Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:10]([CH3:22])([CH3:21])[C:9]=3[O:23][C:4]=2[CH:3]=1.CC(C)([O-])C.[Na+].C(O)CO.CN(C)C=O.[F:39][C:40]1[CH:41]=[C:42]([SH:46])[CH:43]=[CH:44][CH:45]=1>[Cu]I>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][C:8]2[C:5]3[CH:6]=[CH:7][C:2]([S:46][C:42]4[CH:43]=[CH:44][CH:45]=[C:40]([F:39])[CH:41]=4)=[CH:3][C:4]=3[O:23][C:9]=2[C:10]1([CH3:22])[CH3:21])=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: Fc1cccc(S)c1
Reactant: CC(C)(C)OC(=O)N1CCc2c(oc3cc(I)ccc23)C1(C)C
Agent: [Cu]I
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: OCCO
Product: CC(C)(C)OC(=O)N1CCc2c(oc3cc(Sc4cccc(F)c4)ccc23)C1(C)C
Temperature: 120 °C
Reaction time: 15 h

Procedure:
To tert-butyl 7-iodo-1,1-dimethyl-3,4-dihydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate P30 (0.505 g, 1.18 mmol) was added sodium tert-butoxide (341 mg, 3.55 mmol), copper(I) iodide (20 mg, 0.08 mmol), 1,2-ethanediol (132 μL, 2.38 mmol), N,N-dimethylformamide (17 mL, 210 mmol), and finally 3-Fluoro-benzenethiol (101 μL, 1.19 mmol). The reaction mixture was flushed with N2 and heated at 120° C. under N2. After 15 h, the reaction mixture was concentrated under high vacuum, the residue dissolved in 5% methanol-methylene chloride and then filtered through a celite-silica plug. The filtrate was concentrated and purified by silica chromatography (EtOAc/hexane) to afford the product as a pale yellow oil. MS m/z: 428 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:17])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[N:8]([CH:13]1[CH2:15][CH2:14]1)[C:7]2=[O:16].Cl.[CH3:19][C:20]1([NH2:23])[CH2:22][CH2:21]1.C(N(CC)CC)C>CS(C)=O.O>[Br:1][C:2]1[C:3]([F:17])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:23][C:20]1([CH3:19])[CH2:22][CH2:21]1)[N:8]([CH:13]1[CH2:15][CH2:14]1)[C:7]2=[O:16]
Reactant: O=c1c2ccc(F)c(Br)c2nc(Cl)n1C1CC1
Reactant: CC1(N)CC1
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(Nc2nc3c(Br)c(F)ccc3c(=O)n2C2CC2)CC1
Temperature: 100 °C
Yield: 69.2 %

Procedure:
A glass microwave reaction vessel was charged with 8-bromo-2-chloro-3-cyclopropyl-7-fluoroquinazolin-4(3H)-one (721) (125 mg, 0.394 mmol) and 1-methylcyclopropanamine hydrochloride (127 mg, 1.18 mmol, Small Molecules Inc.) in DMSO (1.0 mL) followed by triethylamine (0.16 mL, 1.18 mmol). The reaction mixture was stirred and heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 100° C. for 1 h. The mixture was diluted with water (20 mL) and extracted with DCM (30 mL×4). The combined organic layers were washed with water (15 mL), dried (MgSO4), filtered and concentrated. The residue was triturated with hexanes and filtered to give the crude product 96 mg. MS (ESI, pos. ion) m/z: 352 (M+1); 1H NMR (400 MHz, CDCl3) δ ppm 8.03 (1H, dd, J=8.8, 6.1 Hz), 6.90 (1H, t, J=8.4 Hz), 2.65-2.74 (1H, m), 1.61 (3H, s), 1.30-1.37 (2H, m), 0.83-0.96 (6H, m).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1.[NH2:17][C:18]([NH2:20])=[S:19]>>[CH3:1][O:2][C:3]([C:4]1[N:17]=[C:18]([NH2:20])[S:19][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1)=[O:16]
Reactant: COC(=O)C(=O)C(Cl)c1cccc(OC)c1
Reactant: NC(N)=S
Product: COC(=O)c1nc(N)sc1-c1cccc(OC)c1

