Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Cl.[NH2:11][C:12]([NH2:14])=[NH:13].O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:13][C:12](=[NH:14])[N:11]=[CH:1][C:2]2[CH:9]=[CH:8][C:5]([CH3:6])=[CH:4][CH:3]=2)=[CH:4][CH:3]=1
Reactant: N=C(N)N
Reactant: Cc1ccc(C=O)cc1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(C=NC(=N)N=Cc2ccc(C)cc2)cc1

Procedure:
4-Methylbenzaldehyde (MBA) (0.50 mols-60 grams) is admixed with guanidine hydrochloride (0.25 mols, 25 grams) in molar ratio of 2:1. They are then heated under reflux in 150 ml of toluene under a Dean Stark water collector trap for approximately 17 hours to collect the theoretical amount of H2O evolved. The hot solution is rapidly decanted to ensure the removal of insoluble residues. The solution is then evaporated to dryness on a rotary evaporator. The crude immine is then recrystalized twice from absolute ethanol.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26](O)=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:74][N:75]1[CH2:80][CH2:79][NH:78][CH2:77][CH2:76]1>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([N:78]4[CH2:79][CH2:80][N:75]([CH3:74])[CH2:76][CH2:77]4)=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Reactant: CN1CCNCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(C(=O)COc2cccc(-c3nc(Nc4ccc5[nH]ncc5c4)c4ccccc4n3)c2)CC1
Temperature: 25 °C
Reaction time: 0.21 h

Procedure:
A suspension of 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (100 mg, 0.24 mmol), PyBOP® (125 mg, 0.24 mmol), DIEA (125 μL, 0.24 mmol) in CH2Cl2 (5 mL) stirred at RT for 10-15 minutes. To this solution of activated acid was added 1-methylpiperazine (27 μL, 0.24 mmol) and the reaction mixture was stirred at RT for 1.5 h. Concentrated in vacuo and the crude product was purified using prep HPLC (method 10-35_90 mins) to afford 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-1-(4-methylpiperazin-1-yl)ethanone. (32 mg, 0.065 mmol, 27%)
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[S:10]([OH:12])=[O:11].C(N(CC)CC)C.I[CH:21]([CH3:23])[CH3:22]>CN(C=O)C>[F:9][C:6]1[CH:5]=[CH:4][C:3]([S:10]([CH:21]([CH3:23])[CH3:22])(=[O:12])=[O:11])=[C:2]([F:1])[C:7]=1[F:8]
Reactant: CC(C)I
Reactant: O=S(O)c1ccc(F)c(F)c1F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)c1ccc(F)c(F)c1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 20.4 mmol 2,3,4-trifluoro-benzenesulfinic acid (prepared in analogy to example 2.20(a) from 2,3,4-trifluoro-benzenesulfonyl chloride) and 61.2 mmol triethylamine in 20 ml DMF was added 40.8 mmol 2-iodopropane, and the mixture stirred at room temperature for 16 h. The reaction mixture was then poured onto water and extracted three times with ethyl acetate. The combined organic phases were then washed twice with saturated aq. NaCl solution, dried over Na2SO4, and concentrated in vacuo. The residue was chromatographed on silica gel (eluant: ethyl acetate/heptane 1:4) to afford the title compound.
Reaction SMILES: [CH3:1][CH:2]([SH:4])[CH3:3].Cl[C:6]1[C:7]2[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:8]=2[S:9][C:10]=1[C:11]([NH:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1)=[O:12].C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>CN(C=O)C.C(OCC)(=O)C>[CH3:29][O:28][C:26]1[CH:25]=[CH:24][C:8]2[S:9][C:10]([C:11]([NH:13][C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=3)=[O:12])=[C:6]([S:4][CH:2]([CH3:3])[CH3:1])[C:7]=2[CH:27]=1
Reactant: COC(=O)c1ccc(NC(=O)c2sc3ccc(OC)cc3c2Cl)cc1
Reactant: CC(C)S
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(NC(=O)c2sc3ccc(OC)cc3c2SC(C)C)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 72 %

