Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S([O:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])(=O)=O.[F:20][C:21]([N+:27]([O-:29])=[O:28])([N+:24]([O-:26])=[O:25])[CH2:22]O.C(Cl)(Cl)(Cl)Cl>C(Cl)Cl>[F:20][C:21]([N+:27]([O-:29])=[O:28])([N+:24]([O-:26])=[O:25])[CH2:22][O:12][CH2:13][Si:14]([CH3:15])([CH3:16])[CH3:17]
Reactant: C[Si](C)(C)COS(=O)(=O)C(F)(F)F
Reactant: O=[N+]([O-])C(F)(CO)[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: C[Si](C)(C)COCC(F)([N+](=O)[O-])[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 16 h
Yield: 43.9 %

Procedure:
Potassium carbonate (6 g) was added to a solution of 3.5 g (0.0148 mol) of trimethylsilylmethyl trifluoromethanesulfonate and 2.3 g of 2-fluoro-2,2-dinitroethanol in 5 ml of methylene chloride, and the mixture was stirred for 16 hrs. This suspension was added with stirring to a mixture of 30 ml of ice water and 30 ml of carbon tetrachloride. The carbon tetrachloride layer was washed with 10 ml of water, dried over magnesium sulfate, and distilled to give 1.56 g (45%) of trimethylsilylmethyl 2-fluoro-2,2-dinitroethyl ether, bp 52° (0.75 mm).
Reaction SMILES: N[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC(C(OC)=O)=CC=2)=CC3)CC1.CN(C)CC[C:45]([NH:47][C@:48]12[CH2:82][CH2:81][C@@H:80]([C:83]([CH3:85])=[CH2:84])[C@@H:49]1[C@@H:50]1[C@@:63]([CH3:66])([CH2:64][CH2:65]2)[C@@:62]2([CH3:67])[C@@H:53]([C@:54]3([CH3:79])[C@@H:59]([CH2:60][CH2:61]2)[C:58]([CH3:69])([CH3:68])[C:57]([C:70]2[CH:78]=[CH:77][C:73]([C:74]([OH:76])=[O:75])=[CH:72][CH:71]=2)=[CH:56][CH2:55]3)[CH2:52][CH2:51]1)=[O:46].[CH3:87][N:88]1[CH:92]=[CH:91][N:90]=[C:89]1[CH2:93][CH2:94]C(O)=O>>[CH3:66][C@:63]12[C@@:62]3([CH3:67])[C@@H:53]([C@:54]4([CH3:79])[C@@H:59]([CH2:60][CH2:61]3)[C:58]([CH3:69])([CH3:68])[C:57]([C:70]3[CH:71]=[CH:72][C:73]([C:74]([OH:76])=[O:75])=[CH:77][CH:78]=3)=[CH:56][CH2:55]4)[CH2:52][CH2:51][C@@H:50]1[C@H:49]1[C@H:80]([C:83]([CH3:85])=[CH2:84])[CH2:81][CH2:82][C@:48]1([NH:47][C:45](=[O:46])[CH2:94][CH2:93][C:89]1[N:88]([CH3:87])[CH:92]=[CH:91][N:90]=1)[CH2:65][CH2:64]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NC(=O)CCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: Cn1ccnc1CCC(=O)O
Agent: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)CCc3nccn3C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 29 %

