Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].C(OC(Cl)=O)C.[CH2:25]([NH2:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>O1CCCC1>[N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[CH2:25]([NH-:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCN
Agent: CCOC(=O)Cl
Agent: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Solvent: C1CCOC1
Product: CCCCCC[NH-]
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
50 g (0.1 mol) of Z-Pro-OH were dissolved in 400 ml of anhydrous tetrahydrofuran, 28 ml of triethyl amide were added. The mixture was cooled to -10° and then 19.5 ml (0.2 mol) of chloroformic acid ethyl ester were added dropwise. After stirring for 10 minutes at -10°C, 96 ml (1 mol) of n-hexyl amine were added portionwise at this temperature, and the whole was stirred for another 6 hours without cooling. Subsequently it was evaporated under reduced pressure and taken up with ethyl acetate. The ethyl acetate solution was extracted with a 5 % KHSO4 -solution, saturated NaHCO3 -solution and water. After evaporating the ethyl acetate solution, dried over sodium sulfate, the product was crystallized.
Reaction SMILES: O.[CH3:2][CH2:3][CH2:4][CH2:5][C:6]#[C:7][CH2:8][CH2:9][CH2:10][CH3:11]>C1COCC1.[Pd]>[CH3:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCC#CCCCC
Agent: [Pd]
Agent: *O[SiH2]*
Solvent: C1CCOC1
Solvent: O
Product: CCCC/C=C\CCCC
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 94 %

Procedure:
To a solution of polysiloxane containing a homogeneous dispersion of palladium particles (0.13 g) prepared as described above in THF and water (0.05 mmol Pd), 5-decyne (0.138 g, 0.18 mL, 1.0 mmol) in a solution of THF (5mL) and water (1 mL) was added. Hydrogen was bubbled through the solution for 30 seconds and the reaction was then placed under a hydrogen atmosphere (balloon). The reaction was stirred at room temperature for 4.5 h. Capillary gas chromatograph analysis showed complete consumption of the alkyne and a 94% yield of Z-5-decene using dodecane as an internal standard. The product was too volatile for an accurate isolated yield. However, a portion was isolated and analyzed spectroscopically. IR (neat) 2925.5, 2850.0 1460.1 cm -1. 1H NMR (300MHz, CDCl3)δ5.33 (br t, J=4.5 Hz, 2H), 2.01 (br q, J=5.6 Hz, 4H), 1.3-1.2 (m, 8H), 0.86 (t, J= 6.8 Hz, 6H) [>12:1 Z/E stereochemistry]. 13C NMR (20 MHz, CDCl3)δ129.87, 30.25, 26.93, 22.25, 13.98.
Reaction SMILES: CCN=C=NCCCN(C)C.CC1C=C(C)C=C(C)N=1.[OH:21][C:22]1[CH:27]=[CH:26][N:25]2[C:28]([C:31]([OH:33])=O)=[CH:29][N:30]=[C:24]2[CH:23]=1.[CH2:34]([N:41]1[C:49]2[CH:48]=[CH:47][CH:46]=[C:45]([NH2:50])[C:44]=2[CH:43]=[N:42]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C=O)C.CCOC(C)=O>[CH2:34]([N:41]1[C:49]2[C:44](=[C:45]([NH:50][C:31]([C:28]3[N:25]4[CH:26]=[CH:27][C:22]([OH:21])=[CH:23][C:24]4=[N:30][CH:29]=3)=[O:33])[CH:46]=[CH:47][CH:48]=2)[CH:43]=[N:42]1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C(O)c1cnc2cc(O)ccn12
Reactant: Nc1cccc2c1cnn2Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: Cc1cc(C)nc(C)c1
Product: O=C(Nc1cccc2c1cnn2Cc1ccccc1)c1cnc2cc(O)ccn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.6 %