Procedure:
prepared by reaction of 3-chloro-3-(3-methoxy-phenyl)-2-oxo-propionic acid methyl ester with thiourea. LC-MS: tR=0.75 min; [M+H]+=265.3.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14].Br[CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C=O)C.C(OCC)C>[CH2:20]([O:19][C:17](=[O:18])[CH:16]([O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[F:7])[CH3:22])[CH3:21]
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)C(C)Oc1ccccc1F
Temperature: 90 °C
Reaction time: 0.08 h
Yield: 94.1 %

Procedure:
Cesium carbonate (65.69 g, 201.61 mmol) is added to a solution of 2-fluorophenol (9 mL, 100.84 mmol, d=1.256) in anhydrous DMF (300 mL) at room temperature under an atmosphere of nitrogen. After five minutes, ethyl 2-bromopropionate (130.1 mL, 100.84 mmol, d=1.394) is added rapidly dropwise and the resultant mixture is allowed to stir at 90° C. for 18 h. The reaction mixture is diluted with diethyl ether, then extracted twice with 1N HCl and twice with water. The organic layer is dried, concentrated, and purified by flash chromatography (25% ether in hexanes) to provide the titled compound (20.14 g, 94%). 1H NMR (400 MHz, CDCl3): □. 7.07-6.96 (m 2H), 6.93-6.87 (m, 2H), 4.73, 4.71 (ABq, 1H, J=6.7 Hz). 4.21-4.15 (m, 2H), 1.61 (d, 3H, J=6.7 Hz), 1.21 (t, 3H, J=6.7 Hz). MS [EI+] 507 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:13]=[CH:12][C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=1)=[O:3].[C:14]([O:17][CH2:18][CH3:19])(=[O:16])[CH3:15].ClC1C=CC(C(C2CC2)(O)CC(OCC)=O)=CC=1>>[O:8]1[C:7]2[CH:12]=[CH:13][C:4]([C:2]([OH:3])([CH3:1])[CH2:15][C:14]([O:17][CH2:18][CH3:19])=[O:16])=[CH:5][C:6]=2[O:11][CH2:10][CH2:9]1
Reactant: CCOC(C)=O
Reactant: CC(=O)c1ccc2c(c1)OCCO2
Agent: CCOC(=O)CC(O)(c1ccc(Cl)cc1)C1CC1
Product: CCOC(=O)CC(C)(O)c1ccc2c(c1)OCCO2

Procedure:
The title compound was prepared starting from 2.00 g (11.22 mmol) of 1,4-benzodioxan-6-yl methyl ketone and 4.74 ml (22.45 mmol) of ethyl acetate in analogy to the synthesis of the compound from Example 90A. 2.52 g (84% of theory) of the title compound were obtained.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].Br[C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[CH2:15][C:16]([O:18][CH3:19])=[O:17].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC>C1COCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:14][C:12]1[CH:11]=[CH:10][C:9]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:8]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH:13]=1
Reactant: COC(=O)Cc1ccc(F)cc1Br
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(F)cc1C#C[Si](C)(C)C
Temperature: 35 °C