Procedure:
2-Propanethiol (32 μL, 0.35 mmol) is added to a solution of methyl 4-[[[3-chloro-5-methoxybenzo[b]thien-2yl]carbonyl]amino]benzoate (100 mg, 0.27 mmol) in 1 mL of DMF. Diazabicycloundecene (DBU) (52 μL, 0.35 mmol) is added and the mixture is stirred at room temperature for 5 hours. The reaction mixture is diluted with ethyl acetate and washed with 1N HCl, water, and brine. The organic layer is dried over MgSO4. Filtration followed by concentration in vacuo and recrystallization from ethyl acetate:hexane gives methyl 4-[[[5-methoxy-3-[(1-methylethyl)thio]benzo[b]thien-2yl]carbonyl]amino]benzoate in 72% yield; mp=157.5°-158.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][C:8]([NH:11][C:12](=[O:15])[CH:13]=[CH2:14])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1.O1CCOCC1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([NH:11][C:12](=[O:15])[CH2:13][CH2:14][N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)([CH3:9])[CH3:10])=[CH:16][CH:17]=1
Reactant: c1c[nH]cn1
Reactant: C=CC(=O)NC(C)(C)COc1ccc(Cl)cc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(COc1ccc(Cl)cc1)NC(=O)CCn1ccnc1
Temperature: 95 °C

Procedure:
A mixture of N-[2-(4-chlorophenoxy)-1,1-dimethylethyl]acrylamide (4.5 g), imidazole (1.24 g), benzyltrimethylammonium hydroxide (0.62 ml of a 40% solution in methanol, Triton®B) and 1,4-dioxane (40 ml) was heated at 95° C. for 7 hours. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane. This solution was extracted with 5M hydrochloric acid. The combined acid extracts were basified with 10M sodium hydroxide solution and extracted with dichloromethane to give N-[2-(4-chlorophenoxy)-1,1-dimethylethyl]-3-(imidazol-1-yl)propionamide.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:16]([OH:18])=O)[CH2:10][C:11]1[S:12][CH:13]=[CH:14][N:15]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[NH:29][C:30](=[O:45])[C@H:31]([CH2:34][CH2:35][CH2:36][NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[NH:32][CH3:33]>>[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[NH:29][C:30](=[O:45])[C@H:31]([CH2:34][CH2:35][CH2:36][NH:37][C:38]([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[O:39])[N:32]([C:16](=[O:18])[C@H:9]([CH2:10][C:11]1[S:12][CH:13]=[CH:14][N:15]=1)[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH3:33]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1nccs1)C(=O)O
Reactant: CN[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)Nc1ccc2ccccc2c1
Product: CN(C(=O)[C@H](Cc1nccs1)NC(=O)OC(C)(C)C)[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)Nc1ccc2ccccc2c1

Procedure:
Boc-β-(2-thiazolyl)alanine and Nδ-Boc-Nα-methylornithine β-naphthylamide were coupled under the conditions described in Procedure B, afforded a glassy solid which was purified by silica gel chromatography (1 to 2% MeOH/CH2Cl2): 1H NMR (400 MHz, CDCl3) δ1.45 (s, 9H), 1.50 (s, 9H), 1.52 (m, 2H), 1.77 (m, 1H), 2.18 (m, 1H), 3.01 (s, 3H), 3.19 (m, 3H), 3.49 (m, 1H), 4.98 (m,1H), 5.36 (m, 1H), 7.12 (s, 1H), 7.43 (m, 2H), 7.59 (d, J=7.2 Hz, 1H), 7.78 (m, 3H), 8.28 (s, 1H), 8.58 (s, 1H); mass spectrum (ES+) m/e 626 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[Cu][C:20]#[N:21].[OH-].[NH4+]>CN(C)C=O.O>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:20]#[N:21])=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(Br)cc1
Reactant: N#C[Cu]
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(CC1CCCC1)c1ccc(C#N)cc1
Temperature: 170 °C
Yield: 15933 %

