Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1([S:7]([NH:10][C:11]2[CH:16]=[C:15]([CH3:17])[C:14](=[O:18])[N:13]([CH3:19])[C:12]=2[N:20]([C:28]2[CH:33]=[CH:32][C:31]([I:34])=[CH:30][C:29]=2[F:35])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:9])=[O:8])[CH2:6][CH2:5]1)[CH:2]=C.CC1C=CC=C(C)N=1.[O:44]1CCOCC1>O.O=[Os](=O)(=O)=O>[CH3:19][N:13]1[C:14](=[O:18])[C:15]([CH3:17])=[CH:16][C:11]([NH:10][S:7]([C:4]2([CH2:1][CH:2]=[O:44])[CH2:6][CH2:5]2)(=[O:8])=[O:9])=[C:12]1[N:20]([C:28]1[CH:33]=[CH:32][C:31]([I:34])=[CH:30][C:29]=1[F:35])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:24])[CH3:25]
Reactant: C=CCC1(S(=O)(=O)Nc2cc(C)c(=O)n(C)c2N(C(=O)OC(C)(C)C)c2ccc(I)cc2F)CC1
Reactant: C1COCCO1
Agent: O=[Os](=O)(=O)=O
Solvent: Cc1cccc(C)n1
Solvent: O
Product: Cc1cc(NS(=O)(=O)C2(CC=O)CC2)c(N(C(=O)OC(C)(C)C)c2ccc(I)cc2F)n(C)c1=O
Temperature: 0 °C
Reaction time: 18 h
Yield: 79 %

Procedure:
To a solution of tert-butyl 3-(1-allylcyclopropanesulfonamido)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-2-yl(2-fluoro-4-iodophenyl)carbamate (2.370 g, 3.838 mmol) in dioxane (38.4 ml) under a nitrogen atmosphere was added H2O (7.7 ml). Then NalO4 (4 eq, 3.284 g, 15.353 mmol) and 2,6-dimethyl pyridin (2 eq, 0.894 ml, 7.676 mmol) were added and the mixture was cooled to 0° C. At this temperature OsO4 (4% in t-butanol, 0.04 eq, 1,925 ml, 0.154 mmol) was added. The mixture was allowed to come to room temperature and then stirred for 18 hours. The mixture was diluted with H2O (4 ml) to form a fine suspension. After stirring for 30 min the precipitate was filtered off and washed with water, which dissolved the precipitate. The filtrate was extracted twice with ethyl acetate, washed once with brine, dried and concentrated in vacuo. The residue was purified by flash chromatography (Biotage system) to afford the title compound (1.92 g, 79%) as a mixture of the aldehyde and a cyclised 1,2-thiazolidin-3-ol 1,1-dioxide form.
Reaction SMILES: ClCl.[Cl:3][C:4]1[N:9]=[C:8]([CH3:10])[CH:7]=[CH:6][CH:5]=1.C1C(=O)N([Cl:18])C(=O)C1>>[Cl:18][CH2:10][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:3])[N:9]=1
Reactant: Cc1cccc(Cl)n1
Reactant: O=C1CCC(=O)N1Cl
Agent: ClCl
Product: ClCc1cccc(Cl)n1

Procedure:
MS (ESI) 162, 164, 166 (M+H)+, Cl2 pattern. Prepared from 6-chloro-2-picoline and NCS in place of NBS.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([Si](C(C)C)(C(C)C)C(C)C)[C:5]2=[N:6][CH:7]=1.[I:21]I>O1CCCC1>[I:21][C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)[NH:8][CH:9]=1
Reactant: Cc1cnc2c(ccn2[Si](C(C)C)(C(C)C)C(C)C)c1
Reactant: II
Solvent: C1CCOC1
Product: Cc1cnc2[nH]cc(I)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.6 %

Procedure:
To a solution of 5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (8, 1 g, 2.0 mmol) in 10 mL of tetrahydrofuran, iodine (0.43 g, 1.7 mmol) in 5 mL of tetrahydrofuran was added. The reaction was stirred at room temperature overnight, then quenched with 20 mL of 1M aqueous sodium thiosulfate and extracted with ethyl acetate. The organic layers were combined and washed with water, brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with ethyl acetate and hexanes. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as a white solid (10, 20 mg). MS (ESI) [M+H+]+=258.70.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.Cl[C:13](=[O:18])[C:14]([O:16]C)=[O:15].[OH-].[Na+:20]>CO>[Na+:20].[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:13](=[O:18])[C:14]([O-:16])=[O:15])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: COC(=O)C(=O)Cl
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])C(=O)Nc1ccc(Cl)cc1[N+](=O)[O-]

