Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]#[C:2][CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[N:5]1.[C:9]([C:11]1[CH:27]=[CH:26][C:14]([CH2:15][NH:16][C:17](=[O:25])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20](I)[CH:19]=2)=[CH:13][CH:12]=1)#[N:10].C(N(C(C)C)CC)(C)C>CN(C)C=O.C1COCC1.[Cu]I.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>[C:9]([C:11]1[CH:12]=[CH:13][C:14]([CH2:15][NH:16][C:17](=[O:25])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:1]#[C:2][CH2:3][N:4]3[CH:8]=[CH:7][N:6]=[N:5]3)[CH:19]=2)=[CH:26][CH:27]=1)#[N:10]
Reactant: N#Cc1ccc(CNC(=O)c2cccc(I)c2)cc1
Reactant: C#CCn1ccnn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(CNC(=O)c2cccc(C#CCn3ccnn3)c2)cc1
Temperature: 55 °C
Reaction time: 5 h
Yield: 36.4 %

Procedure:
A solution of 1-propyn-3-yl-1H-[1,2,3]triazol (0.086 g, 0.8 mmol) in N,N-dimethylformamide (“DMF”, 1 mL) was treated with the N-(4-cyano-benzyl)-3-iodo-benzamide (0.225 g, 0.62 mmol) prepared in Step (1), diisopropylethylamine (0.32 g, 2.5 mmol), copper (I) iodide (0.024 g, 0.013 mmol), and dichlorobis(triphenylphosphine)palladium (II) (0.025 g, 0.004 mmol), respectively. The reaction mixture was stirred under nitrogen atmosphere for 5 hours at 55° C., then cooled to room temperature. The crude reaction mixture was diluted with THF (5 mL) and passed through a pad of silica gel (elution with THF). The partially purified product obtained was further purified using silica gel chromatography (elution with THF/hexane [3:1]) to give the title compound (0.077 g, 36%) as cream color solid. 1H-NMR (CDCl3/DMSO-d6) δ 8.3 (m, 1H), 7.9 (s, 1H), 7.8 (m, 2H), 7.6 (s, 1H), 7.4 (m, 3H), 7.3 (m, 2H), 5.3 (s, 2H), 4.5 (d, 2H) ppm. Mp 145° C.-147° C.
Reaction SMILES: Cl.[C@@H:2]12[NH:9][C@@H:6](C[CH2:8]1)[CH2:5][N:4]([CH2:10][C@@H:11]([C:13]1[C:14]([CH3:23])=[C:15]3[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[O:17][CH2:16]3)[OH:12])[CH2:3]2.[N:24]1([C:29]2[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=2)[CH:28]=[N:27][N:26]=[N:25]1>>[OH:12][C@H:11]([C:13]1[C:14]([CH3:23])=[C:15]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[O:17][CH2:16]2)[CH2:10][N:4]1[CH2:3][C@@H:2]2[CH2:8][C@H:5]1[CH2:6][N:9]2[S:35]([C:32]1[CH:33]=[CH:34][C:29]([N:24]2[CH:28]=[N:27][N:26]=[N:25]2)=[CH:30][CH:31]=1)(=[O:37])=[O:36]
Reactant: Cc1c([C@@H](O)CN2C[C@H]3CC[C@@H](C2)N3)ccc2c1COC2=O
Reactant: O=S(=O)(Cl)c1ccc(-n2cnnn2)cc1
Agent: Cl
Product: Cc1c([C@@H](O)CN2C[C@@H]3C[C@H]2CN3S(=O)(=O)c2ccc(-n3cnnn3)cc2)ccc2c1COC2=O