Procedure:
A suspension of (trimethylsilyl)acetylene (0.696 g, 7.08 mmol), methyl 2-(2-bromo-4-fluorophenyl)acetate (A48) (0.500 g, 2.02 mmol), PPh3 (0.053 g, 0.202 mmol), CuI (39 mg, 0.202 mmol), Et3N (1.41 mL, 10.1 mmol) and PdCl2(PPh3)2 (0.142 g, 0.202 mmol) in THF (25 mL) was heated at 35° C. for 16 hours. The resulting mixture was adsorbed onto silica gel and purified using column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-40% EtOAc in petroleum benzine 40-60° C.) to yield the title compound A49 as a clear oil (0.212 g, 40%); LCMS-A: rt 6.830 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]([NH:21][NH2:22])=O)=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:23]([F:26])([F:25])[F:24].[CH3:27]OC(OC)OC.C(#N)C.[CH2:37]([O:39][C:40](=[O:45])[CH2:41][CH:42]([NH2:44])[CH3:43])[CH3:38]>C(O)(=O)C>[CH2:37]([O:39][C:40](=[O:45])[CH2:41][CH:42]([N:44]1[CH:27]=[N:22][N:21]=[C:19]1[C:13]1[C:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:23]([F:24])([F:25])[F:26])[CH:4]=2)(=[O:9])=[O:10])=[CH:17][C:16]([Cl:18])=[CH:15][N:14]=1)[CH3:43])[CH3:38]
Reactant: NNC(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: COC(OC)OC
Reactant: CCOC(=O)CC(C)N
Solvent: CC(=O)O
Solvent: CC#N
Product: CCOC(=O)CC(C)n1cnnc1-c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
A mixture of 4-Chloro-N-(5-chloro-2-hydrazinocarbonyl-pyridin-3-yl)-3-trifluoromethyl-benzenesulfonamide (42.8 mg, 0.10 mmol), trimethylorthoformate (53 mg, 0.50 mmol), acetonitrile (1.5 mL), 3-Amino-butyric acid ethyl ester (131 mg, 1.0 mmol) and acetic acid (0.2 mL) was stirred at 120° C. for 2 hours. After evaporation of solvent under reduced pressure, the residue was further purified through automated normal-phase chromatography and dried (Lyophilizer) to afford title compound. MS (ES) [M+H]+ expected 552.0. found 552.0.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]#[N:11])[C:4]=2[CH:3]=[CH:2]1.C1C(=O)N([Cl:19])C(=O)C1>CN(C=O)C.CCOC(C)=O>[Cl:19][C:3]1[C:4]2[C:5]([C:10]#[N:11])=[CH:6][CH:7]=[CH:8][C:9]=2[NH:1][CH:2]=1
Reactant: N#Cc1cccc2[nH]ccc12
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cccc2[nH]cc(Cl)c12
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.8 %

Procedure:
To 1H-indole-4-carbonitrile (514.0 mg, 3.61 mmol) in anhydrous DMF (2.8 mL) at 0° C. was added dropwise NCS (517.3 mg, 3.80 mmol) dissolved in DMF (8.5 mL). The reaction mixture was slowly warmed to RT. After stirring for 20 h, the mixture was diluted with EtOAc. The organic layer was washed with satd. aq. NaHCO3 solution, water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by SiO2 chromatography eluting with heptane:EtOAc to afford 3-chloro-1H-indole-4-carbonitrile as a white solid (630 mg, 98.7%). MS (ESI) m/z: 177.1 [M+1]+. 1H NMR (400 MHz, DMSO) 11.99 (br s, 1H), 7.80 (d, J=2.8 Hz, 1H), 7.78 (d, J=8.2 Hz, 1H), 7.61 (d, J=7.2 Hz, 1H), 7.37-7.26 (m, 1H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:16]=[C:17]([O:21]C)[C:18]=1[O:19]C)[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]([SH:15])=[S:14])[CH2:9][CH2:8]1.C(Cl)Cl.B(Br)(Br)Br>O>[OH:21][C:17]1[CH:16]=[C:5]([CH:4]=[C:3]([OH:2])[C:18]=1[OH:19])[CH2:6][N:7]1[CH2:8][CH2:9][N:10]([C:13]([SH:15])=[S:14])[CH2:11][CH2:12]1
Reactant: COc1cc(CN2CCN(C(=S)S)CC2)cc(OC)c1OC
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Oc1cc(CN2CCN(C(=S)S)CC2)cc(O)c1O
Temperature: -78 °C
Reaction time: 120 h
Yield: 11.4 %

