Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>CC#N>[Cl:2][CH2:1][CH:3]([OH:5])[CH2:4][N:17]1[CH2:16][CH2:15][N:14]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][CH3:6])[CH2:19][CH2:18]1
Reactant: ClCC1CO1
Reactant: COc1ccccc1N1CCNCC1
Solvent: CC#N
Product: COc1ccccc1N1CCN(CC(O)CCl)CC1

Procedure:
To epichlorohydrin (3.9 ML, 50 mmol) in CH3CN (3 mL) at 0° C. was added 1-(2-methoxyphenyl)piperazine (9 mL, 50 mmol) in CH3CN (20 mL) dropwise over 5 minutes under a nitrogen atmosphere. After 16 hours the resultant white precipitate was filtered away, washed with CH3CN and acetone, dried at 30° C. in a vacuum oven and identified as pure product (7.28 g, 51.1%). mp 96°-98° C. DCI/MS M+1=285. (100 MHz) 1 H nmr (dmso-d6) δ:6.9 (m, 4H), 3.76(m, 1H), 3.76 (s, 3H), 3.62 (d of d, 2H), 2.96 (m, 4H), 2.56 (m, 6H).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:15])[C:12](Cl)=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CC(C)=O>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH3:15])[CH:12]=[O:13])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc(C(C)C(=O)Cl)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)=O
Product: CC(C)Cc1ccc(C(C)C=O)cc1
Temperature: 20 °C

Procedure:
An aliquot of the so obtained (2RS)-2-(4-isobutylphenyl)-propanoyl chloride (44.8 g; 0.199 moles) is dissolved in acetone (200 ml); this solution is added dropwise to a suspension of triphenyl phosphine (112 g; 0.427 moles) and bistriphenyl phosphine cupper boron hydride (128 g; 0.212 moles) in acetone (600 ml) kept under stirring at 20° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([C@H:10]2[C:19]3[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=3)[O:13][CH2:12][C@H:11]2[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[CH:6]=[CH:7][C:8]=1[OH:9].[CH2:29](N(CC)CC)[CH3:30].C(O)(=O)C>O>[CH3:21][O:20][C:16]1[CH:15]=[C:14]2[C:19]([C@H:10]([C:5]3[CH:6]=[CH:7][C:8]4[O:9][C:29]([CH3:30])=[N:2][C:3]=4[CH:4]=3)[C@H:11]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)[CH2:12][O:13]2)=[CH:18][CH:17]=1
Reactant: COc1ccc2c(c1)OC[C@@H](c1ccc(C)cc1)[C@H]2c1ccc(O)c(N)c1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2c(c1)OC[C@@H](c1ccc(C)cc1)[C@H]2c1ccc2oc(C)nc2c1
Temperature: 25 °C

Procedure:
To a stirred mixture of (±)-cis4-(3-amino-4-hydroxyphenyl)-7-methoxy-3-(4-methylphenyl)-chromane hydrochloride (0.475 g, 1.19 mmol), triethylamine (0.173 ml, 1.25 mmol) and acetic acid (15 ml) was heated to gentle reflux for 18 h., giving a deep red coloured mixture. This was cooled to room temperature, poured into water (100 ml) and the product extracted into ethyl acetate (2×100 ml). The combined extracts were washed with water (6×50 ml), brine, dried over magnesium sulfate and evaporated to give a dark gum. This was purified by column chromatography on silica gel 60, with a 1:1 petrol/ethyl acetate eluent. This gave the product, on vacuum drying, as a stable pale pink coloured foam.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[NH:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:37][CH2:36][CH2:35]1>>[CH3:1][O:2][C:3](=[O:33])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:27][CH:28]=2)[CH:12]=[C:13]([N:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH2:37][CH2:36][CH2:35]2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: c1ccc2c(c1)CCCN2
Reactant: COC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Product: COC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(N2CCCc3ccccc32)c1
Yield: 25 %