Procedure:
5-((R)-1-Hydroxy-2-((1S,4S)-5-(4-(1H-tetrazol-1-yl)phenylsulfonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethyl)-4-methylisobenzofuran-1 (3H)-one was prepared in a similar fashion to that described for the synthesis of EXAMPLE 14 starting from 5-((R)-2-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-1-hydroxyethyl)-4-methylisobenzofuran-1(3H)-one hydrochloride (INTERMEDIATE 15) and commercially available 4-(1H-tetrazol-1-yl)benzene-1-sulfonyl chloride.
Reaction SMILES: [ClH:1].NC1C2C(=CC(CC(NC(=O)CNS(C3C(C)=C(C)C4OC(C)(C)CCC=4C=3C)(=O)=O)C(=O)N3CCCCC3)=CC=2)C=CN=1.[NH2:46][C:47]1[C:56]2[C:51](=[CH:52][C:53]([CH2:57][CH:58]([NH:67][C:68](=[O:74])OC(C)(C)C)[C:59](=[O:66])[N:60]3[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]3)=[CH:54][CH:55]=2)[CH:50]=[CH:49][N:48]=1.[NH:75]([S:87]([C:90]1[C:99]([CH3:100])=[C:97]([CH3:98])[C:94]([O:95][CH3:96])=[CH:93][C:91]=1[CH3:92])(=[O:89])=[O:88])[C@H:76](C(O)=O)[CH2:77][CH2:78][C:79](=[O:83])[O:80][CH2:81][CH3:82].N(C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H](C(OC(C)(C)C)=O)CCC(=O)O.[Cl-].N1(C(=O)C[C@H](NS(C2C(C)=CC(OC)=C(C)C=2C)(=O)=O)C(O)=O)CCOCC1>C(O)C>[ClH:1].[CH2:81]([O:80][C:79](=[O:83])[CH2:78][CH2:77][C@H:76]([NH:75][S:87]([C:90]1[C:91]([CH3:92])=[CH:93][C:94]([O:95][CH3:96])=[C:97]([CH3:98])[C:99]=1[CH3:100])(=[O:88])=[O:89])[C:68]([NH:67][CH:58]([CH2:57][C:53]1[CH:52]=[C:51]2[C:56](=[CH:55][CH:54]=1)[C:47]([NH2:46])=[N:48][CH:49]=[CH:50]2)[C:59](=[O:66])[N:60]1[CH2:61][CH2:62][CH2:63][CH2:64][CH2:65]1)=[O:74])[CH3:82]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc2c(N)nccc2c1)C(=O)N1CCCCC1
Reactant: CCOC(=O)CC[C@H](NS(=O)(=O)c1c(C)cc(OC)c(C)c1C)C(=O)O
Agent: CC(C)(C)OC(=O)[C@H](CCC(=O)O)NC(=O)OCC1c2ccccc2-c2ccccc21
Agent: COc1cc(C)c(S(=O)(=O)N[C@@H](CC(=O)N2CCOCC2)C(=O)O)c(C)c1C
Agent: Cc1c(C)c(S(=O)(=O)NCC(=O)NC(Cc2ccc3c(N)nccc3c2)C(=O)N2CCCCC2)c(C)c2c1OC(C)(C)CC2
Solvent: CCO
Product: CCOC(=O)CC[C@H](NS(=O)(=O)c1c(C)cc(OC)c(C)c1C)C(=O)NC(Cc1ccc2c(N)nccc2c1)C(=O)N1CCCCC1

Procedure:
The procedure described for 5c was used. Deprotection of 5a and coupling with Mtr-Glu(OEt)-OH (prepared from Fmoc-Glu-OtBu, ethanol and Mtr-chloride according to the procedure described for 51a) yielded after purification the title compound (76%) as a mixture of diastereomers (1:1). 1H-NMR 400 MHz (CD3OD) δ: 1.15-2.32 (11H, m), 2.13 (3H, s), 2.40 and 2.42 (3H, 2× s), 2.44 and 2.47 (3H, 2× s), 2.75-4.08 (11H, m), 4.99-5.19 (1H, m), 6.71 and 6.72 (1H, 2× s), 7.16-7.20(1H, m), 7.51-7.76 (3H, m), 8.30-8.36 (1H, m).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:12])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.Cl[C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[C:16](=O)[C:17](=O)N2>>[C:15]1([CH:16]([C:17]2[CH:9]=[CH:10][CH:2]=[CH:3][CH:4]=2)[N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:10]=3)[C:6](=[O:12])[C:7]2=[O:11])[CH:19]=[CH:20][CH:21]=[CH:22][CH:14]=1
Reactant: O=C1Nc2cccc(Cl)c2C1=O
Reactant: O=C1Nc2cc(F)ccc2C1=O
Product: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2cc(F)ccc21