Procedure:
In a manner similar to that described in Referential Example 242, 4-chloro-2-nitroaniline was condensed with methyl chlorooxoacetate. In a manner similar to that described in Referential Example 266, the condensed compound was hydrolyzed. The residue was dissolved in methanol, 1N aqueous sodium hydroxide was added thereto, and the precipitated material was recoverd by filtration, whereby the title compound was obtained.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:49][CH3:50])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([CH:47]=O)[CH:42]=5)[CH:36]=[CH:37][C:38]=4[O:39][CH3:40])=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:51][N:52]1[CH2:58][CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:49][CH3:50])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][N:55]6[CH2:56][CH2:57][CH2:58][N:52]([CH3:51])[CH2:53][CH2:54]6)[CH:42]=5)[CH:36]=[CH:37][C:38]=4[O:39][CH3:40])=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(-c3cccc(C=O)c3)ccc2OC)c1
Reactant: CN1CCCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(-c3cccc(CN4CCCN(C)CC4)c3)ccc2OC)c1

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-{[3′-formyl-4-(methyloxy)-3-biphenylyl]methyl}-1,3-benzenedicarboxamide (54 mg, 0.00008 mol) in DCM, 1-methylhexahydro-1H-1,4-diazepine (13.7 mg, 15.2 μL, 0.00012 mol) and sodium triacetoxyborohydride (34 mg., 0.00016 mol) and AcOH (6 μL) were agitated overnight on a shaker. LC-MS was used to monitor the reaction. The reaction was quenched with sat. aq. NaHCO3, then extracted with DCM (2×). Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. Purification was carried out on Gilson HPLC instrument with acetonitrile-water (0.1% TFA) gradient; C18-RP column. Fractions containing the clean desired product were combined; diluted with EtOAc; washed with sat. aq. NaHCO3; and the aq. phase was back-extracted with EtOAc. Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. It was taken up in a small amount of DCM and transferred to a vial and pumped down to afford the title compound as a chalky white solid. Further purification was carried out on an Agilent HPLC with RP-CH3CN:H2O-conc. aq. NH3 gradient [4.5 mg (7.25%)]. LC-MS m/z 773.5 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[N:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[N:9]=2)=[N:4][C:3]=1O.[NH3:26]>S(Cl)(Cl)=O.C(#N)C>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][N:10]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:16]2[C:8]([C:5]2[N:6]=[N:7][C:2]([NH2:1])=[C:3]([NH2:26])[N:4]=2)=[N:9]1
Reactant: Nc1nnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1O
Reactant: N
Solvent: CC#N
Solvent: O=S(Cl)Cl
Product: Nc1nnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.602 g (10.677 mmol) of 6-amino-3-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-1,2,4-triazin-5-ol in 45 ml of thionyl chloride were added and heated under reflux for 3 h. The reaction mixture was diluted with 200 ml of dry acetonitrile and, with ice-cooling, added dropwise to 500 ml of concentrated aqueous ammonia solution (35% strength). The mixture was stirred at RT overnight. The acetonitrile was removed on a rotary evaporator and the precipitate was filtered off with suction. This gave 3.541 g (purity 67%, 66% of theory) of the target compound. A small amount was purified by preparative HPLC (mobile phase: acetonitrile/water with 0.1% TFA, gradient 30:70→95:5).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12]C)[CH:10]=2)[C:5]([C:14]#[N:15])=[CH:4]1)[CH3:2].B(Br)(Br)Br.[OH-].[Na+]>C(Cl)Cl>[OH:12][C:9]1[CH:10]=[C:11]2[C:6]([C:5]([C:14]#[N:15])=[CH:4][N:3]2[CH2:1][CH3:2])=[CH:7][CH:8]=1
Reactant: CCn1cc(C#N)c2ccc(OC)cc21
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCn1cc(C#N)c2ccc(O)cc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 81.3 %

