Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:49])[C@H:4]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]2[N:33]([CH3:34])[C:32]3[CH:35]=[C:36]([O:39][C:40]4[CH:45]=[C:44]([CH3:46])[C:43]([NH2:47])=[C:42]([CH3:48])[CH:41]=4)[CH:37]=[CH:38][C:31]=3[N:30]=2)=[CH:23][CH:22]=1)[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O.[OH-].[Li+].[ClH:53].Cl.O1CCOCC1>O1CCCC1.O>[ClH:53].[ClH:53].[NH2:47][C:43]1[C:42]([CH3:48])=[CH:41][C:40]([O:39][C:36]2[CH:37]=[CH:38][C:31]3[N:30]=[C:29]([CH2:28][O:27][C:24]4[CH:23]=[CH:22][C:21]([CH2:20][C@@H:4]([C:3]([OH:49])=[O:2])[NH:5][C:6]5[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=5[C:12](=[O:19])[C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=5)=[CH:26][CH:25]=4)[N:33]([CH3:34])[C:32]=3[CH:35]=2)=[CH:45][C:44]=1[CH3:46]
Reactant: COC(=O)[C@H](Cc1ccc(OCc2nc3ccc(Oc4cc(C)c(N)c(C)c4)cc3n2C)cc1)Nc1ccccc1C(=O)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(Oc2ccc3nc(COc4ccc(C[C@H](Nc5ccccc5C(=O)c5ccccc5)C(=O)O)cc4)n(C)c3c2)cc(C)c1N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4-[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]-N-(2-benzoylphenyl)phenylalanine methyl ester (0.25 g), lithium hydroxide monohydrate (0.04 g), tetrahydrofuran (5 ml) and water (2 ml) was stirred at room temperature for 3 hours. The reaction mixture was neutralized with 1N hydrochloric acid and partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was chromatographed on LiChroprepDIOL (Merck) using ethyl acetate as the eluant to give a yellow material. To a solution of the material in tetrahydrofuran (3 ml) was added 4N hydrogen chloride/dioxane (1 ml) to give crystals. The crystals were isolated by filtration to afford the title compound (0.11 g, mp 148-155° C.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:18])[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1.[Li]C(C)(C)C.[CH3:24][O:25][CH2:26][CH2:27][N:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[CH:33]=[O:34]>C1COCC1.CCCCC>[OH:34][CH:33]([C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:18])[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1)[C:29]1[N:28]([CH2:27][CH2:26][O:25][CH3:24])[CH:32]=[CH:31][CH:30]=1
Reactant: CN(c1ccc(Br)cc1)S(=O)(=O)c1ccccc1
Reactant: COCCn1cccc1C=O
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: COCCn1cccc1C(O)c1ccc(N(C)S(=O)(=O)c2ccccc2)cc1
Temperature: -30 °C

