Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[CH:17]=[CH:16][N:15]=[CH:14]3)[CH:8]=2)=[CH:4][CH:3]=1.CCN(CC)CC.ClC(Cl)(Cl)[C:27](Cl)=[O:28].Cl.Cl.[CH:34]([N:37]1[CH2:42][CH2:41][CH:40]([NH2:43])[CH2:39][CH2:38]1)([CH3:36])[CH3:35]>C(Cl)Cl>[CH:34]([N:37]1[CH2:42][CH2:41][CH:40]([NH:43][C:27]([C:14]2[N:13]([CH2:12][C:9]3[CH:8]=[C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)[O:11][N:10]=3)[CH:17]=[CH:16][N:15]=2)=[O:28])[CH2:39][CH2:38]1)([CH3:36])[CH3:35]
Reactant: Clc1ccc(-c2cc(Cn3ccnc3)no2)s1
Reactant: CC(C)N1CCC(N)CC1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)N1CCC(NC(=O)c2nccn2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-(5-Chloro-thiophen-2-yl)-3-imidazol-1-ylmethyl-isoxazole (85 mg) and NEt3 (89 μL) in DCM (3 mL) was added trichloroacetyl chloride (43 μL) dropwise at 0° C. The mixture was stirred for 5 min at 0° C. and for 30 min at RT. More NEt3 (133 μL) and 1-isopropyl-piperidin-4-ylamine dihydrochloride (88 mg) were added and stirring was continued for 2 h at RT. The mixture was concentrated and the residue was purified by preparative HPLC. The fractions containing the product were evaporated to provide 67 mg of the title compound as its trifluoroacetate salt. MS (ESI+): mi/e=434, chloro pattern.
Reaction SMILES: [O:1]1[C@H:3]2[C:4](=[O:30])C=C3[C@:27](C)([C@@H:2]12)[C@@H]1[C@H]([C@H]2[C@](C)(CC1)[C@@H]([C@H](C)CCCC(O)(C)C)CC2)C=C3.C([O:34][C:35](=[O:37])[CH3:36])(=O)C.N1C=CC=CC=1>>[CH3:27][C:2]([CH2:3][C:4]([CH2:36][C:35]([OH:34])=[O:37])=[O:30])=[O:1]
Reactant: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)CC(=O)CC(=O)O

Procedure:
The cholest-5-ene from Example 4 (c) was acetylated with acetic anhydride/pyridine to yield the triacetate which was subjected to bromination with dibromodimethylhydantoin followed by dehydrobromination with trimethylphosphite according to the procedure of Example 3 (b) to yield, after chromatography on silver nitrate impregnated silica gel, 1α,3β,25-triacetoxycholesta-5,7-diene (m.p. 96°-101°; αD -24° in CHCl3 ; λmaxEt2O 262 (7,900), 271 (11,500), 282 (12,400), 294 (7,300) nm.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH2:11][CH2:12][O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[N:3]=1.[Br:20][C:21]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:22]=1[CH:23]=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:20][C:21]1[CH:28]=[CH:27][C:26]([O:29][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH2:11][CH2:12][O:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][O:15]3)[N:3]=2)=[CH:25][C:22]=1[CH:23]=[O:24]
Reactant: O=Cc1cc(O)ccc1Br
Reactant: N#Cc1ccc(Cl)nc1OCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc(Br)c(C=O)c2)nc1OCCOC1CCCCO1
Temperature: 80 °C
Yield: 71.2 %