Procedure:
Following the procedure as described in PREPARATION 4A, and making non-critical variations using 6-fluoroisatin (Sadler, P. W., J. Org. Chem. (1956), 21(2):169-70) to replace 4-chloroisatin, 1-(diphenylmethyl)-6-fluoro-1H-indole-2,3-dione was obtained (76%): mp 167-169° C. (diethyl ether); 1H NMR (300 MHz, DMSO-d6) δ 7.41-7.27 (m, 11H), 6.77 (s, 1H), 6.30-6.26 (m, 1H), 5.82-5.80 (m, 1H); MS (ES+) m/z 354.1 (M+23).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[O:11].[F:12][C:13]1[CH:23]=[C:17]([C:18](OCC)=[O:19])[C:16]([NH2:24])=[CH:15][CH:14]=1.C[O-].[Na+]>CCCCCC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18](=[O:19])[C:17]2[C:16](=[CH:15][CH:14]=[C:13]([F:12])[CH:23]=2)[NH:24][C:10]1=[O:11]
Reactant: CCOC(=O)c1cc(F)ccc1N
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CCCCCC
Product: O=c1[nH]c2ccc(F)cc2c(=O)n1-c1ccc(Cl)cc1Cl
Yield: 96 %

Procedure:
2,4-dichlorophenyl isocyanate (18.8 g, 0.10 mol) is introduced in portions at room temperature into a solution of ethyl 5-fluoroanthranilate (18.3 g, 0.10 mol) in hexane (120 ml). After addition is complete, the mixture is stirred under reflux for 2 hours. 3.60 ml of a 30% strength solution of methanolic sodium methoxide (0.020 mol) are metered in and the mixture is stirred under reflux for a further 2 hours, ethanol and methanol being distilled off. After cooling, the product is filtered off with suction and washed with 3×15 ml of hexane. The hexane-moist precipitate is treated with dilute hydrochloric acid and the residual hexane is removed by azeotropic distillation. The product is then filtered off with suction, washed with water and dried. 31.2 g of 3-(2,4-dichlorophenyl)-6-fluoro-2,4(1H,3H) -quinazolinedione (yield: 96.0% of theory) of melting point 312° to 314° C. are obtained.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][C@H:12]([NH2:16])[C:13]([OH:15])=[O:14])[C:4]2=[CH:3][CH:2]=1.[N:17]1([C:23](Cl)=[O:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>[OH-].[Na+].C([O-])([O-])=O.[Na+].[Na+]>[N:17]1([C:23]([NH:16][C@@H:12]([CH2:11][C:10]2[C:4]3[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=3)[CH:7]=[CH:8][CH:9]=2)[C:13]([OH:15])=[O:14])=[O:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: N[C@@H](Cc1cccc2ccccc12)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)[C@H](Cc1cccc2ccccc12)NC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.1 %