Procedure:
The title compound was prepared in 25% yield from 4-methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid methyl ester and 1,2,3,4-tetrahydroquinoline under the conditions described in Example 24, steps (a).
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.[F:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([F:35])[C:28]=1[C:36]1[N:41]=[C:40]([C:42](O)=[O:43])[CH:39]=[CH:38][C:37]=1[F:45]>>[NH2:9][C@H:8]1[C@H:2]([F:1])[CH2:3][O:4][C@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[NH:23][C:42](=[O:43])[C:40]2[CH:39]=[CH:38][C:37]([F:45])=[C:36]([C:28]3[C:29]([F:35])=[CH:30][C:31]([O:33][CH3:34])=[CH:32][C:27]=3[F:26])[N:41]=2)[CH2:6][CH2:7]1
Reactant: COc1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: COc1cc(F)c(-c2nc(C(=O)Nc3cnn(C)c3[C@@H]3CC[C@@H](N)[C@H](F)CO3)ccc2F)c(F)c1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 80), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 6-(2,6-difluoro-4-methoxyphenyl)-5-fluoropicolinic acid (see US2012/225062) gave 201. 1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.26 (dd, J=8.7, 4.0 Hz, 1H), 8.11 (t, J=8.9 Hz, 1H), 7.90 (s, 1H), 6.94 (d, J=10.2 Hz, 2H), 4.82 (dd, J=10.4, 3.7 Hz, 1H), 4.40-4.14 (m, 1H), 4.08-3.91 (m, 2H), 3.86 (s, 3H), 3.76 (s, 3H), 3.18-3.04 (m, 1H), 2.12-2.02 (m, 1H), 1.83-1.60 (m, 3H). LCMS (ES+) m/z 494 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:29][CH2:28][C:11]2[N:12]=[C:13]([C:18]3[C:26]([CH3:27])=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[N:21][NH:22]4)[N:14]=[C:15]([O:16][CH3:17])[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[S:32](Cl)([C:35]1[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=1)(=[O:34])=[O:33].[NH4+].[Cl-]>C1COCC1>[CH2:1]([N:8]1[CH2:29][CH2:28][C:11]2[N:12]=[C:13]([C:18]3[C:26]([CH3:27])=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[N:21][N:22]4[S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[N:14]=[C:15]([O:16][CH3:17])[C:10]=2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1nc(-c2c(C)ccc3[nH]ncc23)nc2c1CN(Cc1ccccc1)CC2
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1nc(-c2c(C)ccc3c2cnn3S(=O)(=O)c2ccc(C)cc2)nc2c1CN(Cc1ccccc1)CC2
Reaction time: 0.33 h

Procedure:
6-Benzyl-4-methoxy-2-(5-methyl-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (2.00 g, 5.19 mmol) was added to a suspension of NaH (60% dispersion in mineral oil, 415 mg, 10.4 mmol) in THF (50 mL) at 0° C. After 20 min, TsCl (1.19 g, 6.23 mmol) was added. The reaction mixture was stirred for 20 min and sat aq NH4Cl solution was added to quench excess base. The resulting mixture was extracted with EtOAc (3×). The combined organics were dried (Na2SO4) and concentrated. The residue was purified by silica gel chromatography (0-100% EtOAc/heptane) to provide 6-benzyl-4-methoxy-2-(5-methyl-1-tosyl-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. MS (ESI+) m/z 540.2 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:14])[CH:5]([C:7]1[CH:12]=[CH:11][C:10](I)=[CH:9][CH:8]=1)[CH3:6])[CH3:2].[C:15]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)#[CH:16]>C(#N)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.CCOC(C)=O>[CH2:1]([NH:3][C:4](=[O:14])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([C:16]#[C:15][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:9][CH:8]=1)[CH3:6])[CH3:2]
Reactant: CCNC(=O)C(C)c1ccc(I)cc1
Reactant: C#Cc1ccc(OC)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCNC(=O)C(C)c1ccc(C#Cc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
300 mg (0.99 mmol) N-Ethyl-2-(4-iodo-phenyl)-propionamide (XVIII.1) are added to 148 μL (1.14 mmol) 1-ethynyl-4-methoxybenzene in 8 mL ACN under inert gas atmosphere. 276 μL (1.99 mmol) TEA as base, 6 mg (0.03 mmol) copper(I)iodide and 42 mg (0.060 mmol) bis(triphenylphosphine)palladium(II)chloride as catalyst are added and the mixture is stirred at rt under inert gas atmosphere for 5 h. After that time, the mixture is diluted with EtOAc, washed with saturated ammonium chloride solution and brine, and the organic layer is dried over sodium sulphate. The solvent is evaporated and the residue is purified by column chromatography (silicia gel; heptane:EtOAc 50:50).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[NH:11][CH2:12][CH2:13][N:7]3[C:6]=2[C:5]([CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:4][CH:3]=1.Br[C:20]1[C:25]([Cl:26])=[CH:24][C:23]([C:27]([F:30])([F:29])[F:28])=[CH:22][N:21]=1.N1C=CC=CC=1C1C=CC=CN=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O.C(OCC)(=O)C.[Cu]I>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:20]4[C:25]([Cl:26])=[CH:24][C:23]([C:27]([F:30])([F:28])[F:29])=[CH:22][N:21]=4)[CH2:12][CH2:13][N:7]3[C:6]=2[C:5]([CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1cnc(Br)c(Cl)c1
Reactant: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCN3
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCN3c1ncc(C(F)(F)F)cc1Cl
Temperature: 150 °C
Reaction time: 4 h