Procedure:
To a mixture of 6-chloro-2-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-nicotinonitrile (2.4 g, 8.48 mmol) and 2-bromo-5-hydroxy-benzaldehyde (1.87 g, 9.33 mmol) in DMF (25 mL) was added potassium carbonate (1.75 g, 12.69 mmol). The resulting mixture was heated at 80° C. overnight. DMF was removed under reduced pressure, the residue was diluted with EtOAc (200 mL), washed with water (20 mL) and brine (3×20 mL), dried over Na2SO4, filtered, and concentrated to give white solid. Purification was accomplished by flash chromatography on silica gel using 5-25% EtOAc/hexanes as gradient elution yielding the title compound (2.7 g, 71%) as white solid. 1H NMR (400 MHz, CDCl3) δ ppm 10.35 (s, 1H), 7.88 (d, J=8.2 Hz, 1H), 7.75 (d, J=2.7 Hz, 1H), 7.70 (d, J=8.2 Hz, 1H), 7.28 (dd, J=8.6, 3.5 Hz, 1H), 6.60 (d, J=8.2 Hz, 1H), 4.64 (s, 1H), 4.28 (t, J=4.9 Hz, 2H), 3.97-3.80 (m, 2H), 3.72-3.60 (m, 1H), 3.55-3.42 (m, 1H), 1.84-1.64 (m, 2H), 1.61-1.49 (m, 4H).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1C1C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].[Br:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([Cl:31])=[O:30])=[CH:27][CH:26]=1>C(=S)=S>[Br:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([C:8]2[CH:13]=[CH:12][C:11]([C:11]3[CH:10]=[CH:9][C:8]([CH:4]4[CH2:5][CH2:6][CH2:7][N:3]4[CH3:2])=[CH:13][CH:12]=3)=[CH:10][CH:9]=2)=[O:30])=[CH:27][CH:26]=1.[ClH:31]
Reactant: CN1CCCC1c1ccccc1-c1ccccc1
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CN1CCCC1c1ccc(-c2ccc(C(=O)c3ccc(Br)cc3)cc2)cc1
Yield: 30.8 %

Procedure:
350 mg of N-methyl-2-biphenylyl-pyrrolidine hydrochloride are suspended in 10 ml of carbon disulphide and treated with 341 mg of aluminium chloride. A solution of 842 mg of 4-bromo-benzoyl chloride in 3 ml of carbon disulphide is added dropwise to this viscous mass. The mixture is held at reflux for 2 hours and evaporated. The residue is triturated in toluene and then in ethyl acetate, with 90 mg of (±)(4-bromophenyl)-[4′-(1-methylpyrrolidin-2-yl)-biphenyl-4-yl]-methanone•hydrochloride, m.p. 225° C., being obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[S:11][C:10]3[N:12]=[CH:13][CH:14]=[N:15][C:9]=3[NH:8][C:7]=2[CH:16]=1.[CH3:17][NH:18][C:19](SC)=[CH:20][N+:21]([O-:23])=[O:22]>O1CCCC1.O>[N:15]1[C:9]2[NH:8][C:7]3[CH:16]=[C:3]([CH2:2][NH:1][C:19]([NH:18][CH3:17])=[CH:20][N+:21]([O-:23])=[O:22])[CH:4]=[CH:5][C:6]=3[S:11][C:10]=2[N:12]=[CH:13][CH:14]=1
Reactant: CNC(=C[N+](=O)[O-])SC
Reactant: NCc1ccc2c(c1)Nc1nccnc1S2
Solvent: O
Solvent: C1CCOC1
Product: CNC(=C[N+](=O)[O-])NCc1ccc2c(c1)Nc1nccnc1S2
Temperature: 60 °C
Reaction time: 8 h
Yield: 13.9 %

Procedure:
0.7 g of 8-aminomethyl-10H-pyrazino[2,3-b][1,4]-benzothiazine and 1.35 g of N-methyl-1-methylthio-2-nitro-1-ethenamine were dissolved in a solvent mixture of tetrahydrofuran (50 ml) with water (3 ml) and stirred at 60° C. for 8 hours. After filtering off the insoluble matters, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with methanol/dichloromethane) to thereby give 0.14 g of the title compound as yellow crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][NH2:20].[NH:25]1[CH:29]=[C:28]([CH:30]=O)[N:27]=[N:26]1>>[CH3:15][O:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][NH:20][C:8]1[CH:7]=[CH:6][C:5]2[C:4]([NH:1][CH2:30][C:28]3[N:27]=[N:26][NH:25][CH:29]=3)=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: COc1ccccc1CN
Reactant: O=Cc1c[nH]nn1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Product: COc1ccccc1CNc1ccc2c(NCc3c[nH]nn3)cccc2n1

