Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][OH:10].[Cl:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1F>CN(C=O)C>[Cl:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[O:10][CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=1
Reactant: OCc1ccccn1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCc2ccccn2)c(Cl)c1
Temperature: 0 °C
Reaction time: 36 h
Yield: 100 %

Procedure:
Sodium hydride (95%, 0.935 g, 37 mmol) is suspended in dry DMF (20 ml) under a nitrogen atmosphere and the resulting mixture is cooled in ice water. To above suspension is added dropwise over 15 minutes pyridin-2-yl-methanol (3.42 g, 31.3 mmol) in dry DMF (20 mL). Next, to the cold reaction mixture is added dropwise over 20 minutes a solution of 2-Chloro-1-fluoro-4-nitro-benzene (5 g, 28.5 mmol) in dry DMF (20 ml). Upon the end of addition the cold bath is removed and the reaction mixture is stirred for another 36 hours. Water (80 mL) was added slowly to the reaction mixture, and a yellow precipitate resulted. The resultant solid is isolated by suction filtration, washed with water (80 ml), and air dried to yield 7.52 g (28.5 mmol, 100%) of the clean desired material as a yellow powder.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7](=[O:27])[C:8]([F:26])([F:25])[C:9]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[F:24])([OH:16])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1)([CH3:5])[CH3:4].[H-].[Na+].[CH3:30]I.Cl>CN(C)C=O.O.C(OCC)(=O)C>[CH3:30][O:1][CH2:2][C:3]([NH:6][C:7](=[O:27])[C:8]([F:25])([F:26])[C:9]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[F:24])([OH:16])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1)([CH3:5])[CH3:4]
Reactant: CC(C)(CO)NC(=O)C(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCC(C)(C)NC(=O)C(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 29 %

Procedure:
In 2 ml of N,N-dimethylformamide was dissolved 0.1 g of N-(1-hydroxy-2-methylpropan-2-yl)-3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanamide. To the resulting solution was added 0.012 g of 60% sodium hydride at 0°-5° C. The solution was subjected to reaction at 20°-25° C. for 30 minutes. To the reaction mixture was added 0.04 g of methyl iodide at 0°-5° C. The resulting mixture was subjected to reaction at 20°-25° C. for 12 hours. The reaction mixture was introduced into a mixed solvent consisting of 10 ml of ethyl acetate and 5 ml of water. The resulting solution was adjusted to pH 2.0 with 6N hydrochloric acid. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography (eluant: chloroform/methanol=100/1) to obtain 30 mg of N-(1-methoxy-2-methylpropan-2-yl)-3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4- (1H-1,2,4-triazol-1-yl)butanamide.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH:21]2[CH2:26][CH2:25][N:24]([C:27](OC(C)(C)C)=O)[CH2:23][CH2:22]2)[C:10](=[O:20])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[OH:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1C=O.[BH4-].C(OC(=O)C)(=O)C>C(O)C>[OH:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:27][N:24]1[CH2:25][CH2:26][CH:21]([N:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:10](=[O:20])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:22][CH2:23]1
Reactant: O=Cc1ccccc1O
Reactant: COc1ccc(CC(=O)N(Cc2ccc(C)cc2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [BH4-]
Solvent: CCO
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(CC(=O)N(Cc2ccc(C)cc2)C2CCN(Cc3ccccc3O)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The product from example 13 above (20 mg, 0.06 mmol) was dissolved in abs. ethanol (2 ml). 2-Hydroxybenzaldehyde (0.122 ml, 1.1 mmol) was added followed by solid-supported borohydride (150 mg, 2.5 mmol/g resin; Aldrich 32,864-2). The mixture was shaken at room temperature. After 48 h, the resin was filtered off and acetic anhydride (0.02 ml, 0.2 mmol) was added to the organic solution. After 24 h, the mixture was concentrated and redissolved in methanol (2 ml). The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3×6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 16 mg; HRMS (FAB+, NBA) (M+H)+ 459.2633, C29H35N2O3 requires 459.2648; LC-MS: (M+H)+ 459.2, tr 5.81 min.
Reaction SMILES: [Br:1]Br.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[CH:5]([N:11]1[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]1=[O:21])[CH2:4]2>C(O)(=O)C>[N:3]12[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10]1)[CH:5]([N:11]1[CH:20]=[C:19]([Br:1])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]1=[O:21])[CH2:4]2
Reactant: O=c1c2ccccc2ccn1C1CN2CCC1CC2
Reactant: BrBr
Solvent: CC(=O)O
Product: O=c1c2ccccc2c(Br)cn1C1CN2CCC1CC2