Procedure:
To a solution of 1.49 g (4.59 mmol) of N-(4-bromophenyl)-N-methyl benzenesulfonamide (see Preparative Example A, Step C) in 37.5 mL THF at −78° C. was added dropwise 5.94 mL (10.10 mmol) of a 1.7 M solution of tert-BuLi in pentane and the resultant mixture was stirred at −78° C. for 15 min. To this mixture was then added a solution of 1.01 g (6.59 mmol) of N-methoxyethylpyrrole-2-carboxaldehyde in 6 mL THF and the mixture was allowed to gradually warm to −30° C. over a 4 h period. After this time, the reaction mixture was quenched by the addition of a saturated aqueous solution of ammonium chloride and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by chromatography on silica gel (hexanes:EtOAc, 13:7) to give the title compound.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(OC([NH:32][C:33]1([C:48]([OH:50])=O)[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=O)(C)(C)C.[Cl:51][C:52]1[CH:57]=[CH:56][C:55]([C@@H:58]([NH2:60])[CH3:59])=[CH:54][CH:53]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[NH2:32][C:33]1([C:48]([NH:60][C@H:58]([C:55]2[CH:56]=[CH:57][C:52]([Cl:51])=[CH:53][CH:54]=2)[CH3:59])=[O:50])[CH2:34][CH2:35][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:37][CH2:38]1
Reactant: C[C@H](N)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)C1(N)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 70.4 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.418 g) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (0.361 g), (S)-1-(4-chlorophenyl)ethanamine (0.140 mL) and DIPEA (0.524 mL) in DMA (10 mL) at 25° C. under nitrogen. The resulting solution was stirred at 60° C. for 4 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and pure fractions were evaporated to dryness. This crude material was then treated with a 20% solution of TFA in DCM (10 mL) and stirred at room temperature. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M ammonia/MeOH and pure fractions were evaporated to dryness. This material was purified by preparative LCMS using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford (S)-4-amino-N-(1-(4-chlorophenyl)ethyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide as a white solid (0.281 g, 70.4%). 1H NMR (400.13 MHz, DMSO-d6) δ 1.37 (3H, d), 1.42-1.45 (2H, m), 1.88-2.01 (2H, m), 2.27 (2H, s), 3.49-3.59 (2H, m), 4.34-4.44 (2H, m), 4.83-4.90 (1H, m), 6.57-6.58 (1H, m), 7.14-7.16 (1H, m), 7.32-7.38 (4H, m), 8.12 (1H, s), 8.30 (1H, d), 11.62 (1H, s).
Reaction SMILES: [Br:1][CH:2]([C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[CH2:3][C:4]([OH:6])=[O:5].[CH3:16][N:17]1[CH2:22][N:21]([CH3:23])[CH2:20][NH:19][C:18]1=[S:24]>CO>[Br-:1].[C:4]([CH2:3][CH:2]1[S:24][C:18]2=[N+:17]([CH3:16])[CH2:22][N:21]([CH3:23])[CH2:20][N:19]2[C:7]1([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[OH:15])([OH:6])=[O:5]
Reactant: O=C(O)CC(Br)C(=O)c1ccc(Cl)cc1
Reactant: CN1CNC(=S)N(C)C1
Solvent: CO
Product: CN1CN2C(=[N+](C)C1)SC(CC(=O)O)C2(O)c1ccc(Cl)cc1
Product: [Br-]
Yield: 55 %

Procedure:
A solution of 3-bromo-3-(p-chlorobenzoyl) propionic acid (7.29 g, 0.025 moles) in methanol (40 ml) was mixed with a solution of 1,5-dimethyl-3,4,5,6-tetrahydro-s-triazin-2(1H)thione (3.625 g, 0.025 mole) in the same solvent (100 ml). After 2 hours at room temperature the solvent was evaporated to give a foam which was crystallised from isopropanol to give 7-carboxymethyl-6-(p-chlorophenyl)-1,3-dimethyl-6-hydroxy-3,4,6,7-tetrahydro-2H-thiazolo[3,2-a]-s-triazinium bromide as a colourless solid (6.0 g), m.p. 160°-161° C. (decomposition).
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([CH2:9][CH2:10][C:11](=[O:13])[CH3:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH2:14](O)[CH2:15][OH:16].C(OCC)(OCC)OCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[CH3:12][C:11]1([CH2:10][CH2:9][C:7]2[S:8][C:4]([C:1]([CH3:2])=[O:3])=[CH:5][CH:6]=2)[O:16][CH2:15][CH2:14][O:13]1
Reactant: CC(=O)CCc1ccc(C(C)=O)s1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCOC(OCC)OCC
Product: CC(=O)c1ccc(CCC2(C)OCCO2)s1

Procedure:
4-(5-Acetyl-2-thienyl)-2-butanone (Tetrahedron 35, 1979, 329) was reacted with ethylene glycol, triethyl orthoformate and p-toluenesulphonic acid in methylene chloride to give methyl 5-[2-(2-methyl-1,3-dioxolan-2-yl)ethyl]-2-thienyl ketone. Oxidation with sodium hypobromite and subsequent hydrolysis gave 5-(3-oxobutyl)-2-thiophene carboxylic acid. With sodium borohydride there was obtained therefrom 5-(3-hydroxybutyl)-2-thiophenecarboxylic acid which was converted in dimethylacetamide with methyl iodide and sodium carbonate into the methyl ester. Treatment with p-toluenesulphochloride in pyridine and reaction with sodium azide in dimethyl sulphoxide gave methyl 5-(3-azidobutyl)-2-thiophenecarboxylate from which there was obtained by saponification the corresponding acid. The acid was treated with thionyl chloride to give the acid chloride from which there was obtained with concentrated ammonia in ether 5-(3-azidobutyl)-2-thiophenecarboxamide. Reduction of the azido group with triphenylphosphine and subsequent hydrolysis gave (R,S)-5-(3-aminobutyl)-2-thiophenecarboxamide of melting point 65°-75°. UV: ε256 =7780; ε275 =9900.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]([OH:17])[CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:4][CH:3]=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20].C(OCC)(=O)C>N1C=CC=CC=1>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]([O:17][S:19]([CH3:18])(=[O:21])=[O:20])[CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:4][CH:3]=1
Reactant: OC(CCc1ccc(Cl)cc1)Cn1ccnc1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CS(=O)(=O)OC(CCc1ccc(Cl)cc1)Cn1ccnc1
Product: Cl
Reaction time: 8 h