Procedure:
The title compound, MS: m/e=361.5 (M+H+), was prepared from 5-nitro-2-chloroquinoline, 2-methoxybenzylamine and 1H-[1,2,3]triazole-4-carbaldehyde as described in example 26.
Reaction SMILES: [NH2:1][C@:2]1([CH2:24][OH:25])[CH2:6][CH2:5][C@@H:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:9][CH:8]=2)[CH2:3]1.[CH:26]([OH:28])=[O:27]>>[NH2:1][C@:2]1([CH2:24][OH:25])[CH2:6][CH2:5][C@@H:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:27])[CH2:14][CH2:15][CH2:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:9][CH:8]=2)[CH2:3]1.[C:26]([OH:28])(=[O:27])[CH3:2]
Reactant: N[C@]1(CO)CC[C@@H](c2ccc(C#CCCCc3ccccc3)cc2)C1
Reactant: O=CO
Product: CC(=O)O
Product: N[C@]1(CO)CC[C@@H](c2ccc(C(=O)CCCCc3ccccc3)cc2)C1
Temperature: 80 °C
Yield: 28.8 %

Procedure:
((1R,3R)-1-amino-3-(4-(5-phenylpent-1-ynyl)phenyl)cyclopentyl)methanol (900 mg, 2.70 mmol) was dissolved in formic acid (20 mL) and heated to about 80° C. After 4 h the reaction mixture was cooled to room temperature, concentrated in vacuo, diluted with water (10 mL) and reheated to about 80° C. After 4 h the reaction mixture was purified by RP HPLC. Concentration of the fractions containing the desired product provided 1-(4-((1R,3R)-3-amino-3-(hydroxymethyl)cyclopentyl)phenyl)-5-phenylpentan-1-one, Acetic Acid (320 mg, 0.778 mmol, 28.8% yield) as an off white foam.
Reaction SMILES: CC1[CH2:7][CH2:6][CH:5]([OH:8])CC1.[CH2:9]([CH:11]1[O:13][CH2:12]1)Cl.[OH-:14].[Na+]>[Cl-].C[N+](C)(C)C.C(OCC)(=O)C>[CH2:9]([O:14][CH2:7][CH:6]1[O:8][CH2:5]1)[CH:11]1[O:13][CH2:12]1
Reactant: CC1CCC(O)CC1
Reactant: [OH-]
Reactant: ClCC1CO1
Agent: C[N+](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C(OCC1CO1)C1CO1
Temperature: 100 °C
Reaction time: 7 h
Yield: 99 %

Procedure:
In a 750 ml sulfonation flask equipped with thermometer, reflux condenser, N2 inlet and metering device, 114.19 g (1.0 mol) of 4-methylcyclohexanol are added to 1.7 g of catalyst B and the reaction mixture is heated to 100° C. With efficient stirring, 98.0 ml (1.25 mol) of epichlorohydrin are added, and the reaction mixture is thereafter allowed to react for 3 h. After cooling to 50° C., 1 g of tetramethylammonium chloride is added and to the solution are then added 8 g (0.1 mol) of a 50% aqueous solution of NaOH over 5 min, followed by the addition of 42 g (1.05 mol) of pulverised NaOH in increments over 45 min and the suspension is stirred for 7 h. After addition of 200 ml of ethyl acetate, the reaction mixture is filtered, washed with 100 ml of ethyl acetate and the phases are separated. The organic phase is dried over MgSO4 , filtered, and the filtrate is freed from solvent on a rotary evaporator at a bath temperature of 60° C., giving 168.5 g (99% of theory) of colourless glycidyl ether of 4-methylcyclohexanol having the following properties: epoxy value: 4.93 eq/kg (84% of theory); total chlorine content: 4.75%; concentration of hydrolisable chlorine: 5900 ppm.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C@@H:16]3[C@@H:11]([C:12]4[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[C:13]=4[CH2:14][CH2:15]3)[CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:22]([N:24]([CH2:27]C)[CH2:25]C)C.CC(N(C)Cl)=[O:31].O>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:22][N:24]([CH3:27])[C:25](=[O:31])[O:21][C:17]1[C:13]2[CH2:14][CH2:15][C@H:16]3[C@H:11]([CH2:10][CH2:9][N:8]3[CH2:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:12]=2[CH:20]=[CH:19][CH:18]=1
Reactant: Oc1cccc2c1CC[C@H]1[C@@H]2CCN1CC1CCCCC1
Reactant: CC(=O)N(C)Cl
Reactant: CCN(CC)CC
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: O
Product: CN(C)C(=O)Oc1cccc2c1CC[C@H]1[C@@H]2CCN1CC1CCCCC1
Yield: 95.1 %