Procedure:
To a solution of L-1-naphthylalanine (215 mg, 1 mmol) (Peptech Corp.) in 5 mL 1N NaOH and 0.5 mL saturated Na2CO3 (resulting solution at pH 10) was added morpholine-4-carbonyl chloride (150 mg, 1.0 mmol) dissolved in 5 mL. Afterwards, the reaction mixture was stirred at room temperature for 2 h. The alkaline solution was extracted once with ether (10 mL) and the aqueous phase was acidified with 1N HCl. This was extracted twice with 20 mL EtOAc, and the combined organic phases were washed with 50 mL 1N HCl. The organic phase was dried over Na2SO4, filtered and evaporated to an oil, which solidifies to yields 125 mg (38%) of the desired material. This compound was used as such in the next step.
Reaction SMILES: [F:1][CH:2]([F:28])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([O:25][CH2:26][CH3:27])[CH:16]=2)[CH:4]=1.[S:29]([C:33]1[CH:34]=[C:35]([NH2:39])[CH:36]=[CH:37][CH:38]=1)(=[O:32])(=[O:31])[NH2:30]>>[S:29]([C:33]1[CH:34]=[C:35]([NH:39][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:28])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[C:17]([O:25][CH2:26][CH3:27])[CH:16]=4)=[N:6][C:7]=23)=[O:13])[CH:36]=[CH:37][CH:38]=1)(=[O:31])(=[O:32])[NH2:30]
Reactant: CCOc1cc(-c2cc(C(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Reactant: Nc1cccc(S(N)(=O)=O)c1
Product: CCOc1cc(-c2cc(C(F)F)n3ncc(C(=O)Nc4cccc(S(N)(=O)=O)c4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(3-ethoxy-4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.12) and 3-sulfamoyl-phenylamine [commercially available] according to general procedure II. Light yellow solid. MS (ISP) 554.0 [(M−H)−]; mp 254° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([C:7]([N:9](C)[C:10]2[CH:11]=[C:12]([CH:28]=[CH:29][CH:30]=2)[CH2:13][NH:14][C:15]2[C:24]3[C:19](=[C:20]([C:25]([NH2:27])=[O:26])[CH:21]=[CH:22][CH:23]=3)[N:18]=[CH:17][N:16]=2)=[O:8])=[CH:5][CH:4]=1.NC1C([F:43])=C(C=CC=1)C#N.COC1C=CC(C(O)=O)=CC=1>>[F:43][C:11]1[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:32]=[CH:33][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:30][CH:29]=[CH:28][C:12]=1[CH2:13][NH:14][C:15]1[C:24]2[C:19](=[C:20]([C:25]([NH2:27])=[O:26])[CH:21]=[CH:22][CH:23]=2)[N:18]=[CH:17][N:16]=1
Reactant: COc1ccc(C(=O)N(C)c2cccc(CNc3ncnc4c(C(N)=O)cccc34)c2)cc1
Reactant: N#Cc1cccc(N)c1F
Agent: COc1ccc(C(=O)O)cc1
Product: COc1ccc(C(=O)Nc2cccc(CNc3ncnc4c(C(N)=O)cccc34)c2F)cc1