Procedure:
A mixture of 1-[4-(4-chlorophenyl)-2-hydroxy-n-butyl]imidazole (20 g) in dry pyridine (100 ml) was cooled in an ice bath and treated dropwise with stirring with 7.0 ml of methanesulfonyl chloride. The mixture was allowed to come to room temperature overnight and diluted to 500 ml by the addition of ethyl acetate, with stirring. The resulting solid was then filtered off, washed with acetone and dried in air to give 1-[4-(4-chlorophenyl)-2-(methanesulfonyloxy)-n-butyl]imidazole hydrochloride as a white solid (27.4 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:43][CH:44]([CH3:46])[CH3:45])[C@H:12]([CH2:41][OH:42])[CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([C@@H:20]([NH:32][C:33]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[O:34])[CH2:21]C2C3C(=CC=CC=3)C=CC=2)=[O:19])(=[O:10])=[O:9])=[CH:4][C:3]=1[Cl:47].N1(C(N[C@@H](C[C:62]2[CH:71]=[CH:70][C:69]3[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=3)[CH:63]=2)C(O)=O)=O)CCOCC1.C1C=C2C(C=C(C[C@H](N)C(O)=O)C=C2)=CC=1.N1(C(N[C@@H](CC2C3C(=CC=CC=3)C=CC=2)C(O)=O)=O)CCOCC1.C1C=C2C=CC=C(C[C@H](N)C(O)=O)C2=CC=1>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:43][CH:44]([CH3:46])[CH3:45])[C@H:12]([CH2:41][OH:42])[CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([C@@H:20]([NH:32][C:33]([N:35]2[CH2:36][CH2:37][O:38][CH2:39][CH2:40]2)=[O:34])[CH2:21][C:62]2[CH:71]=[CH:70][C:69]3[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=3)[CH:63]=2)=[O:19])(=[O:10])=[O:9])=[CH:4][C:3]=1[Cl:47]
Reactant: O=C(O)[C@H](Cc1ccc2ccccc2c1)NC(=O)N1CCOCC1
Reactant: CC(C)CN([C@H](CO)CCCCNC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)N1CCOCC1)S(=O)(=O)c1ccc(N)c(Cl)c1
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: N[C@@H](Cc1cccc2ccccc12)C(=O)O
Agent: O=C(O)[C@H](Cc1cccc2ccccc12)NC(=O)N1CCOCC1
Product: CC(C)CN([C@H](CO)CCCCNC(=O)[C@H](Cc1ccc2ccccc2c1)NC(=O)N1CCOCC1)S(=O)(=O)c1ccc(N)c(Cl)c1
Yield: 25 %

Procedure:
This derivative was prepared from (1S)-4-amino-N-(5-amino-1-hydroxymethyl-pentyl)-3-chloro-N-isobutyl-benzenesulfonamide (XII) (example 44, step B) as described in general procedure B using (2S)-2-[(morpholine-4-carbonyl)-amino]-3-naphthalen-2-yl-propionic acid. The latter derivative was prepared from L-2-naphthylalanine as described for the preparation of (2S)-2-[(morpholine-4-carbonyl)-amino]-3-naphthalen-1-yl-propionic acid from L-1-naphthylalanine. The final product was obtained in 25% yield (51 mg).
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([NH2:13])=[N:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1)#[N:23]>>[CH2:1]([C:8]1[S:12][C:11]([NH:13][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:24]([C:22]#[N:23])=[CH:25][CH:26]=2)=[N:10][C:9]=1[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(-c2nc(N)sc2Cc2ccccc2)cc1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Product: COc1ccc(-c2nc(NC(=O)c3ccc(C#N)cc3)sc2Cc2ccccc2)cc1
Yield: 39.5 %