Procedure:
In a nitrogen atmosphere, 1,033 mg (3.02 mmol.) of 4-(3,4,5-trimethoxybenzyl)-1-piperazinecarbodithioic acid was suspended indry methylene chloride, and under chilling to -78° C. in a dry ice-acetone bath, to this was dropwise added 50 ml of methylene chloride solution containing 3 ml of boron tribromide. The mixture was left to slowly reach room temperature, and then stirred for 5 days at room temperatuere. To the reaction mixture was added water, and insolubles wereremoved by filtration. The insolubles were then washed with water, and thusobtained yellow solid was dissolved in methanol. The methanol solution was filtered to remove insoubles, and the solvent of the filtrate was distilled off. To the obtained yellow semi-oil was added ether, and insolubles were removed by filtration. The filtrate was dried and further purified by cellulose column chromatography (Avicel, trademark, eluent: butanol/acetic acid/water (10/1/1)). The eluate was treated to distill offthe solvent (eluent). To the residue was added ether, and insolubles were removed by filtration. The solvent of the filtrate was distilled off, leaving 103 mg of the desired compound, m.p. higher than 250° C., yield 11.4%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:4][N:3]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>N1C=CC=CC=1>[C:22]([O:21][C:18]1[CH:17]=[CH:16][C:15]([C:5]2[N:6]=[C:7]([CH2:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:2]([NH2:1])=[N:3][CH:4]=2)=[CH:20][CH:19]=1)(=[O:24])[CH3:23]
Reactant: Nc1ncc(-c2ccc(O)cc2)nc1Cc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(-c2cnc(N)c(Cc3ccccc3)n2)cc1
Temperature: 0 °C
Yield: 96.7 %

Procedure:
Under an argon atmosphere, 2-amino-3-benzyl-5-(4-hydroxyphenyl)pyrazine (coelenteramine) (c-5) (prepared by the method described in Adamczyk, M. et al., Org. Prep. Proced. Int., 33, 477-485 (2001)) (303 mg, 1.09 mmol) was dissolved in pyridine (2 mL) and cooled to 0° C. To this was added acetic anhydride (133 μL, 1.40 mmol) and stirred for an hour after warming to room temperature. To the mixture was added saturated aqueous solution of sodium bicarbonate and ethyl acetate to stop the reaction. After separating the aqueous layer and organic layer, it was extracted 3 times with ethyl acetate. The organic layer was washed 3 times with water and once with saturated brine, and then dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated under reduced pressure with a rotary evaporator. The residue was purified by column chromatography (50 g, n-hexane/ethyl acetate=1/1) to give 5-(4-acetoxyphenyl)-2-amino-3-benzylpyrazine (c-19) as a pale yellow solid (337 mg, 96.7%). Rf=0.31 (n-hexane/ethyl acetate=3/2). Mp. 183.5-185.5° C. 1H NMR (400 MHz, DMSO-d6) δ 2.27 (s, 3H), 4.07 (s, 2H), 6.42 (s, 2H), 7.12-7.17 (AA′BB′, 2H), 7.19 (d, J=7.2 Hz, 1H), 7.27 (t, J=7.5 Hz, 2H), 7.33 (d, J=7.0 Hz, 2H), 7.90-7.95 (AA′BB′, 2H), 8.41 (s, 1H). IR (KBr, cm−1) 513, 596, 640, 654, 710, 746, 851, 910, 1016, 1136, 1167, 1198, 1217, 1373, 1423, 1452, 1466, 1493, 1508, 1535, 1630, 1746, 3148, 3289.
Reaction SMILES: BrCC1CC1.[Cl:6][C:7]1[C:8](=[O:44])[N:9]([C:23]2[C:41]([F:42])=[CH:40][C:26]([CH2:27][N:28]([CH2:36][CH:37]3[CH2:39][CH2:38]3)C(=O)OC(C)(C)C)=[CH:25][C:24]=2[F:43])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22]>>[ClH:6].[Cl:6][C:7]1[C:8](=[O:44])[N:9]([C:23]2[C:41]([F:42])=[CH:40][C:26]([CH2:27][NH:28][CH2:36][CH:37]3[CH2:38][CH2:39]3)=[CH:25][C:24]=2[F:43])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22]
Reactant: CC(C)(C)OC(=O)N(Cc1cc(F)c(-n2ccc(OCc3ccc(F)cc3F)c(Cl)c2=O)c(F)c1)CC1CC1
Agent: BrCC1CC1
Product: Cl
Product: O=c1c(Cl)c(OCc2ccc(F)cc2F)ccn1-c1c(F)cc(CNCC2CC2)cc1F