Procedure:
A mixture of 8-chloro-5-(1-ethylpropyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazole (28.6 mg, 0.108 mmol), 2-bromo-3-chloro-5-(trifluoromethyl)pyridine (56.3 mg, 0.217 mmol), copper(I) iodide (20.6 mg, 0.108 mmol), 2,2′-bipyridyl (33.9 mg, 0.217 mmol) and cesium carbonate (70.7 mg, 0.217 mmol) in 1-methyl-2-pyrrolidinone (1.0 mL) was stirred at 150° C. for 4 hrs. After cooling, the mixture was diluted with ethyl acetate, the precipitate was filtered through a pad of celite. The filtrate was extracted with ethyl acetate (×3). The combined organic layer was washed with 1N hydrochloric acid (×1) and brine (×1), dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-15%, ethyl acetate/n-hexane gradient mixture to give the title compound as a yellow amorphous (14.2 mg, 0.0320 mmol, 30%).
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[C:29]([Cl:30])=[C:28]([CH3:31])[S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:26]=[N:25][CH:24]=[CH:23][N:22]=2)[N:20]=1>>[N:22]1[CH:23]=[CH:24][N:25]=[CH:26][C:21]=1[C:19]1[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:13][CH2:1][O:2][C:3]=3[CH:4]=2)[C:16]2[C:29]([Cl:30])=[C:28]([CH3:31])[S:27][C:17]=2[N:18]=1
Reactant: NCCc1ccc2c(c1)OCCO2
Reactant: Cc1sc2nc(-c3cnccn3)nc(Cl)c2c1Cl
Product: Cc1sc2nc(-c3cnccn3)nc(NCCc3ccc4c(c3)OCCO4)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyrazin-2-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3,4-ethylenedioxyphenethylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[CH3:28][O:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[C:34]([O:38][CH3:39])[C:35]=1[O:36][CH3:37].C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:32]4[CH:33]=[C:34]([O:38][CH3:39])[C:35]([O:36][CH3:37])=[C:30]([O:29][CH3:28])[CH:31]=4)[CH:3]=3)[NH:8][CH:9]=2)=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccc(F)cc3)c3cc(Br)cnc32)cc1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cc(-c2cnc3[nH]cc(-c4ccc(F)cc4)c3c2)cc(OC)c1OC
Yield: 28.7 %

Procedure:
5-Bromo-3-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (3 mg, 0.147 mg, 0.083 mmol), 3,4,5-trimethoxyphenylboronic acid (21 mg, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium (II) (3 mg, 0.004 mmol) were combined in CH3CN (1.5 ml) and 1 M Na2CO3 (2 ml) and reacted in a microwave reactor for 20 min at 150° C. EtOAc was added and the mixture was washed with water, dried, evaporated and purified by silica gel chromatography using 0-2% MeOH:DCM to yield 9 mg (29%) of the title compound. MS ESI (m/z): 379.2 (M+1)+, calc. 378.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[C:8]1([C:13]([C:15]2[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[O:14])[S:12][CH:11]=[CH:10][CH:9]=1>[OH-].[Na+].C(OCC)C>[C:8]1([C:13]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[O:14])[S:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(c1ccc(S(=O)(=O)Cl)cc1)c1cccs1
Reactant: NCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C(O)CCCNS(=O)(=O)c1ccc(C(=O)c2cccs2)cc1