Procedure:
The title compound was prepared in 29% yield from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except 3-(1-methyl-1H-imidazol-2-yl)propanoic acid was used instead of 3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 666.4 (M+H)+, 4.15 min (method 8). 1H NMR (500 MHz, METHANOL-d4) δ=7.95 (d, J=8.5 Hz, 2H), 7.53-7.46 (m, 2H), 7.25 (d, J=8.2 Hz, 2H), 5.33 (dd, J=1.8, 6.1 Hz, 1H), 4.79 (d, J=1.5 Hz, 1H), 4.66 (s, 1H), 3.91 (s, 3H), 3.30-3.18 (m, 2H), 2.84-2.79 (m, 2H), 2.73 (dt, J=5.2, 11.1 Hz, 1H), 2.64 (d, J=12.5 Hz, 1H), 2.35 (dd, J=8.2, 12.2 Hz, 1H), 2.18 (dd, J=6.4, 17.4 Hz, 1H), 1.96 (dt, J=3.2, 12.1 Hz, 1H), 1.91-1.78 (m, 2H), 1.77 (s, 1H), 1.74 (s, 3H), 1.71-1.66 (m, 1H), 1.60 (br. s., 2H), 1.46-1.26 (m, 7H), 1.22-1.13 (m, 1H), 1.11 (s, 3H), 1.07 (s, 3H), 1.05 (s, 4H), 0.99 (s, 3H), 0.97 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:32]=[CH:31][C:12]([O:13][C:14]3[CH:15]=[C:16]([CH:21]=[C:22]([O:24][C@H:25]4[CH2:29][CH2:28][NH:27][C:26]4=[O:30])[CH:23]=3)[C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:10]=2)=[N:6][N:5]=1.[CH3:33]I>CN(C=O)C>[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:10]=[CH:11][C:12]([O:13][C:14]3[CH:15]=[C:16]([CH:21]=[C:22]([O:24][C@H:25]4[CH2:29][CH2:28][N:27]([CH3:33])[C:26]4=[O:30])[CH:23]=3)[C:17]([O:19][CH3:20])=[O:18])=[CH:31][CH:32]=2)=[N:6][N:5]=1
Reactant: COC(=O)c1cc(Oc2ccc(-c3nnc(C)o3)cc2)cc(O[C@H]2CCNC2=O)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Oc2ccc(-c3nnc(C)o3)cc2)cc(O[C@H]2CCN(C)C2=O)c1
Reaction time: 0.25 h

Procedure:
Sodium hydride suspension (0.71 g, 50%) was added to a stirring solution of (S)-(−)-methyl 3-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy)-5-((2-oxopyrrolidin-3-yl)oxy)benzoate (5.5 g) (Intermediate 15) in dry DMF taken in a round bottomed flask fitted with anhydrous CaCl2 guard tube at room temperature. The reaction mixture was stirred at the same temperature for 15 min. Methyl iodide (0.91 mL) was added and stirred till the reaction completion. The reaction mixture was quenched with ice-water, extracted with DCM. All organic layers were combined, washed with water, brine, dried over sodium sulphate, filtered and concentrated in vaccuo to get the thick liquid product. The liquid was triturated with EtOAc:hexane to get the white solid product (5.3 g).
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5](C)=[CH:4][N:3]=1.C([Mg][Cl:31])(C)C.[Cl:32][C:33]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:34]=1[CH:35]=[O:36]>C1COCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([N:8]([C:7]2[C:2]([CH:35]([C:34]3[C:37]([F:41])=[CH:38][CH:39]=[CH:40][C:33]=3[Cl:32])[OH:36])=[N:3][CH:4]=[C:5]([Cl:31])[CH:6]=2)[CH2:23][O:24][CH3:25])(=[O:10])=[O:11])=[CH:13][C:14]=1[C:19]([F:20])([F:21])[F:22]
Reactant: O=Cc1c(F)cccc1Cl
Reactant: CC(C)[Mg]Cl
Reactant: COCN(c1cc(C)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C(O)c1c(F)cccc1Cl)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
To a solution of N-(2-bromo-5-methyl-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (246 mg, 0.5 mmol) in THF (3 mL) under nitrogen atmosphere at −30° C. was added isopropylmagnesium chloride (2 M solution in THF, 0.6 mL, 1.2 mmol) via dropwise addition. The mixture was then stirred for 30 min at 0° C. followed by the addition of a solution of 2-chloro-6-fluoro-benzaldehyde (150.6 mg, 0.95 mmol) at −30° C. The mixture was stirred at room temperature for 3 h, quenched with saturated aqueous NH4Cl solution (5 mL) and extracted with EtOAc (2×25 mL). The combined organic layers were washed with saturated aqueous NH4Cl solution (25 mL) and brine (25 mL), dried (Na2SO4), and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography on silica gel (30% EtOAc-hexanes) to obtain 4-chloro-N-{5-chloro-2-[(2-chloro-6-fluoro-phenyl)-hydroxy-methyl]-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (144 mg) as yellow syrup in 51% yield. MS m/z 573 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[C:4]([CH3:24])[N:3]=1.P([C:33]#[N:34])(=O)(OCC)OCC.C(N(CC)CC)C.CN>CN(C)C=O>[OH2:20].[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:16]=[CH:17][C:18]([C:19]([NH:34][CH3:33])=[O:20])=[CH:22][CH:23]=3)[CH2:13][CH2:14]2)=[C:4]([CH3:24])[N:3]=1
Reactant: CCOP(=O)(C#N)OCC
Reactant: Cc1nc(N)nc(N)c1N1CCN(c2ccc(C(=O)O)cc2)CC1
Agent: CN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(N2CCN(c3c(C)nc(N)nc3N)CC2)cc1
Product: O
Temperature: 25 °C
Reaction time: 5 h
Yield: 1043.3 %