Procedure:
A solution of Br2 (1.0M) in glacial acetic acid (0.8 mL) was added to a solution of (RS)-2-(1-azabicyclo[2.2.2]oct-3-yl)-l(2H)-isoquinolinone (0.20 g; 0.787 mmol), from Example 2, in glacial acetic acid (5.0 mL). Thesolvent was removed under pressure and the residue was partitioned between methylene chloride (100 ml) and sodium carbonate (2.0M, 30 ml). The organic phase was separated and dried over anhydrous sodium sulfate. The mixture was then filtered and concentrated under reduced pressure. The solid residue was dissolved in ethyl alcohol (2 ml) and the solution acidified with hydrochloric acid (10%). A small amount of ethyl ether was added and crystals were collected and dried in vacuo to give (RS)-2-(1-azabicyclo[2.2.2]oct-3-yl)-4-bromo-1(2H)-isoquinolinone (0.0832 g, 0.248 mmol), m.p. 208°-209° C.
Reaction SMILES: [Br:1][CH2:2][CH:3](OCC)OCC.[Br:10][C:11]1[N:16]=[C:15]([NH2:17])[CH:14]=[CH:13][CH:12]=1>C(O)CCC>[BrH:1].[Br:10][C:11]1[N:16]2[CH:2]=[CH:3][N:17]=[C:15]2[CH:14]=[CH:13][CH:12]=1
Reactant: Nc1cccc(Br)n1
Reactant: CCOC(CBr)OCC
Solvent: CCCCO
Product: Br
Product: Brc1cccc2nccn12
Yield: 81.1 %

Procedure:
Add 2-bromo-1,1-diethoxyethane (3.64 g, 18.48 mmol) to a solution of 6-bromopyridin-2-ylamine (1.0 g, 5.77 mmol) in n-butanol (40 ml). Reflux overnight and cool. Filtration of the reaction mixture gives 1.3 g (81%) of 5-bromoimidazo[1,2-a]pyridine hydrobromide as a white solid. ESMS (M++1): 198.9 m/z.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:25]=[CH:24][C:13]3[C@:14]4([CH3:23])[CH:19]([CH2:20][CH2:21][C:12]=3[CH:11]=2)[NH:18][C:17](=[O:22])[CH:16]=[CH:15]4)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:26](O)(C)(C)C.CC(C)([O-])C.[K+].CI>C(OCC)(=O)C>[CH3:26][N:18]1[C@H:19]2[C@@:14]([CH3:23])([C:13]3[CH:24]=[CH:25][C:10]([C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=4)=[CH:11][C:12]=3[CH2:21][CH2:20]2)[CH:15]=[CH:16][C:17]1=[O:22]
Reactant: C[C@]12C=CC(=O)NC1CCc1cc(-c3cccc([N+](=O)[O-])c3)ccc12
Reactant: CC(C)(C)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Product: CN1C(=O)C=C[C@]2(C)c3ccc(-c4cccc([N+](=O)[O-])c4)cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
A 15 mL round bottom flask was charged with (+)-4aR)-(10bR)-8-(3-nitrophenyl)-10b-methyl-3,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3-one (12 mg, 0.034 mmol), 0.10 mL of t-butanol, and potassium t-butoxide (12 mg, 0.10 mmol). Methyl iodide (0.006 mL, 0.10 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate, and purified by silica gel chromatography (ethyl acetate eluent) to give 9 mg (75%) of the title compound as a white solid, upon trituration from diethyl ether/hexanes. mp 175°-177°. FDMS: m/e=348.
Reaction SMILES: C[N:2]1[CH2:11][C:10](C)(C)[C:9]2[C:4](=CC(N)=C[CH:8]=2)[CH2:3]1.Cl[C:16]1[N:21]=[C:20]2[N:22]([CH3:36])[C:23](=[O:35])[N:24]([C:27]3[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:34])[C:25](=[NH:26])[C:19]2=[CH:18][N:17]=1.ClC1N=C2NC(=O)[N:46]([C:49]3[C:54](Cl)=[CH:53][CH:52]=[CH:51][C:50]=3Cl)C(=N)C2=CN=1>>[Cl:34][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]([Cl:33])[C:27]=1[N:24]1[C:25](=[NH:26])[C:19]2[C:20](=[N:21][C:16]([NH:46][C:49]3[CH:50]=[C:51]4[C:52](=[CH:53][CH:54]=3)[C:3]3([CH2:4][CH2:9][CH2:8]3)[NH:2][CH2:11][CH2:10]4)=[N:17][CH:18]=2)[N:22]([CH3:36])[C:23]1=[O:35]
Reactant: CN1Cc2cc(N)ccc2C(C)(C)C1
Reactant: N=c1c2cnc(Cl)nc2[nH]c(=O)n1-c1c(Cl)cccc1Cl
Reactant: Cn1c(=O)n(-c2c(Cl)cccc2Cl)c(=N)c2cnc(Cl)nc21
Product: Cn1c(=O)n(-c2c(Cl)cccc2Cl)c(=N)c2cnc(Nc3ccc4c(c3)CCNC43CCC3)nc21

