Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])/[C:7](=[CH:15]/[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[C:22]([O:24][CH3:25])=[O:23])/[CH2:6]2.[CH2:26]([Br:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[Br-:33].[CH2:26]([N+:19]1[CH:20]=[CH:21][C:16](/[CH:15]=[C:7]2/[C:8](=[O:14])[C:9]3[C:5]([CH2:6]/2)=[CH:4][C:3]([O:2][CH3:1])=[C:11]([O:12][CH3:13])[CH:10]=3)=[C:17]([C:22]([O:24][CH3:25])=[O:23])[CH:18]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cnccc1/C=C1\Cc2cc(OC)c(OC)cc2C1=O
Product: COC(=O)c1c[n+](Cc2ccccc2)ccc1/C=C1\Cc2cc(OC)c(OC)cc2C1=O
Product: [Br-]

Procedure:
The title compound 150 is prepared according to the procedure reported in Example 38.1 with compound 96 (34 mg, 0.10 mmol) and benzyl bromide (25 μL, 0.21 mmol) as reactants. White solid. (Yield 46.1 mg, 90%).
Reaction SMILES: C([C:4]1[CH:13]=[CH:12][C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=1)(C)C.[CH2:14]([C:21]1C=CC=CC=1OCCO)[CH2:15]CCCCC>>[CH:14]([C:6]1[CH:5]=[CH:4][CH:13]=[CH:12][C:7]=1[O:8][CH2:9][CH2:10][OH:11])([CH3:21])[CH3:15]
Reactant: CCCCCCCc1ccccc1OCCO
Reactant: CC(C)c1ccc(OCCO)cc1
Product: CC(C)c1ccccc1OCCO

Procedure:
2-(4-isopropylphenoxy)ethanol or 2-(heptyl-phenoxy)ethanol
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[NH2:9].[CH3:16][O:17][CH:18]([O:21][CH3:22])[CH:19]=O.C(OC)(C)(C)C>[Pd].C(O)C>[CH3:16][O:17][CH:18]([O:21][CH3:22])[CH2:19][NH:9][C:8]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:15])[CH3:1])[CH:7]=1
Reactant: COc1ccc(N)cc1OCCN(C)C
Reactant: COC(C=O)OC
Agent: [Pd]
Solvent: COC(C)(C)C
Solvent: CCO
Product: COc1ccc(NCC(OC)OC)cc1OCCN(C)C
Reaction time: 16 h
Yield: 67 %