Procedure:
A mixture of 2.6 g (8.0 mmole) of 4-[4-(2,4-diamino-6-methyl-5-pyrimidinyl)-1-piperazinyl]benzoic acid, 4.3 g (26.4 mmole) of diethyl phosphorocyanidate and 3.7 ml (26.4 mmole) of triethyl amine in 500 ml of N,N-dimethylformamide (dried over 4 Å molecular sieves overnight) was stirred at room temperature for five hours. Gaseous monomethylamine was passed into the suspension for one hour. The suspension initially became a clear solution and then a precipitate formed. The solvent was removed under high vacuum (0.1 mm, dry ice-2-propanol trap). The gummy residue was dissolved in 200 ml of ice water and neutralized to pH 7 by adding saturated sodium carbonate solution. The solid was collected and recrystallized from N,N-dimethylformamide to afford 15 g of the product as an off-white solid, mp 305° C. (with decomposition).
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([CH3:25])([CH3:24])[CH2:5][O:6][Si:7]([C:20]([CH3:23])([CH3:22])[CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:27][C:28]([NH2:30])=[S:29].O>C(#N)C>[C:20]([Si:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[O:6][CH2:5][C:4]([C:3]1[N:27]=[C:28]([NH2:30])[S:29][CH:2]=1)([CH3:25])[CH3:24])([CH3:23])([CH3:22])[CH3:21]
Reactant: NC(N)=S
Reactant: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)CBr
Solvent: O
Solvent: CC#N
Product: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1csc(N)n1
Temperature: 25 °C
Yield: 6.1 %

Procedure:
A solution of 1-bromo-4-(tert-butyl-diphenyl-silanyloxy)-3,3-dimethyl-butan-2-one (40 g, 92.3 mmol) and thiourea (8.4 g, 110.5 mmol) in 400.0 mL of acetonitrile is heated under reflux for 4 h. After cooling the reaction mixture to room temperature, water is added and the aqueous layer is extracted with ethyl acetate; the organic layer is dried over anhydrous Na2SO4, filtered and the solvent is removed under reduced pressure to afford the crude product that is purified by silica gel chromatography to afford 2.3 g of 4-[2-(tert-Butyl-diphenyl-silanyloxy)-1,1-dimethyl-ethyl]-thiazol-2-ylamine as a light brown solid. Yield: 4%, over two steps; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.00 (9H, s), 1.25 (6H, s), 3.62 (2H, s), 5.60 (2H, s), 6.15 (1H, s), 7.25-7.40 (6H, m), 7.50-7.60 (4H, m); m/z 411 [M+H].
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH2:54][O:55][CH2:56][CH3:57])=[CH:48][CH:47]=1.C(=O)([O-])[O-].[K+].[K+]>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>[CH2:56]([O:55][CH2:54][CH2:53][O:52][C:49]1[CH:50]=[CH:51][C:46]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:12])(=[O:13])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:26][CH2:27][O:28][CH2:29][CH2:30]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)=[CH:47][CH:48]=1)[CH3:57]
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: CCOCCOc1ccc(OB([O-])[O-])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: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (350 mg) was added toluene/ethanol/water (10/1/1, 13.6 ml) and then were added 4-(2-ethoxyethoxy)phenyl borate (226 mg) and potassium carbonate (205 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (40 mg), and the mixture was stirred at 100° C. for 9 hours and cooled to room temperature. The mixture was added to water and the mixture was extracted with ethyl acetate/THF, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent, was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=3/1) and recrystallized from ethanol to give 7-[4-(2-ethoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 84) (312 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].C([O-])([O-])=O.[K+].[K+].[Br:17][C:18]1[CH:25]=[C:24](F)[CH:23]=[CH:22][C:19]=1[CH:20]=[O:21].Cl>CN(C=O)C.CCOC(C)=O>[Br:17][C:18]1[CH:25]=[C:24]([CH:23]=[CH:22][C:19]=1[CH:20]=[O:21])[O:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[F:1]
Reactant: N#Cc1ccc(O)c(F)c1
Reactant: O=Cc1ccc(F)cc1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Oc2ccc(C=O)c(Br)c2)c(F)c1
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 61.6 %