Procedure:
The title compound was prepared by direct analogy with replacing iodomethane with bromocyclopropylmethane and extending the reaction time to 6 hours in Step 1. Step 1: 1 tert-butyl 4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]-3,5-difluorobenzyl(cyclopropylmethyl)carbamate
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:32])[CH:15]([C:19]2[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:21][CH:20]=2)[CH2:16][CH2:17][CH3:18])=[CH:10][CH:9]=1.[H][H]>CC(O)C>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C@H:14]([OH:32])[C@@H:15]([C:19]2[CH:20]=[CH:21][C:22]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])=[CH:30][CH:31]=2)[CH2:16][CH2:17][CH3:18])=[CH:12][CH:13]=1
Reactant: [H][H]
Reactant: CCCC(C(=O)c1ccc(Cl)cc1)c1ccc(C(=O)OC(C)(C)C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CCC[C@H](c1ccc(C(=O)OC(C)(C)C)cc1)[C@@H](O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To degassed 2-propanol (5.0 mL) was added RuCl2-[(8)-xyl-SEGPHOS][(S)-DAIPEN] (16.2 mg, 0.0134 mmol) and potassium t-butoxide (300 mg, 2.67 mmol). After this mixture was stirred at room temperature for 2 hours, the material obtained in Step A was added in 2-propanol (25 mL). This mixture was then treated with hydrogen (100 psi) at room temperature for 18 hours. The mixture was concentrated, then the residue was recrystallized from IPA/water to afford the title compound. 1H NMR (400 MHz, CDCl3) δ 7.96 (m, 2H), 7.32 (m, 2H), 7.26 (m, 2H), 7.22 (m, 2H), 4.76 (dd, J=7.7, 2.9 Hz, 1H), 2.89 (ddd, J=11.5, 7.7, 4.2 Hz, 1H), 1.84 (d, J=2.9 Hz, 1H), 1.62 (s, 9H), 1.61 (m, 1H), 1.41 (m, 1H), 1.05 (m, 2H), 0.76 (t, J=7.3 Hz, 3H); LC2: 2.38 min. (M−H2O-tBu+H)+ 301; Chiral SFC Method: Chiralpak AD-H (250×4.6 mm), isocratic 15% MeOH/CO2, 1.5 mL/min, 200 bar, 35° C., 215 nm, 15 minutes: desired alcohol retention time=9.8 min; enantiomeric alcohol, retention time=10.6 min; diastereomeric alcohols retention times=5.2 and 6.3 min.
Reaction SMILES: BrC1C=C(C=CC=1)C(NC(C1N=NC(NC2C=C(OC)C(OC)=C(OC)C=2)=NC=1)C)=O.[NH2:32][CH:33]([C:35]1[N:40]=[N:39][C:38]([NH:41][C:42]2[CH:47]=[C:46]([O:48][CH3:49])[C:45]([O:50][CH3:51])=[C:44]([O:52][CH3:53])[CH:43]=2)=[N:37][CH:36]=1)[CH3:34].[N+:54]([C:57]1[NH:61][C:60]([C:62](O)=[O:63])=[CH:59][CH:58]=1)([O-:56])=[O:55].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[N+:54]([C:57]1[NH:61][C:60]([C:62]([NH:32][CH:33]([C:35]2[N:40]=[N:39][C:38]([NH:41][C:42]3[CH:43]=[C:44]([O:52][CH3:53])[C:45]([O:50][CH3:51])=[C:46]([O:48][CH3:49])[CH:47]=3)=[N:37][CH:36]=2)[CH3:34])=[O:63])=[CH:59][CH:58]=1)([O-:56])=[O:55]
Reactant: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Reactant: O=C(O)c1ccc([N+](=O)[O-])[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(Br)c3)nn2)cc(OC)c1OC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Nc2ncc(C(C)NC(=O)c3ccc([N+](=O)[O-])[nH]3)nn2)cc(OC)c1OC
Yield: 75.6 %