Procedure:
A solution of 3-(2-dimethylaminoethoxy)-4-methoxyaniline (D11, 5.7 g, 0.027 mole) ethanol (120 ml) was treated with a solution of 2,2-dimethoxyacetaldehyde in methyl tert-butyl ether (9.5 g of approx. 40% solution, 0.036 mole) and kept at room temperature for 16 hours. The solution was then hydrogenated over 10% Pd-C (0.6 g) at atmospheric pressure and temperature for 7 hours. The catalyst was removed by filtration through kieselguhr and the filtrate concentrated in vacuo. The residue was dissolved in ethyl acetate (100 ml), washed twice with water (2×60 ml), then dried (Na2SO4) and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 5% methanol/chloroform to afford the title compound as a red oil (5.4 g, 67%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:5][C:6]=1[C:7]([O:9]CC)=O.[C:19](#[N:21])[CH3:20].Cl>O1CCOCC1>[F:18][C:15]1[CH:14]=[CH:13][C:12]([C:4]2[S:3][C:2]3[N:1]=[C:19]([CH3:20])[NH:21][C:7](=[O:9])[C:6]=3[CH:5]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1cc(-c2ccc(F)cc2)sc1N
Reactant: CC#N
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc2sc(-c3ccc(F)cc3)cc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
To a solution of ethyl 2-amino-5-(4-fluorophenyl)thiophene-3-carboxylate (0.3 g, 1.13 mmol) and acetonitrile (0.56 ml, 11.3 mmol) in dioxane (4 ml) was added 4M HCl in dioxane (4 ml). The mixture was stirred at room temperature overnight. The solvents were removed under reduced pressure. The residue was diluted with water and made alcaline with a saturated aqueous sodium bicarbonate solution. The precipitate was filtered off, washed with water and dried. The crude residue was purified by flash chromatography on silica gel (CH2Cl2/MeOH 60:1) to yield the title compound as a white solid (0.29 g, 81%).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[NH:4][CH:3]=1.CC([O-])(C)C.[K+].O(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O.C[N:33](C=O)C>>[CH3:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([NH2:33])[CH:3]=1
Reactant: Cc1c[nH]c2ccncc12
Reactant: CN(C)C=O
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: Cc1cn(N)c2ccncc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
A mixture of 3-methyl-1H-pyrrolo[3,2-c]pyridine (1.91 g, 14.47 mmol) and KOtBu (3.25 g, 28.9 mmol) in DMF (65 mL) is purged with N2 and stirred at rt for 2 h. Chloramine in ether (0.15 M, 145 mL) is added and the mixture is stirred for 20 min. The reaction is cooled to 00 C. and a solution of Na2S2O3 (800 mg) in water (130 mL) is added. The mixture is stirred for 10 min at 00 C., and then concentrated in vacuo. The residue is triturated in DCM and filtered. DCM is added to the filtrate, cooled to 0° C. and treated with BOC2O (793 mg, 3.6 mmol). The mixture is concentrated in vacuo, and the residue is purified by silica gel chromatography eluting with 10% MeOH in DCM to afford 3-methyl-pyrrolo [3,2-c]pyridin-1-yl amine (842 mg, 35%). MS: 148 (M+H); 1H NMR (300 MHz, CDCl3): δ 8.85 (s, 1H), 8.36 (d, 1H), 7.32 (d, 1H), 6.95 (s, 1H) 4.77 (s, 2H), 2.37 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[N+:18]([C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24])([O-:20])=[O:19]>>[N+:18]([C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:24])([O-:20])=[O:19]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccccc4[N+](=O)[O-])nc23)CC1
Yield: 89.9 %

Procedure:
Beginning with 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.007 mL (0.048 mMol) 2-nitrobenzoyl chloride, 0.015 gm (92%) of the title compound were prepared essentially by the procedure described in Example 7.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[Cl:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:6]([NH:5][CH2:4][CH2:3][NH:2][S:23]([CH3:22])(=[O:25])=[O:24])=[O:14]
Reactant: NCCNC(=O)c1ccccc1Cl
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NCCNC(=O)c1ccccc1Cl

Procedure:
N-(2-Aminoethyl)-2-chlorobenzamide hydrochloride was suspended in dichloromethane and stirred with triethylamine and methanesulfonyl chloride to obtain 2-chloro-N-{2-[(methylsulfonyl)amino]ethyl}benzamide.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([F:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[Cl:16]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[Cl:16])=[CH:12][C:11]([F:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1cc2cc(F)ccc2[nH]1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1[nH]c2ccc(F)cc2c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.5 %

Procedure:
5-Fluoroindole-2-carboxylic acid ethyl ester (2.0 g) was dissolved in N,N-dimethylformamide (20 mL), and a solution of N-chlorosuccinimide (1.4 g) in N,N-dimethylformamide (10 mL) was added dropwise thereto under ice cooling, followed by stirring at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate, and the diluted mixture was sequentially washed with saturated aqueous sodium hydrogencarbonate and saturated brine. The organic layer was dried over sodium sulfate anhydrate, and the solvent was distilled away under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1), to thereby give the title compound (1.9 g).
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][CH2:5][C@@H:4]([C:16]([NH2:18])=[O:17])[CH2:3]1.[N+:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)([O-:21])=[O:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.CN(C=O)C>[C:12]([O:11][C:9]([NH:8][C@@H:7]1[CH2:6][CH2:5][C@@H:4]([C:16](=[O:17])[NH2:18])[CH2:3][C@@H:2]1[O:1][C:26](=[O:27])[C:25]1[CH:24]=[CH:23][C:22]([N+:19]([O-:21])=[O:20])=[CH:30][CH:29]=1)=[O:10])([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](C(N)=O)C[C@H]1O
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](C(N)=O)C[C@@H]1OC(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 0.08 h
Yield: 53.7 %