Procedure:
2.78 g (0.00973 mol) of rac-cis-3-cyclohexylmethyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-6-ol were dissolved in 50 ml of toluene. 1.97 g (2.71 ml, 0.01948 mol) of triethylamine and 120 mg (980 mmol, 0.1 eq.) of 4-dimethylaminopyridine were added thereto in succession and then 1.79 ml (0.01948 mol) of dimethyl chloroformamide were added dropwise thereto. The mixture was boiled under reflux for 2 hours, then cooled, poured into water and extracted with toluene. The organic phase was washed with water, dried with Na2SO4, filtered and concentrated. By chromatography of the residue over 220 g of silica gel with cyclohexane/ethyl acetate 1:1 there were obtained 3.3 g (95%) of oily rac-cis-3-cyclohexylmethyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-6-yl dimethylcarbamate.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][N:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH:6]2[CH2:5][CH2:4]1.[Cl:13][C:14]1[N:19]=[C:18](Cl)[CH:17]=[CH:16][N:15]=1.[C:21]1(O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[O:1]([CH2:2][CH:3]1[CH2:12][N:7]2[CH2:8][CH2:9][N:10]([C:16]3[CH:17]=[CH:18][N:19]=[C:14]([Cl:13])[N:15]=3)[CH2:11][CH:6]2[CH2:5][CH2:4]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OCC1CCC2CNCCN2C1
Reactant: Oc1ccccc1
Reactant: Clc1ccnc(Cl)n1
Product: Clc1nccc(N2CCN3CC(COc4ccccc4)CCC3C2)n1

Procedure:
A mixture of (7RS,9aSR)-7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (U.S. Pat. No. 5,326,874) and 2,4-dichloropyrimidine were combined according to Preparation 3. The product from this reaction was coupled with phenol according to Example 1 to give the title compound. mp (.HCl) 227–233° C. (dec). HRMS calcd for C19H23ClN4O: 358.1560, found: 358.1560.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[CH2:4][O:5][C:6](=[O:8])[CH3:7].[N+:14]([O-])([OH:16])=[O:15]>>[F:1][C:2]1[C:12]([N+:14]([O-:16])=[O:15])=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[CH2:4][O:5][C:6](=[O:8])[CH3:7]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)OCc1c(F)cccc1F
Product: CC(=O)OCc1c(F)ccc([N+](=O)[O-])c1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
Acetic acid 2,6-difluorobenzyl ester (8 g, 42.9 mmol) was added dropwise to fuming nitric acid (50 mL) at 0° C. and the reaction mixture stirred at 0° C. for 30 min. The reaction mixture was poured onto ice and the product extracted with DCM (3×30 mL). The combined organic fractions were washed with sat, aq, NaHCO3 then brine, dried (MgSO4) and concentrated in vacuo to give the title compound as a yellow oil (8.69 g, 87%). 1H NMR 300 MHz δ (CDCl3): 8.21-8.12 (1H, m), 7.09 (1H, ddd, J=9.6, 7.9, 1.9 Hz), 5.24 (2H, t, J=1.5 Hz), 2.10 (3H, s).
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[F:9][C:10]1[CH:11]=[C:12]([C:2]2[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: O=Cc1cnc(Br)s1
Reactant: OB(O)c1ccc(F)cc1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=Cc1cnc(-c2cccc(F)c2)s1
Temperature: 120 °C
Yield: 54 %