Procedure:
70 mg of the entitled compound was obtained as a white solid according to the same method as in Example 2, for which, however, 3′,4′-dihydro-2′H-spiro[cyclobutane-1,1′-isoquinolin]-6′-amine obtained in Production Example 30 was used in place of 2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-amine in Example 2, and 7-chloro-3-(2,6-dichlorophenyl)-4-imino-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one obtained in Production Example 7 was used in place of 7-chloro-3-(2,6-dichlorophenyl)-4-imino-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:9]([Cl:10])=[N:8][C:7]([S:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:6][C:5]=2[N:19]=1.[NH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1.C(N(C(C)C)C(C)C)C>O1CCCC1>[Cl:10][C:9]1[C:4]2[S:3][C:2]([NH:20][CH2:21][CH2:22][C:23]3[CH:24]=[CH:25][C:26]([S:29]([NH2:32])(=[O:30])=[O:31])=[CH:27][CH:28]=3)=[N:19][C:5]=2[N:6]=[C:7]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=1
Reactant: Clc1nc(SCc2ccccc2)nc2nc(Br)sc12
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(CCNc2nc3nc(SCc4ccccc4)nc(Cl)c3s2)cc1
Reaction time: 16 h
Yield: 78.4 %

Procedure:
A solution of the product from Example 219 (0.3 g) in tetrahydrofuran (2 ml) containing 4-(2-aminoethyl)benzenesulfonamide (0.161 g) and N-ethyldiisopropylamine (0.5 ml) was stirred for 16 hours. The mixture was evaporated to dryness then purified (SiO2, ethyl acetate:dichloromethane 4:6 as eluant) to give the title compound (310 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH:25]=[CH:26][CH:27]=2)[CH2:18][CH2:17]1>C1COCC1.O>[CH3:31][CH:30]([CH3:32])[C:29]([NH:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([CH:19]2[CH2:18][CH2:17][N:16]([CH2:15][CH2:14][CH2:13][NH:12][S:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH2:21][CH2:20]2)[CH:23]=1)=[O:33]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)NCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cc1
Yield: 43.5 %

Procedure:
A solution of 4-methylbenzenesulfonyl chloride (16.6 mg, 0.0870 mmol), N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide (26.4 mg, 0.0870 mmol), TEA (10.0 mg, 0.174 mmol) in THF (1.00 mL) was stirred for 12 h at 25° C. The resulting crude mixture was diluted with water (20 mL), the aqueous layer was extracted with CH2Cl2 (2×20 mL). The combined organic layers were concentrated in vacuo and the residue was purified by preparative TLC using 2.5% of NH3 (2.0 M in methanol) in CH2Cl2 to give the desired product 2-methyl-N-{3-[1-(3-{[(4-methylphenyl)sulfonyl]amino}propyl)-4-piperidinyl]phenyl}propanamide (17.3 mg, 43.6%): 1H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 7.53 (s, 1H), 7.41 (s, 1H), 7.32-7.21 (m, 4H), 7.16 (s, 1H), 6.97 (d, 1H, J=7.9 Hz), 3.44 (t, 2H, J=6.3 Hz), 3.15 (d, 2H, J=9.8 Hz), 2.62-2.45 (m, 4H), 2.15 (m, 3H), 2.05 (s, 3H), 1.95-1.71 (m, 5H), 1.26 (d, 6H, J=6.6 Hz); ESMS m/e: 458.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[C:10](N)[CH:11]=[CH:12][CH:13]=2)[N:5]=[C:4]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=3)[N:16]=2)[N:3]=1.N([O-])=O.[Na+].[S:35](=[O:37])=[O:36].[ClH:38]>C(O)(=O)C.O>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[C:10]([S:35]([Cl:38])(=[O:37])=[O:36])[CH:11]=[CH:12][CH:13]=2)[N:5]=[C:4]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=3)[N:16]=2)[N:3]=1
Reactant: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(N)c1
Reactant: O=S=O
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(S(=O)(=O)Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
To a solution of 3-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-1,2,4-triazol-1-yl)methyl)benzenamine (Example 78, 100 mg, 0.24 mmol) in acetic acid (4 mL) and hydrochloric acid (37% aq., 0.5 mL) at 0° C., was added a solution of sodium nitrite (33 mg, 0.48 mmol) in H2O (1 mL) and the resulting mixture was stirred for 1 h at 0° C. Sulfur dioxide (0.9 M solution in AcOH 4 mL) and CuCl2 (20 mg, 0.20 mmol) were then added at 0° C., and the resulting mixture was stirred at RT for 16 h. The mixture was poured onto H2O (50 mL) and extracted with EtOAc (50 mL). The organic phase was washed with aq. sodium bicarbonate and brine, dried (Na2SO4), filtered and concentrated under reduced pressure to afford the title compound as a yellow solid (72 mg, 69.3%). LC-MS (ES+) C19H13ClF3N5O4S requires: 499. found: 500 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N+:13]([O-:15])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].I[CH2:17][CH2:18][C:19](=[O:30])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1.Cl.[N+](C([N+]([O-])=O)=O)([O-])=O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([N+:13]([O-:15])=[O:14])[CH2:17][CH2:18][C:19](=[O:30])[CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CC[N+](=O)[O-])cc1OC
Reactant: COc1ccc(CCC(=O)CCI)cc1
Agent: Cl
Agent: O=C([N+](=O)[O-])[N+](=O)[O-]
Solvent: C1CCOC1
Product: COc1ccc(CCC(=O)CCC(Cc2ccc(OC)c(OC)c2)[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.23 h