Procedure:
To a solution of 1-ethyl-6-methoxy-1H-indole-3-carbonitrile (2.85 g, 14.2 mmol), prepared by example 1A, step B, in CH2Cl2 (40 mL) is added a 1M solution of BBr3 in CH2Cl2 (28.5 mL, 28.5 mmol) at 0° C. The mixture is allowed to warm to room temperature and kept for 2.5 h. The dark reaction mixture is then poured onto ice and sufficient 1M NaOH is added until the pH is 8-9. The product is extracted with CH2Cl2 (3×) and the combined organic phases are washed with saturated NaHCO3, H2O and saturated NaCl. After drying over MgSO4, the solution is concentrated and the product is purified by chromatography (EtOAc/CH2Cl2, 0-10%) to afford 2.15 g (82%) of 6-hydoxy-1-ethyl-1H-indole-3-carbonitrile as a yellow solid.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[C:6]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:19]5[O:23][C:22]([NH:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[N:21][N:20]=5)[CH:17]=4)[N:12](S(C4C=CC(C)=CC=4)(=O)=O)[CH:11]=3)[N:5]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>O1CCOCC1.O>[CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[C:6]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:19]5[O:23][C:22]([NH:24][CH2:25][C:26]([F:28])([F:29])[F:27])=[N:21][N:20]=5)[CH:17]=4)[NH:12][CH:11]=3)[N:5]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nccc(C4CC4)n3)c3cc(-c4nnc(NCC(F)(F)F)o4)ccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: FC(F)(F)CNc1nnc(-c2ccc3[nH]cc(-c4nccc(C5CC5)n4)c3c2)o1
Temperature: 100 °C
Yield: 22.7 %

Procedure:
5-(3-(4-Cyclopropylpyrimidin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(2,2,2-trifluoroethyl)-1,3,4-oxadiazol-2-amine (117 mg, 0.211 mmol) in a 5 mL glass microwave tube, was suspended in dioxane (1.5 mL). The suspension was treated with NaOH 1.000 n (2 mL, 2.000 mmol) (Fluka Analytical). The tube was sealed and the contents were stirred and heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 100° C. for 10 min. The mixture was diluted with H2O (10 mL) and extracted with EtOAc (2×25 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by flash chromatography (eluting with 0-8% MeOH in DCM) to give 5-(3-(4-cyclopropylpyrimidin-2-yl)-1H-indol-5-yl)-N-(2,2,2-trifluoroethyl)-1,3,4-oxadiazol-2-amine (19.1 mg, 0.048 mmol, 22.61%) as a pale yellow amorphous solid. MS (ESI, pos. ion) m/z: 401.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.95 (br. s., 1H), 9.01 (s, 1H), 8.50-8.59 (m, 2H), 8.27 (d, J=2.3 Hz, 1H), 7.70 (dd, J=8.5, 1.5 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.16 (d, J=5.3 Hz, 1H), 4.05-4.21 (m, 2H), 2.08-2.20 (m, 1H), 1.20-1.29 (m, 2H), 1.07-1.16 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:28](=[O:39])[CH2:29][O:30][C:31]2[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=2)[CH2:24][CH2:23]1>>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:35]([C:34]3[CH:33]=[CH:32][C:31]([O:30][CH2:29][C:28]([N:25]4[CH2:24][CH2:23][N:22]([CH3:21])[CH2:27][CH2:26]4)=[O:39])=[CH:38][CH:37]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: CN1CCN(C(=O)COc2ccc(C=O)cc2)CC1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Product: CN1CCN(C(=O)COc2ccc(-c3nc4c(N[C@H]5[C@@H](C(N)=O)[C@@H]6C=C[C@H]5C6)c(Cl)cnc4[nH]3)cc2)CC1
Yield: 26 %