Procedure:
To a solution of 2-bromothiazole-5-carbaldehyde (0.6 g, 3.125 mmol) in toluene (2 mL) and ethanol (1 mL) was added 4-fluorophenyl boronic acid (0.524 g, 3.75 mmol), 2 M solution of aq. Na2CO3. The reaction mixture degassed with argon, tetrakis (0.180 g, 0.156 mmol) was added, the reaction mixture was again degassed with argon for 10 min, and heated to 120° C. for 4 h. The reaction mixture was evaporated under vacuum to remove ethanol, the reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (50 mL) and dried over sodium sulphate, filtered and evaporated under reduced pressure to obtain crude product. The crude product was purified by Biotage Isolera® One chromatography (using 6% ethyl acetate and hexane) to give 2-(3-fluorophenyl)thiazole-5-carbaldehyde (0.350 g, 54% yield); 1H NMR (400 MHz, DMSO-d6): δ 8.78 (s, 1H), 7.90 (dd, 2H), 7.61 (q, 1H); 7.44 (t, 1H); LC-MS m/z calcd for [M+H]+ 208.02. found 208.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:63])[C@@H:4]([NH:25][C:26](=[O:62])[C@@H:27]([NH:51]C(OCC1C=CC=CC=1)=O)[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[C:31]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:30]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]([O:20][C:21](=[O:24])[NH:22][CH3:23])[CH:7]=1.C([Cl:71])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.CO.[Pd]>[Cl-:71].[CH2:13]([O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][C@H:4]([NH:25][C:26]([C@@H:27]([NH3+:51])[CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)=[C:31]([O:43][CH2:44][C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH:30]=2)=[O:62])[C:3]([O:2][CH3:1])=[O:63])=[CH:7][C:8]=1[O:20][C:21](=[O:24])[NH:22][CH3:23])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: [H][H]
Reactant: ClCc1ccccc1
Reactant: CNC(=O)Oc1cc(C[C@H](NC(=O)[C@H](Cc2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)NC(=O)OCc2ccccc2)C(=O)OC)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CNC(=O)Oc1cc(C[C@H](NC(=O)[C@@H]([NH3+])Cc2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)C(=O)OC)ccc1OCc1ccccc1
Product: [Cl-]

Procedure:
(S)-2-[(S)-2-Benzyloxycarbonylamino-3-(3,4-bis-benzyloxy-phenyl)-propionylamino]-3-(4-benzyloxy-3-methylcarbamoyloxy-phenyl)-propionic acid methyl ester (0.95 g, 1.115 mmol) was suspended in ethyl acetate (20 ml) and methanol (20 ml). Pd/C (5%, 0.19 g) and benzyl chloride (0.155 g, 1.226 mmol) were added. The hydrogenation was carried out under 30 psi of hydrogen for 3 h. After filtration and removal of solvent, the residue was redissolved in methanol (3 ml) and diethyl ether was added and a white solid precipitated. (S)-1-[(S)-2-(4-Benzyloxy-3-methylcarbamoyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-2-(3,4-bis-benzyloxy-phenyl)-ethyl-ammonium chloride was obtained as white solid by filtration, 0.52 g. 1H NMR (400 MHz, d6-DMSO) 2.63 (d, 3H), 2.73 (m, 1H), 2.82-3.01 (m, 3H), 3.61 (s, 3H), 3.92 (m, 1H), 4.46 (m, 1H), 6.52 (m, 1H), 6.68 (m, 2H), 6.83-6.91 (m, 3H), 7.50 (m, 1H), 8.11 (br, 3H), 8.87 (s, 1H), 8.97 (s, 1H), 9.10 (d, J=7.6 Hz, 1H), 9.57 (s, 1H). m/z 448 (MH+). HPLC/MS (Method B) retention time 4.58 min, m/z 448 (MH+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([C:7]2[N:8]=[N:9][N:10]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[NH:17][N:16]=[C:15]4[C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[CH:11]=2)[CH2:2]1.[F:27][C:28]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:29]=1[CH:30]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[F:27][C:28]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:29]=1[CH2:30][N:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([C:7]2[N:8]=[N:9][N:10]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[NH:17][N:16]=[C:15]4[C:21]3[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=3)[CH:11]=2)[CH2:2]1
Reactant: O=Cc1c(F)cccc1F
Reactant: c1cc(-c2n[nH]c3ccc(-n4cc([C@@H]5CCCNC5)nn4)cc23)ccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: Fc1cccc(F)c1CN1CCC[C@@H](c2cn(-c3ccc4[nH]nc(-c5ccncc5)c4c3)nn2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 26.5 %