Procedure:
In a similar manner as described for Intermediate 18, 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (200 mg, 0.65 mmol), 5-nitro-1H-pyrrole-2-carboxylic acid (132 mg, 0.85 mmol), diisopropylethylamine (0.33 mL, 1.9 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (360 mg, 0.94 mmol) in dimethylformamide (5 mL) gave 5-nitro-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)-1H-pyrrole-2-carboxamide (218 mg, 75%) as a yellow solid. MS m/z 443 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:7]2[C:8](C)=[CH:9][NH:10][C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14].[Br:15]Br>C(O)(=O)C.O>[Br:15][C:8]1[C:7]2[N:2]([CH3:1])[C:3](=[O:14])[N:4]([CH3:13])[C:5](=[O:12])[C:6]=2[NH:10][CH:9]=1
Reactant: Cc1c[nH]c2c(=O)n(C)c(=O)n(C)c12
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(=O)c2[nH]cc(Br)c2n(C)c1=O
Reaction time: 3 h
Yield: 57.4 %

Procedure:
To a solution of Intermediate 1 (500 mg, 2.800 mmol) in acetic acid (5 mL) was added a solution of bromine (430 mg, 2.700 mmol) in acetic acid (5 mL) dropwise with stirring, after which water (1.2 mL) was added. The reaction mixture was stirred for another 20 min and diluted with two volumes of cold water. After 3 h, the precipitate was filtered off and washed with diethyl ether to afford 400 mg of the product as a white solid; 1H NMR (δ ppm, 300 MHz, DMSO-d6) 3.23 (s, 3H), 3.65 (s, 3H), 7.42 (s, 1H), 12.59 (br s, 1H); APCI-MS (m/z) 258.19 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[C:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:5]([NH2:14])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:21](Cl)(=[O:25])[CH2:22][CH2:23][CH3:24].O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]#[C:9][C:10]([CH3:11])([CH3:13])[CH3:12])[C:5]([NH:14][C:21](=[O:25])[CH2:22][CH2:23][CH3:24])=[CH:4][CH:3]=1
Reactant: CC(C)(C)C#Cc1nc(Cl)ccc1N
Reactant: CCCC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CCCC(=O)Nc1ccc(Cl)nc1C#CC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 104 %