Procedure:
To a solution of 3-fluoro-4-hydroxy-benzonitrile (5 g, 36 mmol) in DMF (anhydrous, 100 mL) was slowly added K2CO3 (5.54 g, 40.1 mmol). After stirring for 5 minutes, to the solution was added 2-bromo-4-fluoro-benzaldehyde (8.89 g, 43.8 mmol). The reaction was heated at 70° C. and monitored by T.L.C. After 4 hours, the heating was stopped and after cooling to the room temperature, 100 mL of EtOAc was added. With stirring, 1 M HCl (˜50 mL) was slowly added until the pH was 7. The organic layer was then washed with H2O (3×50 mL), dried over MgSO4 and filtered. The filtrate was evaporated under vacuum. The residue was purified over silica gel, eluting with 12.5% EtOAc/hexanes to afford 4-(3-bromo-4-formyl-phenoxy)-3-fluoro-benzonitrile (3) 7.1 g in 61% yield. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.28 (s, 1 H), 7.96 (d, J=8.60 Hz, 1 H), 7.51-7.59 (m, 2 H), 7.21-7.29 (m, 3 H), 7.03 (dd, 1 H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]2[N:14]=[C:13]([N:15]([CH2:25][CH3:26])CC3C=CC(OC)=CC=3)[C:12]3=[N:27][CH:28]=[C:29]([C:30]#[N:31])[N:11]3[N:10]=2)=[CH:6][C:5]([C:32]#[N:33])=[CH:4][C:3]=1[N:34]1[CH2:39][CH2:38][C@@H:37]([NH:40][C:41](=[O:44])[O:42][CH3:43])[C@H:36]([OH:45])[CH2:35]1.C([O:53][P:54]([O:64][CH:65]([CH3:69])[C:66](O)=[O:67])([O:56]CC1C=CC=CC=1)=[O:55])C1C=CC=CC=1.C1CCC(N=C=NC2CCCCC2)CC1.ClC1C(NC2N=C(N(CC)CC3C=CC(OC)=CC=3)C3=NC=C(C#N)N3N=2)=CC(C#N)=CC=1N1CC[C@@H](NC(OC)=O)[C@H](C(OP(OCC2C=CC=CC=2)(OCC2C=CC=CC=2)=O)(C)C([O-])=O)C1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[P:54]([O:64][CH:65]([CH3:69])[C:66]([O:45][CH:36]1[CH:37]([NH:40][C:41]([O:42][CH3:43])=[O:44])[CH2:38][CH2:39][N:34]([C:3]2[CH:4]=[C:5]([C:32]#[N:33])[CH:6]=[C:7]([NH:8][C:9]3[N:14]=[C:13]([NH:15][CH2:25][CH3:26])[C:12]4=[N:27][CH:28]=[C:29]([C:30]#[N:31])[N:11]4[N:10]=3)[C:2]=2[Cl:1])[CH2:35]1)=[O:67])([OH:56])([OH:55])=[O:53]
Reactant: CC(OP(=O)(OCc1ccccc1)OCc1ccccc1)C(=O)O
Reactant: CCN(Cc1ccc(OC)cc1)c1nc(Nc2cc(C#N)cc(N3CC[C@@H](NC(=O)OC)[C@H](O)C3)c2Cl)nn2c(C#N)cnc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN(Cc1ccc(OC)cc1)c1nc(Nc2cc(C#N)cc(N3CC[C@@H](NC(=O)OC)[C@H](C(C)(OP(=O)(OCc4ccccc4)OCc4ccccc4)C(=O)[O-])C3)c2Cl)nn2c(C#N)cnc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCNc1nc(Nc2cc(C#N)cc(N3CCC(NC(=O)OC)C(OC(=O)C(C)OP(=O)(O)O)C3)c2Cl)nn2c(C#N)cnc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl ((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate (0.040 g, 0.063 mmol), 2-((bis(benzyloxy)phosphoryl)oxy)propanoic acid (0.067 g, 0.19 mmol) in DCM (2 mL) was added DCC (0.039 g, 0.190 mmol) followed DMAP (0.77 mg, 0.006 mmol) and stirred at room temperature for 30 min. After completion of starting material (by LC-MS), reaction mixture was diluted with DCM (50 mL), filtered through celite and filtrate was washed with water and brine solution (5 mL). Combined organic extracts were dried over anhydrous Na2SO4, concentrated and purified by flash chromatography on silica gel using an ISCO system (eluted with 1:1 Hexanes and EtOAc) to give diastereomeric mixture of (3R,4R) 1-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4 ((methoxycarbonyl)amino)piperidin-3-yl-2-((bis(benzyloxy)phosphoryl)oxy)propanoate (0.060 g,) as gummy liquid.
Reaction SMILES: C(=O)(O)N.[CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH2:17][CH3:18])[CH3:16])[C:10]=1[O:19]C(=O)N)([CH2:7][CH3:8])[CH3:6].[OH-].[Na+]>O1CCOCC1>[CH:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([CH:5]([CH2:7][CH3:8])[CH3:6])[C:10]=1[OH:19])([CH2:17][CH3:18])[CH3:16]
Reactant: CCC(C)c1cccc(C(C)CC)c1OC(N)=O
Agent: NC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCC(C)c1cccc(C(C)CC)c1O
Yield: 100.3 %