Procedure:
(1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (1 eq.) and 4-(2-(4-methylpiperazin-1-yl)-2-oxoethoxy)benzaldehyde (58) (1.1 eq) were reacted in an analogous manner as compound CCXXIII to yield the desired product (26%) as an off white solid. NMR: δ (1H, 400 MHz, DMSO-d6): 1.38 (1H, d, J=8 Hz), 2.19 (3H, s), 2.20-2.35 (5H, m), 2.62 (1H, d, J=8.4 Hz), 2.78 (1H, s), 2.89 (1H, s), 3.40-3.50 (4H, m), 4.91 (2H, s), 5.16 (1H, t, J=8 Hz), 6.36-6.40 (2H, m), 7.08 (2H, d, J=8.4 Hz), 7.11-7.14 (1H, m), 7.22 (1H, bs), 7.76 (1H, bs), 7.92 (1H, s), 8.05 (2H, d, J=8.4 Hz).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:9]=[C:8](CS([O-])(=O)=O)[CH:7]=[CH:6][N:5]=1.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>O1CCCC1>[CH3:1][O:2][CH2:3][C:4]1[N:9]=[C:8]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH:7]=[CH:6][N:5]=1
Reactant: COCc1nccc(CS(=O)(=O)[O-])n1
Reactant: C1CNCCN1
Solvent: C1CCOC1
Product: COCc1nccc(N2CCNCC2)n1
Temperature: 25 °C

Procedure:
To a solution of 2-methoxymethyl-pyrimidin4-yl-methanesulfonate (prepared according to the method of Preparation One, Step A, 43.6 g, 200 mmol) in tetrahydrofuran (400 mL) was added piperazine (34.4 g, 400 mmol). This mixture was heated to reflux for 0.5 h, cooled to room temperature, and filtered. The filtrate was concentrated and dried under reduced pressure to give the title compound as a semi-solid, 36.6 g (85%). 1H NMR (CDCl3, 300 MHz) δ 2.45 (br s, 1H), 2.88 (m, 4H), 3.45 (s, 3H), 3.72 (m, 4H), 4.46 (s, 2H), 6.38 (d, 1H), 8.22 (d, 1H); MS (TS) 209 (MH+).
Reaction SMILES: [Br:1][Si](C)(C)C.CS(C)=O.[CH:10]1([C:15]([OH:17])=[O:16])[CH2:14][CH:13]=[CH:12][CH2:11]1.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl>[Br:1][CH:12]1[CH:13]2[CH2:14][CH:10]([C:15](=[O:17])[O:16]2)[CH2:11]1
Reactant: C[Si](C)(C)Br
Reactant: O=C(O)C1CC=CC1
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1OC2CC1CC2Br
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Bromotrimethysilane (3.1 mL, 0.023 mol) was added dropwise to a solution of dimethyl sulfoxide (1.6 mL, 0.023 mol) in chloroform (38.0 mL) in a round-bottom flask at 0° C. The resulting mixture was stirred at 0° C. for 2 hours. To the reaction mixture was added dropwise a solution of cyclopent-3-ene-1-carboxylic acid (2.00 g, 0.0178 mol) in chloroform (12 mL) over a period of 15 minutes and the reaction mixture was stirred at 0° C. for 10 minutes. N,N-diisopropylethylamine (4.0 mL, 0.023 mol) was then added and the resulting mixture was stirred at 0° C. After 10 minutes, the mixture was heated to reflux for 16 hours. The reaction mixture was diluted with chloroform, washed with water, brine, dried (MgSO4), and stripped in vacuo. The residue was purified by chromatography on silica gel using 30% EtOAc/hexanes as eluent to give the product. 1H NMR (400 MHz, CDCl3): δ 4.88 (brs, 1H), 4.34 (m, 1H), 2.90 (m, 1H), 2.66 (m, 1H), 2.31 (m, 1H), 1.93 (m, 1H), 1.83 (m, 1H).
Reaction SMILES: [O:1]1[CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:2]12.[Cl-].[Li+]>CN1CCCC1=O>[C:2]1(=[O:1])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: C1CCCCCC2OC2CCCC1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN1CCCC1=O
Product: O=C1CCCCCCCCCCC1
Temperature: 200 °C
Reaction time: 6 h
Yield: 93.5 %

Procedure:
A solution containing 25 g of epoxy-cyclododecane, 1 g of lithium chloride, and 20 g of N-methyl-2-pyrrolidone was stirred at 200° C. for 6 hours. The reaction mixture contained 93.5% yield of cyclododecanone.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH2:22])=[CH:16][CH:15]=1.C(=O)([O-])O.[Na+].C(OCC)(=O)C>O1CCCC1.CN1CCOCC1.ClC(OCC(C)C)=O>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:10](=[O:12])[CH2:9][NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: NCCc1ccc(Br)cc1
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCC(=O)NCCc1ccc(Br)cc1
Reaction time: 0.67 h