Procedure:
To (R)-5-(4-(piperidin-3-yl)-1H-1,2,3-triazol-1-yl)-3-(pyridin-4-yl)-1H-indazole (0.075 g, 0.2 mmol) dissolved in MeOH (3 mL) at 0° C. was added 2,6-difluorobenzaldehyde (0.29 g, 2.1 mmol) and then sodium triacetoxyborohydride (0.11 g, 0.5 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 3 h. Evaporated the solvent, subjected to Preparative Thin Layer chromatography to give (R)-5-(4-(1-(2,6-difluorobenzyl)piperidin-3-yl)-1H-1,2,3-triazol-1-yl)-3-(pyridin-4-yl)-1H-indazole (0.025 g).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][C:15]([NH:17][C:18]3[CH:19]=[C:20]([C:24]([O-:26])=[O:25])[N:21]([CH3:23])[CH:22]=3)=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1>C1COCC1.[Pd]>[CH:10]1[C:11]2[CH:12]([CH2:14][C:15]([NH:17][C:18]3[CH:19]=[C:20]([C:24]([OH:26])=[O:25])[N:21]([CH3:23])[CH:22]=3)=[O:16])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: Cn1cc(NC(=O)CC2c3ccccc3-c3ccccc32)cc1C(=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: Cn1cc(NC(=O)CC2c3ccccc3-c3ccccc32)cc1C(=O)O
Yield: 64.3 %

Procedure:
To a solution of the benzylester (20a) (900 mg) dissolved in THF (10 ml) was added 10% Pd/C (100 mg). The solution was hydrogenated (1 atm) for 19 hours and worked up using standard methods to yield 580 mg (80%) of compound (21a). 1H NMR (DMSO-d6) δ 9.4 (s, 1 H), 8.0 (m, 2 H), 7.8 (m, 2 H), 7.3 (m, 4 H), 7.1 (s, 1 H), 6.8 (s, 1 H), 4.6 (m, 2 H), 4.3 (m, 1 H), 3.8 (s, 3 H).
Reaction SMILES: [CH2:1]([C:3]1[C:8]2[N:9]=[CH:10][O:11][C:7]=2[CH:6]=[CH:5][C:4]=1[N:12]=[C:13]=[S:14])[CH3:2].[CH2:15]([NH2:18])[CH2:16][NH2:17]>C1(C)C=CC=CC=1>[NH2:17][CH2:16][CH2:15][NH:18][C:13](=[S:14])[NH:12][C:4]1[CH:5]=[CH:6][C:7]2[O:11][CH:10]=[N:9][C:8]=2[C:3]=1[CH2:1][CH3:2]
Reactant: CCc1c(N=C=S)ccc2ocnc12
Reactant: NCCN
Solvent: Cc1ccccc1
Product: CCc1c(NC(=S)NCCN)ccc2ocnc12
Reaction time: 0.5 h