Procedure:
To (1R,3R,4R)-3-hydroxy-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid amide (e) (2.78 g, 10.8 mmol), para-nitrobenzoic acid (2.16 g, 12.9 mmol) and triphenylphosphine (3.38 g, 12.9 mmol) in dry THF (200 mL) and DMF (25 mL) under argon was added dropwise diisopropyl azodicarboxylate (2.5 mL, 12.9 mmol) at 0° C. After 5 min at 0° C. and 17 hours at room temperature, the mixture was concentrated in vacuo and the residue purified by flash column chromatography (silica gel, DCM/MeOH, 0-4%) to give a white solid (2.36 g, 5.8 mmol, 54%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[NH:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:13]=1.CO.Cl.O>C1COCC1>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][NH:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:13]=1
Reactant: O=C1NCCCc2cc(I)ccc21
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Ic1ccc2c(c1)CCCNC2
Temperature: 75 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
7-Iodo-2,3,4,5-tetrahydro-1H-2-benzazepin-1-one (Preparation 1) (550 mg, 1.916 mmol) was dissolved in dry THF (70 ml) and treated with borane-THF complex (1M) (11.49 ml, 11.49 mmol) and heated at reflux for 4 hours. Then the reaction was left standing overnight. Additional borane-THF complex (1M, 2 ml) was added and the reaction heated at reflux temperature for a further 2 hours and 30 minutes. Methanol was carefully added to the cooled reaction mixture. The reaction was stirred until fizzing stopped. Then 2N HCl (aq) (20 ml) was carefully added portion-wise and, after fizzing had subsided, the solution heated at 75° C. for 30 minutes. LC/MS showed one major product. The reaction mixture was cooled and water was added (20 ml). The mixture was washed with EtOAc (40 ml), basified with 2 N NaOH (aq) and extracted with EtOAc (50 ml). The EtOAc layer was dried over anhydrous MgSO4 and evaporated to yield the title compound (400 mg) as a white solid. MS (ES) C10H12IN requires 273: found 274 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@H:4]1[CH2:16][C:15]2[C:14]3[C:13]([O:17][CH:18]4[CH2:23][CH2:22][CH:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]4)=[N:12][CH:11]=[N:10][C:9]=3[S:8][C:7]=2[CH2:6][CH2:5]1.C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-:44][Cr](O[Cr]([O-])(=O)=O)(=O)=O>CN(C=O)C>[C:27]([O:26][C:25]([NH:24][CH:21]1[CH2:20][CH2:19][CH:18]([O:17][C:13]2[C:14]3[C:15]4[CH2:16][C@@H:4]([CH2:3][C:2]([OH:44])=[O:1])[CH2:5][CH2:6][C:7]=4[S:8][C:9]=3[N:10]=[CH:11][N:12]=2)[CH2:23][CH2:22]1)=[O:31])([CH3:28])([CH3:30])[CH3:29]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: CC(C)(C)OC(=O)NC1CCC(Oc2ncnc3sc4c(c23)C[C@@H](CCO)CC4)CC1
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCC(Oc2ncnc3sc4c(c23)C[C@@H](CC(=O)O)CC4)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
To a solution of tert-butyl N-(4-[[(12S)-12-(2-hydroxyethyl)-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-3-yl]oxy]cyclohexyl)carbamate (172 mg, 0.38 mmol, 1.00 equiv) in 4 mL of DMF was added PDC (847 mg, 2.25 mmol, 6.00 equiv) and the resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of water and extracted with 4×50 mL of chloroform/isopropanol (3:1). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1) to provide 2-[(12S)-3-[(4-[[(tert-butoxy)carbonyl]amino]cyclohexyl)oxy]-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-12-yl]acetic acid (148 mg, 83%) as an off-white solid. MS: m/z 462 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][O:11][C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH:14]=[C:15]([C:21](O)=[O:22])[NH:16]3)=[CH:2]1.[ClH:24].Cl.Cl.[C@H:27]1([CH2:37][N:38]2[CH2:43][CH2:42][CH:41]([NH2:44])[CH2:40][CH2:39]2)[C@@H:36]2[N:31]([CH2:32][CH2:33][CH2:34][CH2:35]2)[CH2:30][CH2:29][CH2:28]1>>[ClH:24].[ClH:24].[C@H:27]1([CH2:37][N:38]2[CH2:43][CH2:42][CH:41]([NH:44][C:21]([C:15]3[NH:16][C:17]4[C:13]([CH:14]=3)=[C:12]([O:11][CH2:10][C:3]3[C:4]5[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=5[O:1][CH:2]=3)[CH:20]=[CH:19][CH:18]=4)=[O:22])[CH2:40][CH2:39]2)[C@@H:36]2[N:31]([CH2:32][CH2:33][CH2:34][CH2:35]2)[CH2:30][CH2:29][CH2:28]1
Reactant: NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1
Reactant: O=C(O)c1cc2c(OCc3coc4ccccc34)cccc2[nH]1
Agent: Cl
Product: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4ccccc34)cccc2[nH]1