Procedure:
To a solution of N-Boc-glycine (175 mg) in tetrahydrofuran (2 mL), N-methylmorpholine (165 μL) and isobutyl chloroformate (131 μL) were added under ice cooling, and the mixture was stirred at the same temperature for 40 minutes. To the reaction mixture, 2-(4-bromophenyl)ethylamine (100 μL) was added under ice cooling, and the mixture was stirred at room temperature for 5 hours. To the reaction mixture, saturated aqueous sodium hydrogencarbonate and ethyl acetate were added. The organic layer was separated, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain tert-butyl (2-((4-bromophenethyl)amino)-2-oxoethyl)carbamate (R5).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:5]2[S:6][C:7]3[C:8]([CH3:16])([CH3:15])[O:9][CH2:10][CH2:11][C:12]=3[C:13]=2[N:14]=1.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+].O.CC1(C)C(C)(C)OC([C:41]2[CH:42]=[N:43][C:44]([NH2:47])=[N:45][CH:46]=2)O1>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[CH3:15][C:8]1([CH3:16])[C:7]2[S:6][C:5]3[C:4]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[N:3][C:2]([C:41]4[CH:42]=[N:43][C:44]([NH2:47])=[N:45][CH:46]=4)=[N:14][C:13]=3[C:12]=2[CH2:11][CH2:10][O:9]1
Reactant: CC1(C)OCCc2c1sc1c(N3CCOCC3)nc(Cl)nc21
Reactant: CC1(C)OC(c2cnc(N)nc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC#N
Product: CC1(C)OCCc2c1sc1c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Reaction time: 0.25 h
Yield: 22.6 %

Procedure:
3-Chloro-8,8-dimethyl-1-morpholin-4-yl-5,8-dihydro-6H-7-oxa-9-thia-2,4-diaza-fluorene (10 mg, 0.03 mmol) was dissolved in acetonitrile (2 mL, 40 mmol) and added 1 M sodium carbonate in water (2 mL, 2 mmol), 5-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)pyrimidin-2-amine (9.0 mg, 0.041 mmol), and Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (1.1 mg, 0.001 6 mmol). The reaction was placed on the Biotage microwave at 120° C. for 15 minutes. The aqueous layer was pipetted off and the organic layer was concentrated in vacuo and was purified by silica gel chromatography (0 to 100% ethyl acetate/heptanes) on the CombiFlash® Rf system using a basic alumina column and concentrated in vacuo to give (85% pure) 168 (2.7 mg, 20% yield). M+1: 399.3. 1H NMR (400 MHz, CDCl3) δ 9.30 (s, 2H), 5.34 (brs, 2H), 4.08 (t, 2H), 4.01 (m, 4H), 3.87 (m, 4H), 2.95 (t, 2H), 1.62 (s, 6H)
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH:7]=O)[C:3]([O:5][CH3:6])=[O:4].[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[N:20]=[C:19]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:18]3=[CH:27][C:28]([S:30][CH3:31])=[CH:29][N:17]3[CH2:16][C:15]=2[CH:32]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[N:20]=[C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH2:7][C:2]([CH3:1])([CH3:9])[C:3]([O:5][CH3:6])=[O:4])[CH2:23][CH2:22]3)[C:18]3=[CH:27][C:28]([S:30][CH3:31])=[CH:29][N:17]3[CH2:16][C:15]=2[CH:32]=1
Reactant: COC(=O)C(C)(C)C=O
Reactant: CSc1cc2n(c1)Cc1cc(Cl)ccc1N=C2N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C(C)(C)CN1CCN(C2=Nc3ccc(Cl)cc3Cn3cc(SC)cc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
Add methyl 2,2-dimethyl-3-oxo-propanoate (0.928 g, 7.13 mmoles) in DCM (5 mL) to 7-chloro-2-(methylsulfanyl)-11-(piperazin-1-yl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine (1.0 g, 2.85 mmoles) in DCM (10 mL) and stir under nitrogen for 30 minutes at room temperature. Add sodium triacetoxyborohydride (3 equiv; 1.89 g, 8.56 mmoles) to the reaction mixture and stir under nitrogen overnight at room temperature. Add methanol and apply to an SCX-2 column, wash with methanol and elute with 2M ammonia in methanol. Evaporate the methanol solution to give methyl 3-[4-(7-chloro-2-(methylsulfanyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepin-11-yl)piperazin-1-yl]-2,2-dimethylpropanoate (1.23 g, 84%). MS (m/z): 461.12 (M+1).
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[O:29])[N:27]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[O:33]1[CH2:32][CH2:31][N:30]([C:28]([C:26]2[N:27]=[C:23]([N:21]3[CH2:22][CH:19]([OH:18])[CH2:20]3)[S:24][CH:25]=2)=[O:29])[CH2:35][CH2:34]1
Reactant: CC(C)(C)[Si](OC1CN(c2nc(C(=O)N3CCOCC3)cs2)C1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(c1csc(N2CC(O)C2)n1)N1CCOCC1
Reaction time: 1 h
Yield: 97.2 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-(4-morpholinocarbonyl-1,3-thiazol-2-yl)azetidine (1.05 g, 2.07 mmol) (obtained as described in Reference Example 11(1)) in anhydrous tetrahydrofuran (32 ml) was added a solution of 1.0M tetra-n-butylammonium fluoride in tetrahydrofuran (2.48 ml, 2.48 mmol) and the reaction mixture was stirred for 1 hour. After checking the completion of the reaction, the reaction mixture was concentrated under reduced pressure and the residue was purified by chromatography on a silica gel column using ethyl acetate→10% methanol in ethyl acetate as the eluant to afford 1-(4-morpholinocarbonyl-1,3-thiazol-2-yl)-3-hydroxyazetidine (542 mg, yield 97%) as a white solid.
Reaction SMILES: [CH:1]([S:4](Cl)(=[O:6])=[O:5])([CH3:3])[CH3:2].[CH2:8]1[O:17][C:11]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:10][CH2:9]1.C(N(CC)CC)C>ClCCl>[CH2:8]1[O:17][C:11]2([CH2:16][CH2:15][N:14]([S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])[CH2:13][CH2:12]2)[O:10][CH2:9]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: CC(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)N1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.6 %