Procedure:
103 mg (1.10-3 mole) of 4-aminobutyric acid dissolved in 4 ml of a 0.5 N solution of caustic soda are added dropwise to 287 mg (1.10-3 mole) of 4-(2-thenoyl)benzenesulphonyl chloride in 5 ml of ethyl ether.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=O)[C@@H:10]([NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[S:22](=[O:24])(=[O:23])[NH:21][C:20](=[O:25])[CH2:19]2)=[C:14]([Br:26])[CH:13]=1>C(O)(=O)C>[NH:1]1[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N:8]=[C:9]1[C@@H:10]([NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[S:22](=[O:24])(=[O:23])[NH:21][C:20](=[O:25])[CH2:19]2)=[C:14]([Br:26])[CH:13]=1
Reactant: Nc1ccccc1NC(=O)[C@H](Cc1ccc(C2CC(=O)NS2(=O)=O)c(Br)c1)NC(=O)OCc1ccccc1
Solvent: CC(=O)O
Product: O=C1CC(c2ccc(C[C@H](NC(=O)OCc3ccccc3)c3nc4ccccc4[nH]3)cc2Br)S(=O)(=O)N1
Temperature: 60 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
Benzyl (1S)-2-[(2-aminophenyl)amino]-1-[3-bromo-4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)benzyl]-2-oxoethylcarbamate (28.2 mg, 0.0469 mmol) was dissolved in acetic acid (2.76 mL) and stirred at 60° C. for 1 h. The solution was concentrated and purified by preparative LCMS to afford product as a white solid (26.1 mg, 95%). 1H NMR (400 MHz, CD3OD): δ 7.79–7.56 (m, 5H), 7.42–7.12 (m, 7H), 5.61–5.57 (m, 1H), 5.35–5.31 (m, 1H), 5.03 (s, 2H), 3.47–3.28 (m, 1H); LCMS found for C26H24BrN4O5S (M+H)+: m/z=583.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([CH3:13])([CH3:12])[CH2:7][CH2:6][C:5]([CH3:15])([CH3:14])[C:4]=2[CH:3]=1.ClCCl.[Cl-].[Al+3].[Cl-].[Cl-].[C:23](Cl)(=[O:26])[CH2:24][CH3:25]>O>[CH2:24]([C:23]([C:11]1[C:2]([OH:1])=[CH:3][C:4]2[C:5]([CH3:15])([CH3:14])[CH2:6][CH2:7][C:8]([CH3:13])([CH3:12])[C:9]=2[CH:10]=1)=[O:26])[CH3:25]
Reactant: CC1(C)CCC(C)(C)c2cc(O)ccc21
Reactant: CCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCC(=O)c1cc2c(cc1O)C(C)(C)CCC2(C)C
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To 5,6,7,8-tetrahydro-2-hydroxy-5,5,8,8-tetramethylnaphthalene (204 mg, 1.00 mmol) were added anhydrous dichloromethane (1 mL), aluminum chloride (148 mg, 1.12 mmol), and propionyl chloride (101.7 mg, 1.10 mmol) followed by stirring at 60° C. for 16 hours. The reaction solution was poured into cold water and extracted by ethyl acetate. The organic layer was washed by water, a saturated sodium hydrogen carbonate aq. solution, and a saturated saline solution, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using hexane/ethyl acetate (20/1) as an elution solvent. The yield was 117 mg (45%).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10][C:9]([CH3:19])([CH3:18])[C:8]=2[CH:7]=1)[CH2:2][CH2:3][CH3:4].[Cl:20][C:21](Cl)([O:23]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[CH2:1]([N:5]([C:6]1[CH:15]=[CH:14][C:13]2[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10][C:9]([CH3:18])([CH3:19])[C:8]=2[CH:7]=1)[C:21]([Cl:20])=[O:23])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CCCCN(C(=O)Cl)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 0 °C
Yield: 595.2 %