Procedure:
A solution of 2-(4-bromo-phenyl)-3-cyclopentyl-propionic acid methyl ester (500 mg, 1.60 mmol) in N,N-dimethylformamide (4.01 mL) was treated with copper(I) cyanide (144 mg, 1.60 mmol). The mixture was heated at 170° C. for 1 h. At this time, the reaction was cooled to 25° C. and poured into aqueous ammonium hydroxide (5 mL). The solution was diluted with water (25 mL) and extracted with ethyl acetate (3×35 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate) afforded 2-(4-cyano-phenyl)-3-cyclopentyl-propionic acid methyl ester (65.6 g, 15.8%) as a clear oil: EI-HRMS m/e calcd for C16H19NO2 (M+) 257.1415 found 257.1406.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([N+:29]([O-])=O)[C:12]([CH2:26][CH2:27][Cl:28])=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[C:14]2[C:22]([O:24][CH3:25])=[O:23])C1C=CC=CC=1.CCN=C=NCCCN(C)C.[CH3:43][O:44][C:45]1[CH:46]=[C:47]2[C:51](=[C:52]([O:56][CH3:57])[C:53]=1[O:54][CH3:55])[NH:50][C:49]([C:58]([OH:60])=O)=[CH:48]2>[Pd].C1COCC1>[Cl:28][CH2:27][CH2:26][C:12]1[C:11]([NH:29][C:58]([C:49]2[NH:50][C:51]3[C:47]([CH:48]=2)=[CH:46][C:45]([O:44][CH3:43])=[C:53]([O:54][CH3:55])[C:52]=3[O:56][CH3:57])=[O:60])=[CH:10][C:9]([OH:8])=[C:17]2[C:13]=1[C:14]([C:22]([O:24][CH3:25])=[O:23])=[C:15]([C:18]([F:21])([F:19])[F:20])[NH:16]2
Reactant: COC(=O)c1c(C(F)(F)F)[nH]c2c(OCc3ccccc3)cc([N+](=O)[O-])c(CCCl)c12
Reactant: COc1cc2cc(C(=O)O)[nH]c2c(OC)c1OC
Agent: [Pd]
Agent: CCN=C=NCCCN(C)C
Solvent: C1CCOC1
Product: COC(=O)c1c(C(F)(F)F)[nH]c2c(O)cc(NC(=O)c3cc4cc(OC)c(OC)c(OC)c4[nH]3)c(CCCl)c12
Temperature: 25 °C

Procedure:
10% Pd/C (0.023 g) was added to methyl 7-benzyloxy-4-(2-cloroethyl)-5-nitro-2-trifluoromethylindole-3-carboxylate (0.0468 g, 0.102 mmol) and chilled THF (7 mL) was added quickly to the flask. The mixture was placed under reduced pressure and purged three times with H2. The reaction was stirred under H2 at room temperature and atmospheric pressure until completed by TLC. The solution was filtered through Celite pad in a sinter funnel and washed with THF. The amine was then concentrated under reduced pressure and co-evaporated twice with dry CH2Cl2 (2 mL). To the amine were added EDCI (0.040 g, 0.208 mmol) and 5,6,7-trimethoxyindole-2-carboxylic acid (0.026 g, 0.104 mmol). The flask was covered and flushed with N2. The amine was dissolved in dry DMF (10 mL) and stirred for four days under N2. The yellow solution was then diluted with ethyl acetate (100 mL), washed with water three times (100 mL) and 5% NaHCO3 (75 mL). The organic layer was collected, dried with sodium sulfate, gravity filtered and concentrated under reduced pressure. The residue was then purified on a preparative TLC in 2.5% methanol chloroform to yield the crude product. The product was further purified on a preparative TLC in methylene chloride to yield methyl 4-(2-chloroethyl)-7-hydroxy-2-trifluoromethyl-5-(5,6,7-trimethoxyindole-2-carboxamido)indole-3-carboxylate as a yellow solid. Total yield: 0.001 g (0.002 mmol, 2%). TLC (methylene chloride) Rf320.56.500 MHz 1H-NMR (CDCl3): 9.53 (s, 1H), 9.37 (s, 1H), 9.07 (s, 2H), 7.89 (s, 1H), 7.42 (s, 1H), 6.85 (s, 1H), 4.12 (s, 3H), 4.00 (s, 3H), 3.96 (s, 3H), 3.93 (s, 3H), 3.87 (t, 8.0, 2H), 3.72 (t, 8.0, 2H). IR (Neat) 3018, 2965, 2922, 2847, 1729, 1531, 1472, 1344, 1253, 1227, 1178, 1109, 1002, 799.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[OH:7][C:8]1[CH:9]=[CH:10][C:11]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:12]([CH:16]=1)[C:13]([OH:15])=O.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH2:31])[CH:26]=1.C(N(CC)CC)C>ClCCl>[OH:7][C:8]1[CH:9]=[CH:10][C:11]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:12]([CH:16]=1)[C:13]([NH:31][C:27]1[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=1)=[O:15]
Reactant: O=C(O)c1cc(O)ccc1OCc1ccccc1
Reactant: Nc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cccnc1)c1cc(O)ccc1OCc1ccccc1
Reaction time: 2 h