Procedure:
A procedure similar to that in Example 4 was used. 5-benzyl-4-(4-methoxy-phenyl)-thiazol-2-ylamine prepared in Example 1 and p-cyanobenzoyl chloride prepared in the step 1 were used as starting materials, allowed to react at room temperature overnight, followed by post-treatment to obtain a crude product, which was purified by a silica gel column chromatography eluted with a gradient of petroleum ether and ethyl acetate (20:1-10:1) to obtain a product as a white solid in a yield of 39.5%, mp: 194-196 └. 1H-NMR (CDCl3, 400 MHz) δ: 3.77 (3H, s, OCH3), 4.21 (2H, s, CH2), 6.69 (2H, d, J=8.68 Hz, ArH), 7.23˜7.32 (5H, m, ArH), 7.36 (2H, d, J=8.68 Hz, ArH), 7.48 (2H, d, J=8.16 Hz, ArH), 7.72 (2H, d, J=8.16 Hz, ArH); EI-MS m/e (%): 425.2 (M+, 100), 130.0 (40); HREI-MS Calcd. for C25H19N3O2S: 425.1198. found: 425.1191. Anal. Calcd. for C25H19N3O2S: C, 70.57; H, 4.50; N, 9.88. found: C, 70.50; H, 4.39; N, 9.99.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]3[N:14]([CH:16]=[C:17]([NH2:19])[N:18]=3)[N:15]=2)=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:26]=[C:25]([N:27]=[C:28]=[O:29])[CH:24]=[CH:23][C:22]=1[F:30].[N-:31]=[C:32]=[O:33]>>[Cl:20][C:21]1[CH:26]=[C:25]([NH:27][C:28]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]3[CH:11]=[CH:12][C:13]4[N:14]([CH:16]=[C:17]([NH:19][C:32]([NH:31][C:25]5[CH:24]=[CH:23][C:22]([F:30])=[C:21]([Cl:20])[CH:26]=5)=[O:33])[N:18]=4)[N:15]=3)=[CH:4][CH:3]=2)=[O:29])[CH:24]=[CH:23][C:22]=1[F:30]
Reactant: O=C=Nc1ccc(F)c(Cl)c1
Reactant: [N-]=C=O
Reactant: Nc1ccc(C#Cc2ccc3nc(N)cn3n2)cc1
Product: O=C(Nc1ccc(C#Cc2ccc3nc(NC(=O)Nc4ccc(F)c(Cl)c4)cn3n2)cc1)Nc1ccc(F)c(Cl)c1

Procedure:
The compound of Example 15 was by preparing 6-[(4-aminophenyl)ethynyl]imidazo[1,2-b]pyridazin-2-amine as in Example 20, followed by a procedure similar to Example 3 using 2-chloro-1-fluoro-4-isocyanatobenzene as the isocyanate (see also Schemes 1, 2, and 9).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>C1COCC1.O.C(OCC)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(N2CCCCC2)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-Chloro-5-nitropyridine (10 g, 63.3 mmol) was dissolved in 150 mL of THF. 20 mL of piperidine was then added and the resulting mixture was stirred for 18 hours at room temperature. The reaction mixture with copious precipitate was then diluted with 200 mL of water and 100 mL of diethyl ether. The layers were thoroughly mixed and separated. The organic layer was dried over sodium sulfate and concentrated in vacuo. The bright yellow solid was redissolved in 35 mL of dichloromethane and, with vigorous stirring, hexanes were added until the product began to precipitate. The bright yellow solid was collected by filtration and dried to afford 12.5 g of 5′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl.
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].[CH2:6]([CH:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:14][OH:15])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CC)CC)C.Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:6]([CH:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:14][O:15][P:1]([Cl:5])([Cl:3])=[O:2])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCCCCCCC(CO)CCCCCCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCCCCC(CCCCCCC)COP(=O)(Cl)Cl
Temperature: -10 °C
Yield: 34.7 %