Procedure:
R-(+)-1-Phenyl-ethyl)-carbamic acid (+2,6-di-sec-butylphenyl ester (1b) (4.1 g, 11.6 mmol) was dissolved in a 100 ml 1:1 mixture of dioxane: 1M NaOH aq. The reaction mixture was stirred at 70° C. for 15 min. Volatiles were removed at reduced pressure to a volume of ˜50-70 ml. The pH was adjusted to 3-4 with 1M HCl. The phenol was extracted with ether (3×50 ml), washed with 1 M HCl, brine and dried over anhydrous MgSO4. Evaporation yielded crude yellow oil (2.4 g, ˜100%). Vacuum distillation was performed (120-125° C./-5 mm) (2.1 g, 89%). Optical rotation: α20D=−14.11° (c=2, pentane).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24]([O:26]C)=O.[OH-].[NH4+:29]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24](=[O:26])[NH2:29]
Reactant: [NH4+]
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1c(Cl)cccc1Cl
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1c(Cl)cccc1Cl
Yield: 65 %

Procedure:
A solution of the 9-[(2,6-dichlorophenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (240 mg, 0.6 mM) in 5 mL THF and 20 mL concentrated aqueous ammonium hydroxide was stirred at room temperature for 22 hours. The resultant precipitate was collected by filtration and dried in vacuo to afford 151 mg (65%) of the 9-[(2,6-dichlorophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a yellow solid. 1H NMR (DMSO-d6) δ10.35 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.7 (d, 1H, J=8 Hz), 7.6-7.3 (m, 5H), 7.25 (t, 1H, J=8 Hz), 6.85 (d, 1H, J=8 Hz), 6.55 (d, 1H, J=8 Hz), and 5.85 (s, 2H). IR (KBr, cm−1) 3429, 1631, and 1597. MS (ES) m/e 385, 387.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.[O:19]1[CH2:23][CH2:22][CH2:21][CH:20]1[CH2:24][C:25](O)=[O:26].COC1C2N=C(NC(=O)CC3CCOCC3)SC=2C(C2CCOCC2)=CC=1>>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:25](=[O:26])[CH2:24][CH:20]3[CH2:21][CH2:22][CH2:23][O:19]3)[S:11][C:7]=2[C:6]([CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1
Reactant: O=C(O)CC1CCCO1
Reactant: COc1ccc(C2CCOCC2)c2sc(N)nc12
Agent: COc1ccc(C2CCOCC2)c2sc(NC(=O)CC3CCOCC3)nc12
Product: COc1ccc(C2CCOCC2)c2sc(NC(=O)CC3CCCO3)nc12