Procedure:
A solution of butyl-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-amine (7) (143 mg, 0.55 mmole) in 20 mL of THF was treated with 57 mg of triphosgene (0.35 eq.), stirred at reflux for three hours and then poured onto 50 mL ice-water. The mixture was extracted with three portions of 50 mL of ethyl acetate. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo, to provide 368 mg of butyl-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-carbamoyl chloride (9) which was used without purification.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[Cl:11])[NH:4][N:3]=1.[O:12]1[C:16]2([CH2:21][CH2:20][CH:19](O)[CH2:18][CH2:17]2)[O:15][CH2:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[Cl:11])[N:4]([CH:19]2[CH2:20][CH2:21][C:16]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:17][CH2:18]2)[N:3]=1
Reactant: OC1CCC2(CC1)OCCO2
Reactant: Clc1ncnc2[nH]nc(Br)c12
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ncnc2c1c(Br)nn2C1CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.6 %

Procedure:
To a solution of 3-bromo-4-chloropyrazolo[3,4-d]pyrimidine (Intermediate B) (7.5 g, 32 mmol), 1,4-dioxaspiro[4.5]decan-8-ol (Intermediate M) (15.17 g, 96 mmol), triphenylphosphine (16.86 g, 64 mmol) in THF (275 mL) was added diethylazodicarboxylate (11.14 g, 64 mmol) in THF (50 mL) at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. for 1 hour, warmed to room temperature and then stirred at room temperature for 3 hrs. The reaction mixtures was concentrated in vacuo and dissolved in hot heptane/EtOAc/DCM (5:1:5). Flash silica gel column chromatography using heptane, heptane/EtOAc (5/1) then heptane/EtOAc (4/1) gave a solid which was triturated with heptane and the solids removed by filtration to furnish 8.2 g of 3-bromo-4-chloro-1-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrazolo[3,4-d]pyrimidine as a white solid (69%) [Rf in 1:1 heptane:EtOAc=0.5]1H NMR (400 MHz, d6-DMSO): 8.89 (1H, s), 4.92 (1H, m), 3.90 (4H, m), 2.16 (2H, m), 1.96 (2H, m), 1.81 (6H, m) HPLC: Tr=17.11 mins, 96.6%.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:46])([CH3:45])[CH2:9][CH:10]=[CH:11][C:12](=[O:44])[N:13]([CH:15]([C:27](=[O:43])[N:28]([CH:30]([C:39](=[O:42])[NH:40][CH3:41])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[F:38])[CH3:29])[CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1)[CH3:14])(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+].C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl>[F:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[CH2:31][CH:30]([N:28]([CH3:29])[C:27]([CH:15]([N:13]([CH3:14])[C:12](=[O:44])[CH:11]=[CH:10][CH2:9][C:8]([NH2:7])([CH3:46])[CH3:45])[CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1)=[O:43])[C:39](=[O:42])[NH:40][CH3:41]
Reactant: CNC(=O)C(Cc1ccccc1F)N(C)C(=O)C(Cc1ccc2ccccc2c1)N(C)C(=O)C=CCC(C)(C)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)C(Cc1ccccc1F)N(C)C(=O)C(Cc1ccc2ccccc2c1)N(C)C(=O)C=CCC(C)(C)N
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 77.8 %

Procedure:
{4-[(1-{[2-(2-Fluorophenyl)-1-methylcarbamoylethyl]methylcarbamoyl}2-(2-naphthyl)ethyl)methylcarbamoyl]-1,1-dimethyl-but-3-enyl}carbamic acid tert-butyl ester (0.36 g; 0.557 mmol) was dissolved in methylene chloride (3 ml). Trifluoro acetic acid (3 ml) was added and the reaction mixture was stirred 5 min at room temperature. Methylene chloride (25 ml), sodium hydrogen carbonate/sodium carbonate (3 ml) and sodium hydrogen carbonate (s) was added until pH=8. The organic phase was dried (magnesium sulfate) and the solvent was removed in vacuo. The residue was lyophylised to afford 0.237 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@@H:4]([O:23][CH2:24][CH3:25])[C@@H:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[CH:9][C:8]=1[O:21][CH3:22])O.O.O.C(O)(=O)C(O)=O>C(O)(C)C.[Pd]>[CH3:1][O:2][C:3](=[O:26])[C@@H:4]([O:23][CH2:24][CH3:25])[CH2:5][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[O:21][CH3:22]
Reactant: CCO[C@H](C(=O)OC)[C@H](O)c1ccc(OCc2ccccc2)cc1OC
Agent: [Pd]
Agent: O=C(O)C(=O)O
Solvent: CC(C)O
Solvent: O
Product: CCO[C@@H](Cc1ccc(O)cc1OC)C(=O)OC
Yield: 85 %