Procedure:
The title compound was prepared according to example 4-{3-[(4-Methoxy-benzoyl)-methyl-amino]-benzylamino}-quinazoline-8-carboxylic acid amide, starting from 3-Amino-2-fluoro-benzonitrile and 4-Methoxy-benzoic acid:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:10]([N:13]([CH3:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[NH:8][CH3:9].C(N(CC)CC)C.[Cl:28][CH2:29][CH2:30][C:31](Cl)=[O:32].O>CN(C)C=O.C(#N)C>[Cl:28][CH2:29][CH2:30][C:31]([NH:1][C:2]1[CH:3]=[C:4]([S:10](=[O:12])(=[O:11])[N:13]([CH3:20])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:5]=[CH:6][C:7]=1[NH:8][CH3:9])=[O:32]
Reactant: O=C(Cl)CCCl
Reactant: CNc1ccc(S(=O)(=O)N(C)c2ccccc2)cc1N
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: O
Product: CNc1ccc(S(=O)(=O)N(C)c2ccccc2)cc1NC(=O)CCCl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 3-amino-N-methyl-4-(methylamino)-N-phenylbenzene sulfonamide (5.4 g, 0.018 mol) and triethylamine (1.81 g, 0.018 mol) in dimethylformamide (16 ml) being cooled on ice (˜5° C.), chloropropionyl chloride (2.32 g, 0.018 mol) was added. The reaction was stirred at room temperature for 5 h. Thereupon, water (14 ml) and acetonitrile (5 ml) were added for 5 h. The precipitate formed was filtered. The yield of 3-chloro-N-(5-(N-methyl-N-phenylsulfamoyl)-2-(methylamino)phenyl)propanamide was 3.1 g (45%).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[C:3]=1[C:4]([NH:6][C@H:7]([CH3:11])[C:8]([OH:10])=[O:9])=[O:5]>CC(O)=O.[Fe]>[NH2:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:2]([F:1])[C:3]=1[C:4]([NH:6][C@H:7]([CH3:11])[C:8]([OH:10])=[O:9])=[O:5]
Reactant: C[C@@H](NC(=O)c1c(F)cccc1[N+](=O)[O-])C(=O)O
Agent: [Fe]
Solvent: CC(=O)O
Product: C[C@@H](NC(=O)c1c(N)cccc1F)C(=O)O
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
To a suspension of iron powder (1.3 g, 23.42 mmol) in AcOH (12 mL) was added (R)-2-(2-fluoro-6-nitrobenzamido)-propanoic acid (600 mg, 2.34 mmol) at rt and stirred at 60-70° C. for 30 min. Work-up of the reaction mixture as described in example 6 gave the product as an off-white color solid (380 mg, 72%), mp 220-224° C. 1H NMR (400 MHz, DMSO-d6): δ 12.67 (1H, br s), 8.46 (1H, d, J=5.2 Hz), 7.08 (1H, dd, J=14.8, 7.2 Hz), 6.50 (1H, d, J=8.0 Hz), 6.31 (1H, t, J=9.2 Hz), 5.89 (2H, br s), 4.37 (1H, pentet, J=7.2 Hz), 1.35 (3H, d, J=7.2 Hz); LC-MS (positive ion mode): m/z 227 (M+H)+.
Reaction SMILES: N1C=CC=CC=1.[C:7]([O:11][C:12]([N:14]1[C@H:18]([CH:19]=[CH:20][CH2:21][CH2:22][CH2:23]O)[CH2:17][O:16][C:15]1([CH3:26])[CH3:25])=[O:13])([CH3:10])([CH3:9])[CH3:8].[Br:27]C(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[C:7]([O:11][C:12]([N:14]1[C@H:18]([CH:19]=[CH:20][CH2:21][CH2:22][CH2:23][Br:27])[CH2:17][O:16][C:15]1([CH3:26])[CH3:25])=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1[C@H](C=CCCCO)COC1(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@H](C=CCCCBr)COC1(C)C
Reaction time: 12 h
Yield: 88.1 %

Procedure:
7 ml of pyridine are added dropwise at 0° to a solution of 18.5 g of alcohol 3 according to c), 28.2 g of tetrabromomethane and 22.3 g of triphenylphosphine in 600 ml of dichloromethane. The mixture is stirred at 0°-2° for 12 hours, concentrated by evaporation, taken up in 150 ml of ethyl acetate, filtered, concentrated to 50 ml and chromatographed on 200 g of silica gel. Elution with hexane/ethyl acetate 10:1 yields 19.9 g of bromide 4, [α]D =-18.9° (c=1, CHCl3); C15H26NO3Br; calculated: C 51.73%, H 7.53%, N 4.02%, Br 22.94%; found: C 51.7%, H 7.7%, N 4.2%, Br 23.0%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10](I)[C:3]=12.[Cl-].B([C:29]1[CH:34]=[CH:33][C:32]([NH3+:35])=[CH:31][CH:30]=1)(O)O.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10]([C:29]3[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=3)[C:3]=12
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(I)c3c(N)ncnc32)C1
Reactant: [NH3+]c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(-c3ccc(N)cc3)c3c(N)ncnc32)C1
Temperature: 80 °C
Reaction time: 12 h
Yield: 81.4 %