Procedure:
A suspension of EDCI (192 mg, 0.679 mmol), 2,4,6-trimethylpyridine (224 mg, 1.85 mmol), and 7-hydroxyimidazo[1,2-a]pyridine-3-carboxylic acid (110 mg, 0.617 mmol) in DMF (2 mL) was stirred at ambient temperature for two hours. A solution of 1-benzyl-1H-indazol-4-amine (138 mg, 0.617 mmol) in DMF (2 mL) was added, and the resulting mixture was sonicated for 5 minutes. The heterogeneous mixture was stirred at ambient temperature overnight, then diluted with EtOAc, and washed twice with 1M aqueous hydrochloric acid, followed by brine. The organic layer was concentrated and subjected to chromatography on silica with 10% MeOH/DCM as eluent to provide 1.5 mg of desired product. MS (ES+APCI) m/z=384 (M+H) detected.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=2)[CH2:16][CH:17]2[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.CC1CCC(CNC2C=CC(F)=C(F)C=2)CC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[F:31][C:26]1[CH:25]=[C:24]([N:15]([CH2:16][CH:17]2[CH2:18][CH2:19][CH:20]([CH3:23])[CH2:21][CH2:22]2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:32])=[O:3])=[CH:8][N:9]=2)[CH:29]=[CH:28][C:27]=1[F:30]
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCC(C)CC2)c2ccc(F)c(F)c2)s1
Agent: CC1CCC(CNc2ccc(F)c(F)c2)CC1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Product: CC1CCC(CN(C(=O)Nc2ncc(SCC(=O)O)s2)c2ccc(F)c(F)c2)CC1

Procedure:
The title compound was prepared via {2-[3-(3,4-difluoro-phenyl)-3-(4-methylcyclohexylmethyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using 4-methyl-cyclohexylmethyl-(3,4-difluorophenyl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: C(OC([N:8]1[C:16]2[CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][C:11]=2[N:10]=[CH:9]1)=O)(C)(C)C.[OH-].[Na+]>CO.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[C:20]([O:19][C:17]([N:13]1[CH2:12][C:11]2[N:10]=[CH:9][NH:8][C:16]=2[CH2:15][CH2:14]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCc2c(ncn2C(=O)OC(C)(C)C)C1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2[nH]cnc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 6,7-dihydro-4H-imidazo[4,5-c]pyridine-1,5-dicarboxylic acid di-tert-butyl ester (Preparation 19, 26.8 g, 82.9 mmol) in methanol (210 mL) was added 1M sodium hydroxide aqueous solution (170 mL, 170 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with 10% citric acid aqueous solution (250 mL), basified to pH8 and extracted with DCM (2×500 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to give the title compound as a brown foam (18.5 g) in a 97% yield.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:13]([O:16][C@H:17]2[O:22][CH2:21][CH2:20][NH:19][C@H:18]2[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:14][OH:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH2:32][C:33]1[S:34][C:35](Br)=[CH:36][N:37]=1.CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([C@H:13]([O:16][C@H:17]2[O:22][CH2:21][CH2:20][N:19]([C:35]3[S:34][C:33]([NH2:32])=[N:37][CH:36]=3)[C@H:18]2[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:14][OH:15])[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: Nc1ncc(Br)s1
Reactant: OC[C@@H](O[C@H]1OCCN[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: C1COCCO1
Product: Nc1ncc(N2CCO[C@H](O[C@H](CO)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2c2ccc(F)cc2)s1
Temperature: 80 °C