Procedure:
Oxalyl chloride (1.08 ml, 12.28 mmol) was added to a mixture of 5-hydroxy-2-[(phenylmethyl)oxy]benzoic acid (1 g, 4.09 mmol) dissolved in dichloromethane. The mixture was stirred for 2 h, and then concentrated. The residue was dissolved in dichloromethane, and then added to a mixture of pyridin-3-amine (0.39 g, 4.09 mmol) and triethylamine (1.14 ml, 8.19 mmol) in dichloromethane. The mixture was stirred at 40° C. for 3 h. The mixture was filtered, and the filtrate was added to water (10 ml) and extracted with ethyl acetate (30 ml). The organic phase was concentrated to yield the title compound as a crude solid product. 0.72 g.
Reaction SMILES: C([C:5]1([O:11][CH2:12][CH2:13][CH2:14]Br)[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1)(C)(C)C.[OH:16][CH2:17][C:18]1[S:19][CH:20]=[CH:21][CH:22]=1>CN(C=O)C>[S:19]1[CH:20]=[CH:21][CH:22]=[C:18]1[CH2:17][O:16][CH2:14][CH2:13][CH2:12][O:11][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1
Reactant: CC(C)(C)C1(OCCCBr)CCCCO1
Reactant: OCc1cccs1
Solvent: CN(C)C=O
Product: c1csc(COCCCOC2CCCCO2)c1

Procedure:
In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (RS)-2-(3-bromo-propoxy)-tetrahydro-pyran with 2-hydroxymethyl-thiophene in DMF there was obtained (RS)-2-[3-(thiophen-2-ylmethoxy)-propoxy]-tetrahydro-pyran, which after cleavage of the THP group analogously to Example 53(c), yielded 3-(thiophen-2-ylmethoxy)-propan-1-ol. Subsequent conversion into the mesylate according to a procedure known from the literature and alkylation effected with the latter analogously to Example 44(e) of tert-butyl (3RS,4RS)-3-hydroxy-4-(4-hydroxy-phenyl)-piperidine-1-carboxylate gave tert-butyl (3RS,4RS)-3-hydroxy-4-[4-[3-(thiophen-2-ylmethoxy)-propoxy]-phenyl]-piperidine-1-carboxylate. By alkylation with 2-chloromethyl-1,4-dimethoxy-naphthalene analogously to Example 1(g) there was obtained (3RS,4RS)-3-(1,4-dimethoxy-naphthalen-2-ylmethoxy)-4-{4-[3-(thiophen-2-ylmethoxy)-propoxy]-phenyl}-piperidine-1-carboxylate as a pale yellow resin; MS: 648 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][CH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1.[C:21](Cl)(=[O:23])[CH3:22]>ClCCl>[C:21]([O:8][CH2:9][CH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)(=[O:23])[CH3:22]
Reactant: OCCc1cccc2ccccc12
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCCc1cccc2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 102.3 %