Procedure:
Using 4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-ylamine and (tetrahydro-furan-2-yl)-acetic acid, the title compound was prepared in the same manner as described for N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-2-(tetrahydro-pyran-4-yl)-acetamide and obtained as white solid (50% yield). Mp 170-174° C., MS: m/e=377(M+H+).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1.[C:16]1([P:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1C=CC=CC=1>[Br-:1].[CH2:12]([O:11][C:9]([CH2:8][O:7][C:6]1[CH:14]=[CH:15][C:3]([CH2:2][P+:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:4][CH:5]=1)=[O:10])[CH3:13]
Reactant: CCOC(=O)COc1ccc(CBr)cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CCOC(=O)COc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: [Br-]
Temperature: 50 °C

Procedure:
To a 100 mL round bottomed flask with a stirring bar and a reflux condenser topped with an argon inlet was added ethyl 2-(4-bromomethylphenoxy)acetate 35-5 (2.73 g, 10 mmol), triphenylphosphine (2.62 g, 10 mmol) and dry benzene (50 mL). This solution was warmed to 50° C. for 20 h. The mixture was cooled to room temperature and the product was collected by filtration. The white solid was washed with a little benzene and dried in vacuo to give 4-(ethoxycarbonylmethoxy)benzyltriphenyl-phosphonium bromide 35-6 as a white, crystalline solid (4.79 g, 89%). 1H NMR (CDCl3): δ 1.28 (t, J=7 Hz, 3H), 4.27 (q, J=7 Hz, 2H), 4.53 (s, 2H), 5.38 (d, J=14 Hz, 2H), 6.66 (d, J=9 Hz, 2H), 7.06 (d, J=9 Hz, 2H), 7.62 (m, 6H), 7.76 (m, 9H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[C:18]([O:22][C:23](=[O:32])[NH:24][CH:25]1[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1)([CH3:21])([CH3:20])[CH3:19]>ClCCl.CN(C)C=O>[C:18]([O:22][C:23](=[O:32])[NH:24][CH:25]1[CH2:26][CH2:27][CH:28]([NH:31][C:4]([C:3]2[C:2]([Cl:1])=[N:10][CH:9]=[C:8]([F:11])[CH:7]=2)=[O:6])[CH2:29][CH2:30]1)([CH3:21])([CH3:19])[CH3:20]
Reactant: O=C(O)c1cc(F)cnc1Cl
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(F)cnc2Cl)CC1
Reaction time: 4 h
Yield: 39.5 %

Procedure:
2-Chloro-5-fluoro nicotinic acid (3.00 g, 0.017 mol) (see Preparation 41), was dissolved in dichloromethane (100 ml) and N,N-dimethylformamide (1 drop) was added, followed by oxalyl chloride (3.0 ml, 0.034 mol). The reaction mixture was held at room temperature for 4 hours, after which time the solvent was removed in vacuo. The residue was suspended in dichloromethane (100 ml) and triethylamine (5 ml) added followed by addition of (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (5.40 g, 0.026 mol) (Preparation 42a). The reaction mixture was then held under an atmosphere of nitrogen at room temperature for a further 18 hours. The reaction mixture was then washed with water (100 ml) and the organic phase dried over anhydrous magnesium sulphate. The solvent was removed in vacuo, and the residue triturated with ethyl acetate/pentane (1:1, by volume, 10 ml) giving {4-[(2-chloro-5-fluoro-pyridine-3-carbonyl)amino]-cyclohexyl}-carbamic acid tert-butyl ester (2.5 g, 80:20 syn:anti) as a white solid.