Procedure:
To a degassed solution of 2-(R)-(1-(S)-(3,5-bis(trifluoromethyl) -phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)morpholine (0.2 g), 2-amino-5-bromothiazole (0.14 g), sodium tert-butoxide (0.0105 g) and tri-o-tolylphosphine (0.007 g) in dioxane (4 ml) was added tris(dibenzylideneacetone)dipalladium (0) (0.02 g). The solution was degassed and then heated at 80° C. for 24 h under an atmosphere of nitrogen. The solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. The organic layer was dried (MgSO4) and after evaporation of the solvent the residue was chromatographed on silica (eluting with gradient of 2% -4% methanol/ammonia (100:3) in dichloromethane) to give the title compound. 1H NMR (360 MHz, CDCl3) δ3.11 (1H, td, J=11.7 Hz, 3.5 Hz), 3.19 (1H, bd J=11.4 Hz), 3.61 (1H, dd, J=12.2 Hz and 3.3 Hz), 3.67-3.81 (3H, m), 4.47 (1H, d, J=2.8 Hz), 4.54 (1H, td, J=11.7 Hz and 2.8 Hz), 4.80 (2H, bs), 4.92 (1H, dd, J=7.8 Hz and 3.1 Hz), 6.97 (2H, t, J=8.7 Hz), 7.09 (1H, s), 7.14 (2H, s), 4.91 (1H, dd, J=7.8 Hz and 3.1 Hz), 7.67 (1H, s); m/z EI+ 552(M+H).
Reaction SMILES: B(Br)(Br)Br.[Br:5][C:6]1[CH:7]=[CH:8][C:9]2[CH:10]=[CH:11][C:12]3[C:17]([C:18]=2[CH:19]=1)=[CH:16][C:15]([O:20]C)=[CH:14][CH:13]=3>C(Cl)Cl>[Br:5][C:6]1[CH:19]=[C:18]2[C:9](=[CH:8][CH:7]=1)[CH:10]=[CH:11][C:12]1[CH:13]=[CH:14][C:15]([OH:20])=[CH:16][C:17]2=1
Reactant: COc1ccc2ccc3ccc(Br)cc3c2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc2ccc3ccc(Br)cc3c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a flask containing BBr3 (1 M in CH2Cl2, 17 mL) at 0° C. was added a solution of 3-bromo-6-methoxyphenanthrene (1 g, 3.5 mmol) from Step 2, Example 160 in CH2Cl2 (10 mL). The reaction mixture was warmed to room temperature and stirred for 30 minutes, after which it was quenched with water. The aqueous layer was extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered and concentrated to yield crude 6-bromophenanthren-3-ol.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:7]([NH2:8])=[CH:6][NH:5][N:4]=1.C(=O)(O)[O-].[Na+].[O:14]1CC[CH2:16][CH2:15]1.C(OC(=O)C)(=O)C>C(OCC)(=O)C.O.COC(C)(C)C>[Cl:2][C:3]1[C:7]([NH:8][C:15](=[O:14])[CH3:16])=[CH:6][NH:5][N:4]=1
Reactant: C1CCOC1
Reactant: Nc1c[nH]nc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Solvent: COC(C)(C)C
Product: CC(=O)Nc1c[nH]nc1Cl
Temperature: 5 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
A 100-mL 3-neck round bottom flask was charged with 3-chloro-1H-pyrazol-4-amine hydrochloride (5.00 g, 32.5 mmol) and water (25 mL). Sodium bicarbonate (10.9 g, 130 mmol) was added slowly over 10 minutes (off-gassing during addition), followed by tetrahydrofuran (25 mL). The mixture was cooled to 5° C. and acetic anhydride (3.48 g, 34.1 mmol) was added over 30 minutes while maintaining the internal temperature at <10° C. The reaction was stirred at 5° C. for 1 hour, at which point thin layer chromatography (TLC) analysis [Eluent: ethyl acetate] indicated that the starting material had disappeared and a major product was exclusively formed. The reaction mixture was diluted with ethyl acetate (25 mL) and water (25 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×25 mL). The combined organic layers were concentrated to afford an off-white solid, which was suspended in methyl tert-butylether (20 mL), stirred for 1 hour, and filtered. The solid was rinsed with methyl tert-butylether (20 mL) and further dried under vacuum at room temperature (about 22° C.) for 4 hours to give a white solid (4.28 g, 83%): mp 162-164° C.; 1H NMR (400 MHz, DMSO-d6) δ 12.90 (bs, 1H), 9.49 (s, 1H), 7.97 (s, 1H), 2.02 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ 167.81, 130.07, 123.72, 116.73, 22.58; EIMS m/z 159 ([M]+).
Reaction SMILES: N1C=CC=NC=1.CC1C=NC=CC=1C(NC1C=CC([C:19]2[S:20][C:21]([C:25]3[CH:26]=[N:27][CH:28]=[N:29][CH:30]=3)=[CH:22][C:23]=2[CH3:24])=CC=1)=O.B(O)(O)O.S1C=CC=C1.BrC1C=CC=NC=1>[Pd]>[N:29]1[CH:30]=[C:25]([C:21]2[S:20][CH:19]=[C:23]([CH3:24])[CH:22]=2)[CH:26]=[N:27][CH:28]=1
Reactant: Cc1cnccc1C(=O)Nc1ccc(-c2sc(-c3cncnc3)cc2C)cc1
Agent: [Pd]
Agent: OB(O)O
Solvent: Brc1cccnc1
Solvent: c1cncnc1
Solvent: c1ccsc1
Product: Cc1csc(-c2cncnc2)c1