Procedure:
Triethylamine (691 mL, 4.96 mol) was added to an ice cold solution of 1-(2-hydroxy-ethyl)-naphthalene (569 g, 3.30 mol) in dichloromethane (2.2 L). Acetyl chloride (282 mL, 3.97 mol) was added dropwise over 90 minutes. After the addition was complete, the reaction mixture was stirred for an additional 30 minutes with ice-bath cooling. The reaction mixture was washed sequentially with water (2×1 L), 1N HCl (1 L, 500 mL), water (1 L), 5% aqueous NaHCO3 (500 mL), water (1 L), and brine (500 mL), then dried over magnesium sulfate, filtered, and evaporated to afford 1-(2-acetoxy-ethyl)-naphthalene (723.2 g) as a yellow oil that slowly crystallized.
Reaction SMILES: [F:1][CH2:2][C:3]([N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22])([CH2:8][C:9](O)=[O:10])[C:4]([O:6][CH3:7])=[O:5].N1C=CC=CC=1.S(Cl)([Cl:31])=O.Cl.N1C=CC=CC=1>CCOCC>[F:1][CH2:2][C:3]([N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22])([CH2:8][C:9]([Cl:31])=[O:10])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(CF)(CC(=O)O)N1C(=O)c2ccccc2C1=O
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: COC(=O)C(CF)(CC(=O)Cl)N1C(=O)c2ccccc2C1=O

Procedure:
A solution of methyl 2-fluoromethyl-2-phthalimido-3-carboxy-propionate (2.37 g, 13.7 mmol) and pyridine (1.10 g, 13.7 mmol) in dry ether (50 ml) is treated with thionyl chloride (10 ml) at room temperature overnight. After addition of more ether (100 ml), pyridine hydrochloride is removed by filtration, and the solvent is evaporated to give the title compound as an orange oil (2.80 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([Br:13])=[C:7]([CH2:9][C:10](O)=[O:11])[CH:8]=1.CN(C=O)C.S(Cl)([Cl:21])=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([Br:13])=[C:7]([CH2:9][C:10]([Cl:21])=[O:11])[CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(Br)c(CC(=O)O)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(Br)c(CC(=O)Cl)c1
Temperature: 0 °C

Procedure:
5-Methoxy-2-bromophenylacetic acid (56 g, 0.23 mol) is dissolved in CH2Cl2 (350 mL) and a catalytic amount of DMF is added and the solution stirred and cooled to 0° C. Thionyl chloride (41 mL, 0.34 mol) is added dropwise. The reaction mixture is heated at reflux temperature overnight and then cooled to room temperature. Solvents are removed by rotary evaporator. Twice benzene (500 mL) is added to the residual oil and the benzene solution is evaporated by rotary evaporator to remove any additional volatile components. The residual oil is crystallized from hexanes to give 5-methoxy-2-bromophenylacetyl chloride.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)(=O)=O.[N:34]1[CH:39]=[CH:38][N:37]=[C:36]2[NH:40][CH:41]=[CH:42][C:35]=12.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.O>[N:34]1[CH:39]=[CH:38][N:37]=[C:36]2[N:40]([CH2:6][C@H:7]3[CH2:12][N:11]([S:13]([C:16]4[S:17][CH:18]=[CH:19][CH:20]=4)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]3[C:21]3[CH:22]=[CH:23][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:30])([F:31])[F:29])=[CH:25][CH:26]=3)[CH:41]=[CH:42][C:35]=12
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COS(C)(=O)=O)cc1)C(F)(F)F
Reactant: c1cnc2[nH]ccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2Cn2ccc3nccnc32)cc1)C(F)(F)F
Temperature: 80 °C
Reaction time: 18 h
Yield: 72.5 %

Procedure:
To a 50-mL round-bottomed flask was added ((2R)-4-(thiophen-2-ylsulfonyl)-1-(4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)piperazin-2-yl)methyl methanesulfonate (50 mg, 0.095 mmol, Intermediate B), 5H-pyrrolo[2,3-b]pyrazine (17 mg, 0.142 mmol, ARK Pharm., Libertyville, Ill.) and cesium carbonate (62 mg, 0.19 mmol) in acetonitrile (2 mL). The reaction mixture was stirred at 80° C. for 18 h. The mixture was allowed to cool to room temperature. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2×40 mL). The organic extract was washed with saturated NaCl (10 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as an off-white glass. The crude product was purified by silica gel chromatography, eluting with 100% EtOAc to give 2-(4-((S)-2-((5H-pyrrolo[2,3-b]pyrazin-5-yl)methyl)-4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)-1,1,1-trifluoro-2-propanol (38 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]([Cl:8])=[CH:3][CH:4]=[C:5]([CH3:7])[CH3:6].ClC(Cl)(Cl)C(O)=[O:12].O>C(Cl)Cl>[Cl:1][C:2]([Cl:8])=[CH:3][CH:4]1[O:12][C:5]1([CH3:7])[CH3:6]
Reactant: O=C(O)C(Cl)(Cl)Cl
Reactant: CC(C)=CC=C(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CC1(C)OC1C=C(Cl)Cl
Reaction time: 15 h
Yield: 101.8 %