Procedure:
To a solution of 6-chloro-2-(3,3-dimethyl-but-1-ynyl)-pyridin-3-ylamine (11.5 g, 55.2 mmol) and pyridine (13.1 g, 166 mmol) in CH2Cl2 (150 mL) was added butyryl chloride (6.5 g, 61 mmol) dropwise at 0° C. The mixture was allowed to warm to room temperature and was stirred at this temperature overnight. Water (50 mL) was added dropwise at −0° C. The resulting mixture was extracted with ethyl acetate (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give the crude N-[6-chloro-2-(3,3-dimethyl-but-1-ynyl)-pyridin-3-yl]-butyramide (16 g), which was used in the next step without further purification. 1H NMR (CDCl3, 300 MHz) δ 8.72 (d, J=9.0 Hz, 1H), 7.88 (brs, 1H), 7.23 (d, J=8.4 Hz, 1H), 2.40 (d, J=7.2 Hz, 2H), 1.83-1.75 (m, 2H), 1.40 (s, 9H), 1.04 (d, J=7.2 Hz, 3H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@H:11]1[CH2:14][C@H:13]([NH:15][C:16]2[C:21]([N+:22]([O-])=O)=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:12]1.[Cl-].[NH4+]>O.C(O)C.[Fe]>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@H:11]1[CH2:12][C@H:13]([NH:15][C:16]2[C:21]([NH2:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:14]1
Reactant: O=[N+]([O-])c1cccnc1N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cccnc1N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
Trans-N1-(benzo[d]thiazol-2-yl)-N3-(3-nitropyridin-2-yl)cyclobutane-1,3-diamine (580 mg, 1.699 mmol), ammonium chloride (46 mg, 0.849 mmol) and iron dust (0.036 mL, 5.10 mmol) were suspended in a mixture of water (1.000 mL) and ethanol (3 mL). The reaction mixture was stirred at 50° C. for 16 hours then cooled and partitioned between water (100 mL) and ethyl acetate (100 mL). The organic phase was dried with sodium sulfate and evaporated to dryness under reduced pressure. Purification using silica chromatography (hexane to ethyl acetate gradient) gave N2-(trans-3-(benzo[d]thiazol-2-ylamino)cyclobutyl)pyridine-2,3-diamine (370 mg, 1.188 mmol, 69.9% yield) as light-yellow solid.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C-:3]=[N:2]1.[Na+].[CH3:7][O:8][C:9]1[CH:62]=[CH:61][CH:60]=[CH:59][C:10]=1[CH2:11][O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH:24]2[O:36][CH2:37][CH2:38][O:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[CH2:46][CH2:47]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:19][CH:18]=1>CN(C)C=O.COC(C)(C)C>[CH3:7][O:8][C:9]1[CH:62]=[CH:61][CH:60]=[CH:59][C:10]=1[CH2:11][O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:30])[CH2:25][CH:24]2[O:36][CH2:37][CH2:38][O:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[CH2:46][CH2:47][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:21][CH:22]=1
Reactant: [c-]1nc[nH]n1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCOS(=O)(=O)c2ccc(C)cc2)cc1
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCn2cncn2)cc1
Temperature: 90 °C
Reaction time: 0.67 h

Procedure:
0.051 g of sodium 1,2,4-triazolide is admixed with a solution of 0.10 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-(2-{2-[2-(toluene-4-sulphonyloxy)ethyl]phenoxy}-ethoxy)piperidine-1-carboxylate in 3 ml of N,N-dimethylformamide. The reaction mixture is stirred at 90° C. over 40 minutes. The mixture is cooled to room temperature, diluted with tert-butyl methyl ether and washed with water. The water phase is extracted with tert-butyl methyl ether. The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.13 (2:1 EtOAc-heptane); Rt=5.66.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:30]=[CH:29][C:11]([O:12][C:13]2[CH:22]=[C:21]3[C:16]([CH:17]([C:23]([O:25][CH3:26])=[O:24])[CH2:18][CH2:19][O:20]3)=[CH:15][C:14]=2[C:27]#[N:28])=[CH:10][CH:9]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl.CCOC(C)=O>[C:27]([C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:13]=1[O:12][C:11]1[CH:29]=[CH:30][C:8]([C:6]([OH:7])=[O:5])=[CH:9][CH:10]=1)[O:20][CH2:19][CH2:18][CH:17]2[C:23]([O:25][CH3:26])=[O:24])#[N:28]
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)OC(C)(C)C)cc3)c(C#N)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(C#N)cc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.1 %

Procedure:
Methyl 7-(4-(tert-Butoxycarbonyl)phenoxy)-6-cyanochroman-4-carboxylate (18.5 g, 45.185 mmol) was dissolved in dichloromethane (200 mL). Trifluoroacetic acid (50 mL) was added and the mixture was stirred at ambient temperature for 1.5 hours, and then concentrated under reduced pressure to provide a crude solid. The solid was dissolved in EtOAc (200 ml), and hexanes (600 ml) were added with stirring. White solid was crashed out and was collected by filtration to provide 13.11 g of the desired compound as white solid (81.9%). The mother liquor was concentrated and the residue was dissolved in EtOAc (25 ml). Hexanes (100 ml) were added with stirring and a white solid was crashed out and was collected by filtration to provide an additional 1.14 g of the desired compound.