Procedure:
The pyrimidine substituent on the thiophene ring of 3-Methyl-N-[4-(3-methyl-5-pyrimidin-5-yl-thiophen-2-yl)-phenyl]-isonicotinamide was attached using a Suzuki coupling reaction (as describe in Step B of the synthesis of compound 1) by reacting a boric acid derivative of thiophene (o) with 5-bromo-pyridine (p) in the presence of a palladium catalyst to form 2-(pyrimidin-5-yl)-4-methyl-thiophene (q). In general, aromatic substituents such as pyridine, can be added to thiophene, oxazole, thiazole and oxazole ring systems by using a Suzuki coupling reaction. A bromo substituent was added to (q) by reacting it with N-bromo-succinimide in acetic acid to form 2-(pyrimidin-5-yl)-4-methyl-5-bromo-thiophene (r). Compound (r) is then coupled to an amino pyridine using a Suzuki coupling reaction (as describe in Step B of the synthesis of compound 1) to form Compound (s). Compound (s) is then reacted with 2-methyl-isonicotinoyl chloride in a reaction analogous to the reaction described in step A of the synthesis of 4-[4-(2,6-Difluoro-benzoylamino)-phenyl]-5-methyl-thiophene-2-carboxylic acid methyl ester to form 3-Methyl-N-[4-(3-methyl-5-pyrimidin-5-yl-thiophen-2-yl)-phenyl]-isonicotinamide.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[C:13](=[O:14])[CH2:12][C@:11]([CH:18]([CH3:20])[CH3:19])([C:15](O)=[O:16])[CH2:10]1.CS(Cl)(=O)=O.C(N(C(C)C)CC)(C)C.[CH:35]1([C:38]2[CH:39]=[C:40]([NH2:48])[CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=2)[CH2:37][CH2:36]1>C1COCC1>[CH:35]1([C:38]2[CH:39]=[C:40]([NH:48][C:15]([C@@:11]3([CH:18]([CH3:19])[CH3:20])[CH2:12][C:13](=[O:14])[N:9]([C:3]4[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=4[CH3:1])[CH2:10]3)=[O:16])[CH:41]=[C:42]([C:44]([F:46])([F:47])[F:45])[CH:43]=2)[CH2:36][CH2:37]1
Reactant: Cc1cccc(C)c1N1C[C@](C(=O)O)(C(C)C)CC1=O
Reactant: Nc1cc(C2CC2)cc(C(F)(F)F)c1
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cccc(C)c1N1C[C@](C(=O)Nc2cc(C3CC3)cc(C(F)(F)F)c2)(C(C)C)CC1=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of (R)-1-(2,6-dimethylphenyl)-3-isopropyl-5-oxopyrrolidine-3-carboxylic acid (32 mg, 0.12 mmol) and methanesulfonyl chloride (12 μL, 0.15 mmol) in THF (0.6 mL) at 0° C. was added diisopropylethylamine (0.060 mL, 0.35 mmol). The solution was stirred 15 min at 0° C., warmed to ambient temperature, and 3-cyclopropyl-5-(trifluoromethyl)benzenamine (47 mg, 0.23 mmol) was subsequently added and the solution was heated at 55° C. overnight. The following day, the reaction mixture was purified via preparative HPLC to afford the desired amide as a white solid. 1H NMR (400 MHZ, CDCl): δ 9.89 (s, 1H), 7.86 (s, 1H), 7.56 (s, 1H), 7.05-7.17 (m, 4H), 3.97 (d, J=10.4 Hz, 1H), 3.67 (d, J=10.4 Hz, 1H), 3.04 (d, J=17.2 Hz, 1H), 2.65 (d, J=17.2 Hz, 1H), 2.36 (septet, J=6.8 Hz, 1H), 2.16 (s, 3H), 1.99-2.08 (m, 1H), 1.99 (s, 3H), 1.00-1.06 (m, 2H), 0.96 (t, J=6.8 Hz, 6H), 0.70-0.75 (m, 2H). LC-MS Rt (retention time): 3.02 min; MS: (ES) m/z 459 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][CH2:5][CH:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][C:9]1=[O:17])[CH3:7].[I-].[CH3:20][N:21]1[C:29]2[C:24](=[C:25]([CH3:30])[CH:26]=[CH:27][CH:28]=2)[C:23]([CH2:31][N+](C)(C)C)=[CH:22]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:18])[CH2:4][CH2:5][CH:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:31][CH:23]2[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])[N:21]([CH3:20])[CH2:22]2)[C:9]1=[O:17])[CH3:7]
Reactant: COC(=O)CCC(C)n1c(=O)[nH]c2ccccc21
Reactant: Cc1cccc2c1c(C[N+](C)(C)C)cn2C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CCC(C)n1c(=O)n(CC2CN(C)c3cccc(C)c32)c2ccccc21
Temperature: 100 °C
Reaction time: 4 h
Yield: 86.6 %