Procedure:
Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed (R)-tert-butyl 3-[4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (2 g, 4.50 mmol, 1.00 equiv), 4-borono-benzenaminium chloride (0.934 g), Pd(PPh3)4 (0.312 g), ethylene glycol dimethyl ether (100 mL), sodium carbonate (1.194 g), and water (20 mL). The resulting solution was stirred for 12 h at 80° C. in an oil bath. The resulting mixture was concentrated under vacuum and residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (50:1) to give 1.5 g (81%) of (R)-tert-butyl 3-(4-amino-3-(4-aminophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate as a brown solid. MS (ESI, pos. ion) m/z: 410(M+1)
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH:12]([CH3:14])[CH3:13])=[CH:9][CH:8]=[C:7]([Cl:15])[C:3]=1[C:4](O)=[O:5]>O1CCCC1>[Cl:1][C:2]1[C:10]([O:11][CH:12]([CH3:13])[CH3:14])=[CH:9][CH:8]=[C:7]([Cl:15])[C:3]=1[CH2:4][OH:5]
Reactant: CC(C)Oc1ccc(Cl)c(C(=O)O)c1Cl
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(Cl)c(CO)c1Cl
Yield: 70.6 %

Procedure:
To a solution of 2,6-dichloro-3-isopropoxybenzoic acid (2.49 g) in tetrahydrofuran (30 ml) was added borane-methyl sulfide complex (2 ml, 10 Mol solution) through a syringe at ambient temperature. The mixture was refluxed for half an hour, cooled, and quenched with aqueous saturated ammonium chloride solution. The organic layer was dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel to give 2,6-dichloro-3-isopropoxybenzyl alcohol as a colorless oil (1.66 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[O:15][C:16]3[C:22]([C:23]4[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=4)=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]>CO.C1COCC1.[Ni]>[NH2:28][CH2:27][C:26]1[CH:29]=[CH:30][C:23]([C:22]2[C:16]3[O:15][C:14]([NH:13][C:5]4[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=4)=[N:18][C:17]=3[CH:19]=[CH:20][CH:21]=2)=[CH:24][CH:25]=1
Reactant: COc1cc(Nc2nc3cccc(-c4ccc(C#N)cc4)c3o2)cc(OC)c1OC
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(Nc2nc3cccc(-c4ccc(CN)cc4)c3o2)cc(OC)c1OC
Reaction time: 20 h

Procedure:
To a solution of 0.117 g (0.291 mmol) 4-[2-(3,4,5-trimethoxy-phenylamino)-benzooxazol-7-yl]-benzonitrile (example 19) in 5 ml MeOH (MeOH contains 5% NH3), 5 ml THF and 30 mg Ra—Ni (B113W EtOH, Degussa) are added. Then this mixture is hydrogenated under normal pressure for 20 h at room temperature. The reaction mixture is filtered (2 glass fiber filters used) and the filtrate is concentrated in vacuo. The residue is purified by crystallization from dichloromethane/diethyl ether to afford the title compound as a light grey solid. Rt=1.85 min (Waters Symmetry C8, 2.1×50 mm, detection 210-250 nM, 5% to 100% CH3CN in H2O in 2 min+0.05% TFA, flow rate 1.0 ml/min); MS: 406 (M+1)+; m.p. 208-211° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14]O.S(=O)(=O)(O)O>O>[CH3:14][O:7][C:6]([C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1)=[O:8]
Reactant: Cc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1ccc(C)c([N+](=O)[O-])c1
Reaction time: 16 h