Procedure:
Isopropylsulphonyl chloride (5.6 ml, 50 mmol) was added dropwise to an ice-cooled solution of 4-piperidone ethylene ketal (6.4 ml, 50 mmol) and triethylamine (7.7 ml, 55 mmol) in dichloromethane (100 ml), and the reaction stirred at room temperature for 3 hours. The mixture was washed with water (2×), dried (MgSO4), filtered and evaporated in vacuo. The residue was crystallised from ether/pentane to afford the title compound as a solid, (10.55 g, 85%).
Reaction SMILES: [CH3:1]I.[F:3][C:4]1[CH:5]=[C:6]([C:11]2([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][CH2:15][CH2:14][NH:13][C:12]2=[S:17])[CH:7]=[CH:8][C:9]=1[F:10]>C(#N)C.C(OCC)(=O)C>[F:3][C:4]1[CH:5]=[C:6]([C:11]2([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][CH2:15][CH2:14][N:13]=[C:12]2[S:17][CH3:1])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: CI
Reactant: CCOC(=O)C1(c2ccc(F)c(F)c2)CCCNC1=S
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(c2ccc(F)c(F)c2)CCCN=C1SC
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Methyl iodide (0.520 ml,) was added to a mixture of ethyl 3-(3,4-difluorophenyl)-2-thioxopiperidine-3-carboxylate (500 mg) in acetonitrile (5 mL) at room temperature, and the mixture was stirred at 50° C. for 3 hr. The reaction mixture was diluted with ethyl acetate, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (530 mg).
Reaction SMILES: [F:1][C:2]1[C:3]([OH:18])=[C:4]([CH2:11][CH2:12]OS(C)(=O)=O)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.C(N(CC)CC)C.O>C(OCC)(=O)C>[F:1][C:2]1[C:3]2[O:18][CH2:12][CH2:11][C:4]=2[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: CS(=O)(=O)OCCc1cc([N+](=O)[O-])cc(F)c1O
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(F)c2c(c1)CCO2
Yield: 61 %

Procedure:
A suspension of 6 (3.5 g, 12.53 mmol) in ethyl acetate (45 mL) and triethyl amine (4.37 mL, 31.33 mmol) was refluxed overnight. Water was added and the crude was extracted with ethyl acetate. The organic layer was concentrated, purified by column chromatography eluted with 15% ethyl acetate/hexane, to yield the desired compound 7 (1.4 g, yield 61%).