Procedure:
To a mixture of 4-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-pentanoic acid methyl ester (85 mg, 0.34 mmol) and (1,4-dimethyl-1H-indol-3-ylmethyl)-trimethylammonium iodide (175 mg, 0.51 mmol) in DMF (2.5 mL) was added K2CO3 (95 mg, 0.69 mmol). The mixture was stirred at 100° C. for 4 hours. The reaction mixture was allowed to cool to room temperature, diluted with EtOAc (50 mL) and washed with H2O (50 mL×3). The organic layer was dried over sodium sulfate and concentrated. The resulting residue was purified by CombiFlash with 25% EtOAc in Hexane as the eluent to afford the desired 4-[3-(1,4-dimethyl-3H-indol-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-pentanoic acid methyl ester (120 mg, 86%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]([C:9]2[N:10]=[C:11]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N:12]3[CH:18]=2)=[C:6]([CH3:8])[N:7]=1.[BrH:19].[NH+]1C=CC=CC=1.O.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C.O1CCCC1>[CH3:1][NH:2][C:3]1[S:4][C:5]([C:9]2[N:10]=[C:11]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N:12]3[C:18]=2[Br:19])=[C:6]([CH3:8])[N:7]=1
Reactant: Br
Reactant: CNc1nc(C)c(-c2cn3ccc(C)cc3n2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CNc1nc(C)c(-c2nc3cc(C)ccn3c2Br)s1

Procedure:
To a solution of 2-(2-methylamino-4-methylthiazol-5-yl)-7-methylimidazo[1,2-a]pyridine (1.92 g) in a mixture of acetic acid (14 ml) and tetrahydrofuran (10 ml) was added pyridinium hydrobromide perbromide (2.6 g) at ambient temperature and the mixture was stirred for an hour. The reaction mixture was poured into water and the resultant aqueous solution was adjusted to pH 7.5 with saturated potassium carbonate. The product was extracted with chloroform and the extract was dried over magnesium sulfate. The solvent was evaporated in vacuo to afford a crystalline residue, which was recrystallized from a mixture of methylene chloride and diethyl ether to give 2-(2-methylamino-4-methylthiazol-5-yl)-3-bromo-7-methylimidazo[1,2-a]pyridine (2.2 g).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[C:6]([F:13])[C:5]=1[N:14]1[CH2:19][CH2:18][S:17][CH2:16][CH2:15]1>CO.C(OCC)(=O)C>[F:13][C:6]1[CH:7]=[C:8]([NH2:10])[CH:9]=[C:4]([F:3])[C:5]=1[N:14]1[CH2:15][CH2:16][S:17][CH2:18][CH2:19]1
Reactant: O=[N+]([O-])c1cc(F)c(N2CCSCC2)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1cc(F)c(N2CCSCC2)c(F)c1
Yield: 70 %

Procedure:
Sodium borohydride (285 mg, 7.5 mmol) was added to a stirring solution of NiCl2.6H2O (1.16 g, 5.0 mmol) and 4-(2,6-difluoro-4-nitrophenyl)thiomorpholine, obtained in Preparation 3, in methanol (30 mL). The reaction mixture was diluted with ethyl acetate (50 mL) after 0.5 h and the organic portion was washed with water (30 mL×2) followed by brine (30 mL) and dried over sodium sulfate. Evaporation of the volatiles yielded the title compound as light brown solid (400 mg, 70%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][C:10](=[O:25])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:13]=2)=[C:4]([N+:26]([O-:28])=O)[CH:3]=1.[K+].[Br-]>CCO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[Cl:8])[NH:9][C:10](=[O:25])[C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:13]=1)=[N+:26]2[O-:28]
Reactant: O=C(Cc1cccc(Oc2ccccc2)c1)Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCO
Product: O=c1[nH]c2cc(Cl)c(Cl)cc2[n+]([O-])c1-c1cccc(Oc2ccccc2)c1
Yield: 53 %