Procedure:
To 30.6 g (0.2 mole) of 1,1-dichloro-4-methyl-1,3-pentadiene in 400 ml methylene chloride were added 0.35 mole of technical perchloroacetic acid containing 1.0 g sodium acetate at a temperature of 10°-20° C. over a period of 20 minutes. After stirring for 15 hours, the reaction mixture was poured into 500 ml of water. The phases were separated and the aqueous phase extracted twice with 150 ml of methylene chloride. The organic phases were combined and washed with 10% aqueous sodium carbonate (2×100 ml) and saturated aqueous sodium chloride (1×100 ml), dried over Na2SO4 and the solvent evaporated. The product was distilled to give 34 g of 1,1-dichloro-3,4-epoxy-4-methyl-1-pentene (82% yield).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:23][CH2:22][C:21]2[CH:24]=[CH:25][C:18]([F:17])=[CH:19][CH:20]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: NCc1ccc(F)cc1
Solvent: CCN(CC)CC
Product: Fc1ccc(CNc2nc(Cl)nc3c2ncn3C2CCCC2)cc1

Procedure:
2-Chloro-6-[(4-fluorobenzyl)amino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-fluorobenzylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [C:1]([O:4][CH:5]1[C@@H:22]2[CH2:23][C@@H:21]2[C@@:20]2([CH3:24])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[OH:25])[CH2:6]1)(=[O:3])[CH3:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl.C(OCC)C>[C:1]([O:4][CH:5]1[C@@H:22]2[CH2:23][C@@H:21]2[C@@:20]2([CH3:24])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:25])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1C[C@@H]2CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]2C[C@@H]12
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)OC1C[C@@H]2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)[C@H]2C[C@@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.5 %

Procedure:
A solution of 6.8 g of 3-acetoxy-1α,2α-methylene-5α-androstan -17β-ol in 68 ml of dichloromethane is combined with 10.2 g of pyridinium chlorochromate and stirred for one hour at room temperature, then diluted with diethyl ether, washed with water, and dried. Evaporation yields 7.0 g of 3-acetoxy-1α, 2α-methylene -5α-androstan-17-one.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B1C2CCCC1CCC2.C1C=C[NH+]=CC=1.[O-:37][Cr](Cl)(=O)=O>C1COCC1.CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([C:21]3[CH:16]([CH2:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:37])[CH2:14]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[Cr](=O)([O-])Cl
Reactant: CC(C)(C)OC(=O)N1CCC2(C=Cc3ccccc32)CC1
Agent: B1C2CCCC1CCC2
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)C1CC=CC=C12
Temperature: 70 °C
Yield: 46.5 %

Procedure:
To a solution of 661 mg (2.31 mmol) of 1'-(t-butyloxycarbonyl)spiro[1H-indene-1,4'-piperidine][prepared by the method of Chambers, et al, J. Med. Chem., 1992, 35, 2036] in 5.0 ml of THF was added 5.8 ml (1.0M THF, 2.9 mmol) of 9-BBN. The reaction mixture was heated at 70° C. until TLC analysis indicated that the starting material was consumed. The solution was concentrated and the residue was dissolved in dichloromethane. The solution was cooled to 0° C. and 4.1 g (19.2 mmol) of PCC was added slowly over 15 minutes. The reaction mixture was warmed to room temperature and then to reflux for 30 minutes. The solution was then diluted with ether and filtered through a pad of a mixture of celite and florisil. Purification by flash chromotgraphy (silica gel, hexane/ethyl acetate, 4:1) gave 326 mg (47%) of the title compound.