Procedure:
This compound is synthesized from 4-(benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (105) (preparation see below) and amine 61 analogously to the method described in example 1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1CCC[CH2:10][C@@H:9]1[CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)CCN(C)C.[CH:23]([Li])([CH2:25][CH3:26])[CH3:24].CN(C)C=[O:31].[Cl-].[NH4+]>C(OCC)C>[CH:24]([C@H:23]1[CH2:25][CH2:26][CH2:10][C@H:9]([CH3:14])[N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:31]
Reactant: [Li]C(C)CC
Reactant: C[C@H]1CCCCN1C(=O)OC(C)(C)C
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: C[C@H]1CCC[C@H](C=O)N1C(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
To 2.50 g(12.5 mmol) of (S)-N-tert-butoxycarbonyl-2-methylpiperidine in 25 ml of dehydrated diethyl ether solution were added 1.89 ml(1 equivalent) of N,N,N′,N′-tetramethylethylenediamine at −60° C. under an atmosphere of argon, and then 13.3 ml(1.1 equivalent) of sec-butyllithium were added dropwise. After the temperature of reaction mixture was raised to −20° C., it was cooled again to −70° C. and 1.46 ml(1.5 equivalents) of N,N-dimethylformamide were added dropwise. After stirring for about 2 hours, 20 ml of saturated solution of ammonium chloride were added to the reaction mixture to stop the reaction. The aqueous layer was separated, which was extracted with ether(10 ml×3). Combined organic layers were dried over anhydrous magnesium sulfate, filtered and solvent was distilled off. The residue was purified by means of silica gel column chromatography(hexane:ethyl acetate=8:1) to obtain 1.58 g of (2R,6S)-tert-butyl 2-formyl-6-methyl-1-piperidinecarboxylate (yield 55%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8](Br)[CH:9]=[C:10]([CH:11]3[O:16][CH2:15][CH:14]4[CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20][N:13]4[CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.CN(C=O)C.[CH2:34]([N:41]1[CH:49]=[C:48]2[C:43]([CH:44]=[C:45](B3OC(C)(C)C(C)(C)O3)[CH:46]=[CH:47]2)=[N:42]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH2:1][C:2]1[C:7]2=[C:8]([C:45]3[CH:46]=[CH:47][C:48]4[C:43]([CH:44]=3)=[N:42][N:41]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:49]=4)[CH:9]=[C:10]([CH:11]3[O:16][CH2:15][CH:14]4[CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20][N:13]4[CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCN2CC(c3cc(Br)c4c(N)ncnn34)OCC2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN2CC(c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)OCC2C1
Temperature: 100 °C
Yield: 39 %