Procedure:
A solution of (2S,3R)-3-(4-benzyloxy-2-methoxy-phenyl)-2-ethoxy-3-hydroxy-propionic acid methyl ester (100 mg, 200 μmol) and oxalic acid dihydrate (150 mg, 1.2 mmol) in isopropanol (2 ml) was hydrogenated at a pressure of 50 atmospheres over 10% palladium on charcoal (20 mg) at ambient temperature for 6.5 h. The catalyst was filtered off and the solvent evaporated under reduced pressure. The residue was dissolved in ice water/aqueous sodium bicarbonate solution 1/1 and extracted two times with ethyl acetate. The combined extracts were washed two times with ice water/brine 1/1 and dried over sodium sulfate. The solvent was removed under reduced pressure to give a yellow liquid which was purified by column chromatography (silica gel, cyclohexane/AcOEt) to yield 43 mg (170 μmol, 85%) of the title compound as light yellow liquid.
Reaction SMILES: CC1(C)[N:6](C(OC(C)(C)C)=O)[C@@H:5]([CH2:14][CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[C:18]([N:26]3[CH2:32][CH2:31][CH2:30][C:29]4[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=4[CH2:27]3)[CH:17]=2)[CH2:4][O:3]1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[NH2:6][C@@H:5]([CH2:14][CH2:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=[C:18]([N:26]2[CH2:32][CH2:31][CH2:30][C:29]3[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=3[CH2:27]2)[CH:17]=1)[CH2:4][OH:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CCc2cc(N3CCCc4ccccc4C3)nc3ccccc23)COC1(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: N[C@H](CO)CCc1cc(N2CCCc3ccccc3C2)nc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of tert-butyl (4S)-2,2-dimethyl-4-{2-[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethyl}-1,3-oxazolidine-3-carboxylate (340 mg, 0.68 mmol) in ethyl acetate was introduced hydrochloric acid gas for 30 minutes. After being stirred at room temperature overnight, the reaction was poured into ice-water then neutralized with saturated sodium carbonate. The organic layer was separated, dried over sodium sulfate, and then concentrated in vacuo to give the product. It was used in next step without further purification. MS obsd. (ESI+) [(M+H)+] 362.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)=[CH:4][C:3]=1[N+:14]([O-:16])=O.O.[NH2:18][NH2:19].[ClH:20]>C(O)C>[ClH:20].[N:9]1([CH2:8][C:5]2[CH:6]=[CH:7][C:2]3[N:19]=[N:18][N:14]([OH:16])[C:3]=3[CH:4]=2)[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: NN
Reactant: O=[N+]([O-])c1cc(Cn2ccnc2)ccc1F
Agent: Cl
Solvent: CCO
Solvent: O
Product: On1nnc2ccc(Cn3ccnc3)cc21
Yield: 54.3 %

Procedure:
A mixture of 6.5 parts of 1-[(4-fluoro-3-nitrophenyl)methyl]-1H-imidazole, 6.01 parts of hydrazine monohydrate and 80 parts of ethanol was stirred and refluxed for 5 hours. After cooling, 12 parts of a hydrochloric acid solution 5N were added. The whole was evaporated. The residue was stirred with 30 parts of water and the precipitated product was filtered off and boiled in 40 parts of 2-propanol. 2-Propanol, saturated with hydrogen chloride, was added. The salt was allowed to crystallize at room temperature. It was filtered off and dried, yielding 4.1 parts (54.3%) of 6-(1H-imidazol-1-ylmethyl)-1H-benzotriazol- 1-ol-monohydrochloride; mp. 207.4° C. (compound 158).