Procedure:
The title compound was prepared according to the general procedure described in Example 6 by substituting 8 mmol of 135 for 125. Yield: 53%; mp 258°-260° C. (from EtOH); IR (KBr) 3450, 3207, 3180, 3039, 1674, 1617, 1581, 1465, 1361, 1262, 1220 and 1149 cm-1 ; 1H NMR (in DMSO-d6) δ7.10 (m, 3H), 7.37 (m, 5H), 7.44 (s, 1H), 7.50 (s, 1H), 8.27 (s, 1H), 12.58 (br.s, 1H, N--H); HPLC: 98%; HRMS Calcd for C20H12N2O3Cl2 : 398.0225.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[NH:23]1[C:27]([CH:28]=O)=[N:26][N:25]=[N:24]1>CO>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([N:1]=[CH:28][C:27]4[NH:26][N:25]=[N:24][N:23]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1nnn[nH]1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Solvent: CO
Solvent: CC(=O)O
Product: Clc1cccc(Nc2ncnc3[nH]nc(N=Cc4nnn[nH]4)c23)c1
Reaction time: 8 h

Procedure:
With gentle heating, 195 mg (0.75 mmol) of 3-amino-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine (see Step 1.6) and 135 mg of acetic acid are dissolved in 20 ml of methanol. Then, at RT, 1.0 mmol of tetrazole-5-carbaldehyde is added and the reaction mixture is stirred overnight to complete the reaction, during which a solid separates out. Concentration by evaporation to approximately half volume and filtration yield 4-(3-chloro-phenylamino)-3-[(tetrazol-5-yl)-methyleneamino]-1H-pyrazolo[3,4-d]pyrimidine. More material can be recovered from the mother liquor by concentration by evaporation and stirring the residue in isopropanol. Under a nitrogen atmosphere, 208 mg of the above intermediate are dissolved in 27 ml of DMEU and, with ice cooling, 4.2 ml (4.2 mmol) of DIBAL-H are added and the mixture is stirred for 7 hours. 13 ml of ethyl acetate are added and the mixture is stirred for 30 min and diluted with 130 ml of methanol. 0.9 ml of water and 9 g of Na2SO4 are added to the precipitate, followed by stirring for 30 min and then filtration. The filtrate is concentrated by evaporation (RV, HV) and chromatographed (SiO2; CH2Cl2/−methanol=4:1) and the crude product is stirred in isopropanol/diethyl ether to yield 4-(3-chloro-phenylamino)-3-[(tetrazol-5-yl)-methylamino]-1H-pyrazolo[3,4-d]pyrimidine:HPLC: tRet(grad20-100)=6.7; FAB MS (M+H)+=343.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[O:21][CH2:20][CH2:19][NH:18][CH2:17]2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Br[CH2:23][CH2:24][CH2:25][P:26](=[O:33])([O:30][CH2:31][CH3:32])[O:27][CH2:28][CH3:29].[Na+].[I-].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:31]([O:30][P:26]([CH2:25][CH:24]([N:18]1[CH2:19][CH2:20][O:21][CH:16]([C:13]2[CH:12]=[CH:11][C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:15][CH:14]=2)[CH2:17]1)[CH3:23])(=[O:33])[O:27][CH2:28][CH3:29])[CH3:32]
Reactant: CCOP(=O)(CCCBr)OCC
Reactant: CCCCCCCCOc1ccc(C2CNCCO2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCCCOc1ccc(C2CN(C(C)CP(=O)(OCC)OCC)CCO2)cc1
Temperature: 25 °C
Yield: 66.8 %

Procedure:
A mixture of 2-(4-octyloxy-phenyl)-morpholine (1.04 g; 3.6 mmol), diethyl (3-bromopropyl)phosphonate (0.82 mL; 4.3 mmol), NaI (0.11 g; 0.7 mmol), and K2CO3 (0.99 g; 7.1 mmol) in CH3CN (10 mL) was heated under reflux for 2 hours. After cooling to RT the mixture was partitioned between 5% aqueous NaHCO3 solution and Et2O. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, EtOAc: MeOH 90:10) to afford {2-[2-(4-octyloxy-phenyl)morpholin-4-yl]-propyl}-phosphonic acid diethyl ester (1.13 g).