Procedure:
To a stirred solution of tert-butyl 3-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate (1.50 g, 3.31 mmol) and tetrakis(triphenylphosphine)palladium(0) (764 mg, 0.66 mmol), in degassed 1,4-dioxane (15 mL) and DMF (15 mL) was added 2-benzyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole (1.33 g, 3.97 mmol), K2CO3 (1.10 g, 7.94 mmol), and H2O (3.9 mL). The mixture was degassed and heated (100° C.) for 17 h and then cooled to rt. The mixture was partitioned between ethyl acetate (250 mL) and saturated aqueous K2CO3 solution (200 mL). The layers were separated and the organic phase was washed, dried (Na2SO4), and concentrated to dryness. The residue was purified by recrystallization from acetonitrile to obtain 750 mg (39%) of the desired product. 1H-NMR (DMSO-d6) 8.53 (s, 1H), 7.91 (s, 1H), 7.79 (d, 1H), 7.57 (s, 1H), 7.35-7.28 (m, 5H), 7.11 (d, 1H), 6.71 (s, 1H), 5.64 (s, 2H), 5.14-5.10 (m, 1H), 3.88-3.71 (m, 3H), 3.33-3.26 (m, 2H), 3.03-2.99 (m, 1H), 2.89-2.69 (m, 2H), 2.42-2.38 (m, 1H), 2.12-2.08 (m, 2H), 1.38 (s, 9H); LC-MS [M+H]+=581, RT=2.57 min.
Reaction SMILES: [NH2:1][C@@H:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)CC)C>ClCCl>[CH2:22]([O:21][C:19]([CH2:18][NH:1][C@@H:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4])=[O:20])[CH3:23]
Reactant: CCOC(=O)CBr
Reactant: N[C@@H](c1ccccc1)[C@H](O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CN[C@@H](c1ccccc1)[C@H](O)c1ccccc1
Temperature: 25 °C

Procedure:
(1R,2S)-2-amino-1,2-diphenylethanol (2.10 g) was dissolved in dichloromethane (30 ml) and stirred at room temperature. Ethyl bromoacetate (2.00 g), dissolved in dichloromethane (15 ml), was added to the solution. The mixture was stirred at room temperature for 7 days, and then triethylamine (1.5 ml) was added and stirred at room temperature for an additional day. After the spot of the starting material in TLC disappeared, dichloromethane was evaporated under reduced pressure. Benzene (100 ml) was added to the remaining residue, and the triethylamine hydrobromide salt was washed out with water. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solution was filtered and evaporated. The residue (2.60 g, 88%) was recrystallized from hexane (ca. 300 ml). The crystals deposited were collected and dried under reduced pressure. Yield 2.20 g (75%); mp 123°-125° C.; [α]D18 +2.4° (c 1.00, EtOH). IR (KBr): 3180, 1745, 765, 705 cm -1. 1H-NMR (CDCl3): 1.17 (t, 3H, J=7 Hz), 2.35 (bs, 2H), 3.16 (pseudo s, 2H), 3.98 (q, 2H, J=7 Hz), 4.15 (d, 1H, J=6 Hz), 4.76 (d, 1H, J=6 Hz), 7.20 (s, 10H) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:22](=O)[CH:23]([CH3:25])[CH3:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2ccc(Cl)cc2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)CN(Cc1ccc(Cl)cc1)C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(4-chloro-benzylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.4 g, 1.28 mmol) and isobutyraldehyde (0.14 g, 1.92 mmol) in dichloroethane was added sodium triacetoxy borohydride (0.81 g, 3.85 mmol) and catalytic acetic acid. The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated, dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate. The combined organics were washed with brine and dried over sodium sulfate. The crude product was purified on silica using gradient elution from hexane/ethyl acetate (10%) to hexane/ethyl acetate (50%). 1H-NMR (CDCl3) δ: 0.80 (6H, 2×d), 1.45 (9H, s), 1.60–1.90 (2H, m), 2.20 (2H, d), 3.00–3.70 (7H, m), 7.20 (4H,s). ESI-MS m/z: 367 (M+1), UV retention time: 1.89 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)[C:5]([C:15]([F:18])([F:17])[F:16])=[CH:4][N:3]=1.C(OC([N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[CH:37]=[C:36]([CH3:38])[C:35]([NH2:39])=[CH:34][C:33]=2[CH3:40])[CH2:28][CH2:27]1)=O)(C)(C)C>Cl.CC(O)C>[CH3:38][C:36]1[CH:37]=[C:32]([CH:29]2[CH2:28][CH2:27][NH:26][CH2:31][CH2:30]2)[C:33]([CH3:40])=[CH:34][C:35]=1[NH:39][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)[C:5]([C:15]([F:18])([F:17])[F:16])=[CH:4][N:3]=1
Reactant: Cc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)c(C)cc1N
Reactant: Cc1cc(Nc2nc(Cl)ncc2C(F)(F)F)n[nH]1
Agent: Cl
Solvent: CC(C)O
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3C)ncc2C(F)(F)F)n[nH]1
Temperature: 150 °C