Procedure:
With nitrogen substitution, 540 ml of toluene and 138.0 grams (0.9 moles) of phosphorus oxychloride were added and cooled to −10 degrees C. To this mixture, a solution of 243.5 grams (0.9 moles; 1.0 in molar ratio) of 2-heptylundecanol and 91.1 grams (0.9 moles) of triethylamine was dripped, and the mixture was reacted for 12 hours at 0 degrees C. The mixture was then heated to 25 degrees C., and a triethylamine hydrochloride was. removed by filtering to obtain 1003.9 grams of a toluene solution of (2-heptylundecyl)dichlorophosphate (34.7% in concentration).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15](=[S:17])[NH2:16])=[C:10]3[CH2:9][N:8]([CH3:18])[C:7](=[O:19])[C:6]=2[CH:20]=1.[Cl:21][CH2:22][C:23](=O)[CH2:24]Cl>O1CCOCC1>[Cl:21][CH2:22][C:23]1[N:16]=[C:15]([C:14]2[N:13]=[CH:12][N:11]3[C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:20][C:6]=4[C:7](=[O:19])[N:8]([CH3:18])[CH2:9][C:10]=23)[S:17][CH:24]=1
Reactant: CN1Cc2c(C(N)=S)ncn2-c2ccc(F)cc2C1=O
Reactant: O=C(CCl)CCl
Solvent: C1COCCO1
Product: CN1Cc2c(-c3nc(CCl)cs3)ncn2-c2ccc(F)cc2C1=O
Yield: 57.4 %

Procedure:
A suspension of 4.51 g (0.0155 mol) of 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-thiocarboxamide in 100 ml of dioxan was treated with 2.16 g (0.0171 mol) of 1,3-dichloro-2-propanone, The suspension was boiled at reflux for 41 hrs., cooled and completely freed from the solvents. The residue was chromatographed over silica gel with dichloromethane/ethyl acetate 1:1 as the eluent and recrystallized from hot ethyl acetate. There were obtained 3.23 g (57%) of 3-(4-chloromethyl-thiazol-2-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as white crystals; m.p. 239°-241°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[N:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[C:32]1[N:37]=[C:36]([NH2:38])[N:35]=[C:34]([NH2:39])[CH:33]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:32]4[N:37]=[C:36]([NH2:38])[N:35]=[C:34]([NH2:39])[CH:33]=4)=[CH:16][CH:15]=3)=[N:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc(Cl)nc(N)n1
Reactant: Oc1ccc(-c2nnc(Nc3cccc(Cl)c3)o2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: Nc1cc(Oc2ccc(-c3nnc(Nc4cccc(Cl)c4)o3)cc2)nc(N)n1
Temperature: 80 °C
Yield: 31.3 %

Procedure:
4-{5-[(3-chlorophenyl)amino]-1,3,4-oxadiazol-2-yl}phenol (143.8 mg, 0.5 mmol) was dissolved in 3 mL of anhydrous DMF in a 2-5 mL microwave vial (Personal Chemistry). Solid potassium bis(trimethylsilyl)amide (200.0 mg, 1.0 mmol) was added and the reaction mixture was stirred with heating at 80° C. for 10 min, then 6-chloro-2,4-diamino-pyrimidine (86.7 mg, 0.6 mmol) was added, followed by anhydrous K2CO3 (69.1 mg, 0.5 mmol). Then the vial was capped and microwaved at 180° C. for 40 min. Then the reaction mixture was diluted with ca. 1 mL of MeOH, filtered through 0.22 um syringe filter and purified by reverse-phase preparative HPLC in acetonitrile/water system with 0.01% TFA. Fractions, containing the product, were partitioned between ca. 50 nm, of EtOAc and ca. 50 mL of saturated aqueous NaHCO3. EtOAc layer was washed with brine, dried over anhydrous Na2SO4 and filtered. Solvent was removed in vacuo to give the title product as a light-yellow solid (62.0 mg). Yield 31.3%.
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]2[C:13]([C:14]#[N:15])=[C:12]([CH3:16])[C:11](C3C=CC=CC=3)=[C:10](F)[C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N([CH2:29][CH3:30])CC)C.[CH3:31][N:32]([CH3:38])[C@H:33]1[CH2:37][CH2:36][NH:35][CH2:34]1.C(=O)([O-])O.[Na+]>CS(C)=O.C(OCC)(=O)C>[C:1]([CH:5]1[N:9]=[C:8]2[C:10]([N:35]3[CH2:36][CH2:37][C@H:33]([N:32]([CH3:38])[CH3:31])[CH2:34]3)=[CH:11][C:12]([CH3:16])([C:30]3[CH:29]=[CH:10][CH:8]=[CH:7][CH:13]=3)[C:13]([C:14]#[N:15])=[C:7]2[O:6]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCN(CC)CC
Reactant: Cc1c(-c2ccccc2)c(F)c2nc(C(C)(C)C)oc2c1C#N
Reactant: CN(C)[C@H]1CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CN(C)[C@H]1CCN(C2=CC(C)(c3ccccc3)C(C#N)=C3OC(C(C)(C)C)N=C23)C1
Temperature: 90 °C
Reaction time: 6 h
Yield: 87 %