Procedure:
Approximately 18.1 g of 4-methyl-3-nitrobenzoic acid was added to approximately 50 ml of methanol. Approximately 2 ml of concentrated sulfuric acid was added to this solution. The resulting solution was heated to reflux temperature and stirred at this temperature for 16 hours. The solution was cooled and approximately 300 ml of water was added. The resulting composition was extracted with 200 ml of ether. The ether phase was saved and the aqueous phase was discarded. The ether phase was then sequentially washed with 100 ml of water, followed by 100 ml of 10% aqueous sodium carbonate. The ether phase was dried over magnesium sulfate, filtered, and concentrated using a rotary evaporator and a water aspirator vacuum to yield 17.3 g of 4-methoxycarbonyl-2-nitrotoluene as a viscous oil.
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(c1ccccc1)c1ccccc1
Reactant: ClCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: CC(Cc1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
To 4 mols of 1,1-diphenylethane was added 0.001 to 0.005 mol of aluminum chloride. The mixture was heated to 60° C. and allowed to react upon 1 mol of benzyl chloride added thereto for 20 minutes. Then, the reaction mixture was washed with water to remove the used catalyst and subsequently distilled to expel the unreacted portions of the reactants. The isolated 1-(benzylphenyl-1-phenylethane (mixture of isomers) was supplied to an autoclave and, in the presence of a nickel catalyst, subjected to hydrogenation under the conditions of 100 kg/cm2G of initial hydrogen pressure, 140° to 170° C. of temperature for five hours, to afford hydrogenated 1-(benzylphenyl)-1-phenylethane (mixture of isomers). The general attributes of this reaction product were as shown in Table 2.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4]Cl.[CH3:11][C:12]([CH3:15])([O-:14])[CH3:13].[Na+].C1(C)C=CC=CC=1.Cl>C1OCCOCCOCCOCCOC1.O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4][O:14][C:12]([CH3:15])([CH3:13])[CH3:11]
Reactant: CC(C)(C)[O-]
Reactant: Fc1cccc(Cl)c1CCl
Agent: C1COCCOCCOCCOCCO1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OCc1c(F)cccc1Cl
Temperature: 45 °C
Yield: 89.9 %

Procedure:
A mixture of 200 g (1.117 mole) of 2-chloro-6 fluorobenzyl chloride, 118 g (1.23 mole) of sodium t-butoxide, 2.2 mL (11 mmole) of 15-crown-5 (15-C-5) and 1.2 L of toluene was heated at reflux temperature for four hours. After allowing the reaction mixture to cool to 45° C., 600 mL of water was added followed by 90 mL of 2N HCl. After separation, the organic phase was concentrated in vacuo to give a dark oil. Distillation using a 5-tray Oldershaw column, sand bath to 155° C., gave 217.5 g of 1-chloro-3-fluoro-2-[(1,1-dimethylethoxy)methyl]-benzene as a clear liquid (bp 60-64° C./0.6 mm Hg.).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C@@H:10]([C:20](=[O:22])[CH3:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[C@@H:10]([C@H:20]([OH:22])[CH3:21])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 46.1 %

Procedure:
To a solution of 1-[(3R,4S)-1-benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-ethanone (0.52 g, 1.65 mmol) in THF (20 mL) at 0° C. were added portion wise LiAlH4 (55 mg, 1.45 mmol). Stirring was continued for one hour, and the reaction mixture was carefully quenched by addition of aq. NH4Cl, concentrated under vacuo and the product extracted with EtOAC. The combined organic phases were dried on Na2SO4 and concentrated under vacuo. The two diastereoisomeres were separated by column chromatography (SiO2, EtOAc/H, 1:1) to yield (R)-1-[(3R,4S)-1-benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-ethanol (X-B-11) 0.24 g (46%) as a white solid ES-MS m/e: 316.1 (M+H+) and (S)-1-[(3R,4S)-1-benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-ethanol (X-A-11) 0.25 g (47%) as a white solid ES-MS m/e: 316.1 (M+H+).