Procedure:
A mixture of 2-chloro-N-(5-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidin-4-amine (513.0 mg, 0.9 mmol), tert-butyl-4-(4-amino-2,5-dimethylphenyl)piperidine-1-carboxylate (282.7 mg, 0.9 mmol), and concentrated aqueous HCl (10 drops) in i-PrOH (12 mL) was heated at 150° C. in a microwave reactor for 30 min. The crude product was purified by RP-HPLC to afford N2-(2,5-dimethyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine; ESMS m/z 446.2 (M+H+).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17](=O)[CH3:18])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)OCC1.[OH2:20].[OH2:21].O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[Tl+3].C(Cl)Cl.Cl(O)(=O)(=O)=O>CO>[O:1]=[C:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:12]=[CH:13][C:14]([CH2:17][C:18]([OH:21])=[O:20])=[CH:15][CH:16]=2)[CH2:9][CH2:10]1
Reactant: CC(=O)c1ccc(N2CCC3(CC2)OCCO3)cc1
Reactant: O
Agent: O=[N+]([O-])[O-]
Agent: [O-][Cl+3]([O-])([O-])O
Agent: [Tl+3]
Solvent: ClCCl
Solvent: CO
Product: O=C(O)Cc1ccc(N2CCC(=O)CC2)cc1
Reaction time: 3 h
Yield: 17.1 %

Procedure:
1-[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-phenyl]-ethanone (2.61 g, 10 mmol) (Taylor, E. C., Skotnicki, J. S. Synthesis, 1981, 606) was added to a solution of thallium trinitrate trihydrate (4.44 g, 10 mmol) (McKillop, A., Swann, B. P., Taylor, E. C. J. Am. Chem. Soc., 1971, 93, 4919) in methanol (40 mL) and methylene chloride (20 mL) containing perchloric acid (70%, 10 mL). After 5 hours at room temperature the precipitated thallium (I) nitrate was removed by filtration, and the filtrate was diluted with water (100 mL). The organic phase was separated, the aqueous layer was extracted with methylene chloride, and the combined organic phases were washed with water, dried over sodium sulfate and concentrated. The residue was dissolved in concentrated hydrochloric acid (250 mL) at room temperature. After 3 hours the solution pH was adjusted to 5 by ˜28% ammonium hydroxide. The aqueous layer was extracted with methylene chloride, and the combined organic phases were washed with water, dried over sodium sulfate and concentrated. The product was purified by chromatography on silica gel with ethyl acetate/hexanes eluant to give the title compound as a pale yellowish solid (0.4 g, 17%); 1H NMR (300 MHz, DMSO-d6) δ 2.42 (t, J=6.0 Hz, 4 H), 3.41 (s, 2 H), 3.56 (t, J=6.0 Hz, 4 H), 6.98 (d, J=8.7 Hz, 2 H), 7.12 (d, J=8.7 Hz, 2 H), 12.20 (s, 1 H); MS (ES) m/z: 234.3 (MH+); HRMS Calcd. for C13H15NO3(M+): 233.1052. Found: 233.1045.