Procedure:
2-tert-Butyl-4-fluoro-6-methyl-5-phenyl-1,3-benzoxazole-7-carbonitrile (I-239) (105 mg, 0.34 mmol) was dissolved in dimethyl sulfoxide (2 ml), and at room temperature, triethylamine (95 μl, 0.68 mmol) and (3S)-3-(dimethylamino)pyrrolidine (65 μl, 0.51 mmol) were added. The solution was stirred under nitrogen atmosphere at 90° C. for 6 hours. After cooling to room temperature, the reaction liquid was fractionated with ethyl acetate and an aqueous saturated sodium hydrogencarbonate solution. The aqueous layer was further extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, then dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, then the solvent was evaporated away, and the resulting residue was purified by middle-pressure liquid chromatography (eluent, chloroform:methanol=98:2) to obtain the entitled compound (119 mg, 87%) as a pale yellow solid.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[C:12]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=3[F:32])[C:13]([C:17]([O:19]C(C)(C)C)=[O:18])=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:32][C:26]1[CH:27]=[C:28]([I:31])[CH:29]=[CH:30][C:25]=1[NH:24][C:12]1[C:13]([C:17]([OH:19])=[O:18])=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[N:9][NH:8]2
Reactant: CC(C)(C)OC(=O)c1ccc2c(cnn2C(=O)OC(C)(C)C)c1Nc1ccc(I)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccc2[nH]ncc2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
To a solution of 4-(2-fluoro-4-iodophenylamino)-indazole-1,5-dicarboxylic acid di-tert-butyl ester (611 mg, 1.10 mmol) in DCM (5 ml) was added TFA (1.2 mL, 16.2 mmol). The reaction mixture was stirred at room temperature for 16 hours before being concentrated in vacuo. The resultant residue was dissolved in ethyl acetate (10 mL), washed with aqueous saturated sodium bicarbonate solution (10 mL) and the aqueous fraction extracted with ethyl acetate (2×10 mL). The combined organic fractions were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si—PPC, gradient 0-100% ethyl acetate in cyclohexane) to yield the title compound as an off-white solid (367 mg, 84%). LCMS (Method B): RT=3.23 min, [M+H]+=398.
Reaction SMILES: [F:1][C:2]([F:35])([C:31]([F:34])([F:33])[F:32])[C:3]([F:30])([F:29])[C:4]([F:28])([F:27])[O:5][C:6]([F:26])([F:25])[C:7]([F:24])([F:23])[O:8][C:9]([F:22])([F:21])[CH2:10][O:11][CH2:12][C@@H:13]([F:20])[CH2:14][O:15][CH2:16][CH2:17][CH2:18]Cl.[CH2:36]([O:42][C:43]1[CH:44]=[N:45][C:46]([C:49]2[CH:54]=[CH:53][C:52]([OH:55])=[CH:51][CH:50]=2)=[N:47][CH:48]=1)[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>>[CH2:36]([O:42][C:43]1[CH:48]=[N:47][C:46]([C:49]2[CH:50]=[CH:51][C:52]([O:55][CH2:18][CH2:17][CH2:16][O:15][CH2:14][C@H:13]([F:20])[CH2:12][O:11][CH2:10][C:9]([O:8][C:7]([F:24])([F:23])[C:6]([F:26])([F:25])[O:5][C:4]([F:28])([F:27])[C:3]([F:30])([F:29])[C:2]([F:35])([F:1])[C:31]([F:34])([F:33])[F:32])([F:22])[F:21])=[CH:53][CH:54]=2)=[N:45][CH:44]=1)[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: F[C@@H](COCCCCl)COCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCCCCCOc1cnc(-c2ccc(O)cc2)nc1
Product: CCCCCCOc1cnc(-c2ccc(OCCCOC[C@H](F)COCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as described in Example 8 of International Patent Publication No. WO 96/33251 by combining 3-(3-(2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)-(S)-2-fluoropropoxy)propyl chloride (3.0 g, 5.1 mmol) with 5-hexyloxy-2-(4-hydroxyphenyl)pyrimidine (1.4 g, 5.1 mmol). The resulting crude product was purified by Kugelrohr distillation (b.p. 170-80° C. at 0.01 torr).