Procedure:
A solution of 4-ethyl-5-isothiocyanatobenzoxazole (3.58 mmol) in toluene (75 mL) is treated with ethylenediamine (12.53 mmol). The reaction is stirred for 30 minutes as the product precipitates. The precipitate is filtered and dried in an oven to yield 5-[N'-(2-aminoethyl)thioureido]-4-ethylbenzoxazole as a white solid.
Reaction SMILES: [CH:1]1([N:7]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8](=[O:18])[NH:9][C:10]2[S:11][C:12]([C:15]([OH:17])=O)=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CCOC(C)=O.CN(C=O)C>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([C:15]([C:12]2[S:11][C:10]([NH:9][C:8]([N:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)=[O:18])=[N:14][CH:13]=2)=[O:17])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: O=C(O)c1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cnc(NC(=O)N(C3CCCCC3)C3CCCCC3)s2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
2-(3,3-Dicyclohexyl-ureido)-thiazole-5-carboxylic acid (176 mg, 0.50 mmol), piperazine carboxylic acid tert-butyl ester (140 mg, 0.75 mmol), and HBTU (285 mg, 0.75 mmol) were weighed out and added to a 25 mL reaction flask. DMF (5 mL) and DIEA (175 μL, 1.0 mmol) were added. The reaction was stirred under nitrogen at ambient temperature overnight. The reaction was diluted with EtOAc (10 mL) and quenched with saturated aqueous NH4Cl (10 mL). After separation and extraction with EtOAc (2×5 mL) the combined organic portions were dried over MgSO4. Purification with silica gel and 10% EtOAc in CH2Cl2 afforded 187 mg (72%) of the desired compound.
Reaction SMILES: Br[CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[CH3:12][C:13]1[CH:18]=[CH:17][C:16](N)=[CH:15][CH:14]=1.C(#[N:22])C>>[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]([NH2:22])([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([OH:5])=[O:4])=[CH:15][CH:14]=1
Reactant: Cc1ccc(N)cc1
Reactant: O=C(O)C(Br)c1ccccc1
Reactant: CC#N
Product: Cc1ccc(C(N)(C(=O)O)c2ccccc2)cc1
Yield: 78 %

Procedure:
To a solution of α-bromophenylacetic acid (1.00 g, 4.65 mmol) in acetonitrile (20 mL), is added 4-methyl-phenylamine (0.96 g, 9.30 mmol) and the mixture reacted in a closed vessel under MW irradiation at 100° C. for 1 hour (UPLC-MS monitoring: complete conversion). Solvent is evaporated and residue is portioned between EtOAc and 2N HCl. The organic phase is dried over Na2SO4, filtered and evaporated to dryness to get desired compound as a yellow solid (0.88 g, 78% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:18]Br>C(Cl)(Cl)Cl>[Br:18][CH2:16][C:15]([C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)=[O:17]
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: O=C(CBr)c1ccc(OCc2ccccc2)cc1
Reaction time: 0.08 h

Procedure:
Bromination of 4′-benzyloxyacetophenone (step 2): Bromine (80 mmol) was added dropwise over 5 min to a stirred solution of 4′-benzyloxyacetophenone (70 mmol) in 40 ml chloroform. This mixture was stirred for an additional 5 min and quenched with saturated sodium bicarbonate in water until the pH reached 7. The organic layers were combined, dried over MgSO4, and concentrated to dryness. The crude mixture was purified over a silica gel column and eluted with methylene chloride to yield 2-bromo-4′-benyloxyacetophenone. An Rf of 0.62 was observed when resolved by thin layer chromatography using methylene chloride. 1H nmr (δ, ppm, CDCl3), 7.97 (2H, δ, 9.2 Hz, O—Ar—C(O)), 7.43 (5H, m, Ar′CH2O—), 7.04 (2H, δ, 9.0 Hz, O—Ar—C(O)), 5.15 (2H, s, Ar′CH2O—), 4.40 (2H, s, CH2Br).