19]=1>CN(C)C1C=CN=CC=1.ClCCCl>[N:21]1[CH:22]=[CH:23][C:18]([NH:17][C:8]([NH:10][N:11]2[CH2:16][CH:15]=[CH:14][CH2:13][CH2:12]2)=[O:9])=[N:19][CH:20]=1
Reactant: O=C(NN1CC=CCC1)Oc1ccccc1
Reactant: Nc1ccncn1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Product: O=C(Nc1ccncn1)NN1CC=CCC1
Yield: 64.4 %

Procedure:
A mixture of N-(phenoxycarbonylamino)-1,2,3,6-tetrahydropyridine (2.61 g), 4-aminopyrimidine (0.95 g) and 4-dimethylaminopyridine (1.83 g) in 1,2-dichloroethane (80 ml) was refluxed for 2.5 hours. The reaction mixture was evaporated to dryness. The crude residue was dissolved in ethyl acetate (50 ml) and washed with water (50 ml), and then extracted with 5% hydrochloric acid (30 ml×2). The extract was neutralized with sodium bicarbonate and further extracted with chloroform (30 ml×2). The chloroform layer was washed with water (50 ml), dried over magnesium sulfate and evaporated to give N-[(4-pyrimidinylcarbamoyl)amino]-1,2,3,6-tetrahydropyridine (1.41 g), which was recrystallized from ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([O:17][CH2:18][CH3:19])=[C:12]([C:14]([OH:16])=O)[N:13]=1.O.O[C:22]1[C:30]2N=N[NH:27][C:26]=2[CH:25]=[CH:24][CH:23]=1.N=C=N.NC1C=CC=CC=1>C(Cl)Cl>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[O:10][C:11]([O:17][CH2:18][CH3:19])=[C:12]([C:14]([NH:27][C:26]2[CH:30]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:16])[N:13]=1
Reactant: CCOc1oc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: Oc1cccc2[nH]nnc12
Agent: N=C=N
Solvent: ClCCl
Solvent: Nc1ccccc1
Solvent: O
Product: CCOc1oc(-c2c(F)cccc2F)nc1C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102 %

Procedure:
To a solution of 2-(2,6-difluorophenyl)-5-ethoxyoxazole-4-carboxylic acid (0.10 g, 0.37 mmol) and hydroxybenzotriazole monohydrate (0.06 g, 0.39 mmol) in DCM (4 mL) was added PS-carbodiimide resin (0.36 g, 0.45 mmol, 1.25 mmol/g) followed by aniline (39 uL, 0.43 mmol). The resulting mixture was stirred at room temperature for 4 hours when a further portion of aniline (7 uL, 0.08 mmol) was added and the reaction stirred at room temperature overnight. The mixture was filtered through a silica-carbonate cartridge, followed by a MP-TsOH resin cartridge which was rinsed with DCM and MeOH to afford 2-(2,6-difluorophenyl)-5-ethoxy-N-phenyloxazole-4-carboxamide (0.13 g) which was used without further purification. LCMS (1) Rt: 2.30; m/z (ES+) 345.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[OH:12].[Cl:13][C:14]1[N:15]=[C:16](Cl)[C:17]2[CH:22]=[CH:21][S:20][C:18]=2[N:19]=1>C1COCC1.O>[Cl:13][C:14]1[N:15]=[C:16]([O:12][C:5]2[C:6]([CH3:11])=[CH:7][C:8]([CH3:10])=[CH:9][C:4]=2[CH3:3])[C:17]2[CH:22]=[CH:21][S:20][C:18]=2[N:19]=1
Reactant: Cc1cc(C)c(O)c(C)c1
Reactant: Clc1nc(Cl)c2ccsc2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)c(Oc2nc(Cl)nc3sccc23)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
A stirred suspension of NaH (9.5 mg, 0.24 mmol) in dry THF (1 mL) was added 2,4,6-trimethyl phenol (32.1 mg, 0.24 mmol) and stirred at room temperature for 30 min under Argon. The reaction mixture was added to a solution of 2,4-dichlorothieno[2,3-d]pyrimidine (48.1 mg, 0.24 mmol) in dry THF (1.5 mL) at 0° C. and allow it to slowly warmed up to room temperature. After stirring the reaction for 4 h, the resulting mixture was diluted with water and washed with EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (9:1) to give the product as a white solid (71 mg, 97%):
Reaction SMILES: [CH2:1]1[CH:6]([C:7](O)=[O:8])[CH2:5][CH2:4][CH:3]([NH2:10])[CH2:2]1.B.C1COCC1>C1COCC1>[CH2:1]1[CH:6]([CH2:7][OH:8])[CH2:5][CH2:4][CH:3]([NH2:10])[CH2:2]1
Reactant: NC1CCC(C(=O)O)CC1
Agent: B
Solvent: C1CCOC1
Product: NC1CCC(CO)CC1
Temperature: 25 °C
Yield: 77.4 %

Procedure:
To a solution of (1r,4r)-4-aminocyclohexanecarboxylic acid (860 mg, 6.0 mmol, 1.0 eq) in THF (10 mL) was added dropwise BH3/THF (1.0 mol/L in THF, 30 mL, 5.0 equiv.) at 0° C. The reaction was allowed to warm to room temperature. The reaction was heated at reflux for 48 hours. The reaction was quenched with AcOH and concentrated in vacuo to get crude ((1r,4r)-4-aminocyclohexyl)methanol (600 mg, 78%) which was used to the next step without further purification. MS: m/z 130.1 (M+H)+.
Reaction SMILES: CC1C=CC(S([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:25][CH2:26][CH2:27][CH2:28][NH:29]S(C2C=CC(C)=CC=2)(=O)=O)(=O)=O)=CC=1.N.[Na].[Cl-].[NH4+]>>[NH2:29][CH2:28][CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14][CH2:13][CH2:12][NH2:11]
Reactant: Cc1ccc(S(=O)(=O)NCCCCN(CCCCCCCN(CCCCNS(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)cc1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Product: NCCCCNCCCCCCCNCCCCN

Procedure:
Mix 1,6,14,19-tetra[(4-methylphenyl)sulfonyl]-1,6,14,19-tetraazanonadecane (3.9 g, 4 mmol) in dry liquid ammonia (25 mL) at -40° C. Add small pieces of sodium until a permanent blue color remains. Discharge the excess sodium with saturated ammonium chloride. Allow the ammonia to evaporate spontaneously and partition the residue between ethyl acetate and water. Separate the organic phase, dry (MgSO4) and evaporate the solvent in vacuo. Purify by silica gel chromatography to give the title compound.