Procedure:
To a solution of 15 g. (0.071 mole) of 2-(3,4-dimethoxyphenyl)-1-nitroethane in 200 ml. of dry tetrahydrofuran was added 33.45 g. (0.08 mole) of 40% Triton B at room temperature. The solution was stirred at room temperature for 14 minutes under N2. 22.6 g. (0.071 mole) of 1-iodo-5-(4-methoxyphenyl)-3-pentanone was then added in portions. The mixture was heated at 50°-55° for 2 hours under N2 until no more starting material was detected on TLC, and then cooled to room temperature. The resulting reaction solution was poured into cold dil. HCl and extracted with ethyl acetate. The organic layer was dried over anhydrous MgSO4. The crude material was chromatographed on Florisil to provide 22 g. of desired nitro ketone derivative. Recrystallization from 80% ethanol gave a white solid which has m.p. 87°-89° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:37]=[CH:36][CH:35]=[CH:34][C:26]=1[C:27]([NH:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[C:26]([C:27]([NH:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:34][CH:35]=[CH:36][CH:37]=3)=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: CC(C)(C)NC(=O)c1ccccc1Br
Product: CC(C)(C)NC(=O)c1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared using methods analogous to those described in Example 369 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 2-bromo-N-(tert-butyl)benzamide. MS (ESI): mass calcd. for C21H21FN4O, 364.17; m/z found, 365.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.55-8.50 (m, 1H), 8.13 (d, J=1.4, 1H), 8.04-7.95 (m, 1H), 7.64-7.58 (m, 1H), 7.51-7.44 (m, 1H), 7.43-7.37 (m, 2H), 7.36-7.31 (m, 1H), 7.29-7.22 (m, 1H), 5.69 (s, 1H), 5.45 (s, 2H), 2.65-2.54 (m, 1H), 1.24 (m, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:21][CH3:22])[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[CH:11]=3)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C1COCC1.O>[C:17]([C:16]1[C:15]2[C:10](=[CH:11][C:12]([O:19][CH3:20])=[CH:13][CH:14]=2)[N:9]([CH2:21][CH3:22])[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:7][CH:6]=1)#[N:18]
Reactant: CS(=O)(=O)Cl
Reactant: CCn1c(-c2ccc(N)cc2)c(C#N)c2ccc(OC)cc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CCn1c(-c2ccc(NS(C)(=O)=O)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 0 °C
Yield: 67.7 %

Procedure:
A solution of 2-(4-aminophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (70 mg, 0.24 mmol), prepared as described in Example 1Ga, step B in THF (3 mL) is cooled to 0° C. and treated with triethylamine (0.04 mL, 0.31 mmol) and methanesulfonylchloride (0.02 mL, 0.29 mmol) and stirred, warming to room temperature overnight. The reaction mixture is then diluted with H2O and extracted with ethyl acetate (3×). The organic phase is washed with H2O and saturated NaCl, dried and concentrated and purified by flash chromatography using EtOAc/hexanes (30-50%) to afford 60 mg (68%) of N-[4-(3-Cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-methanesulfonamide as a tan solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[C:7]([CH:11]=1)[C:8]([OH:10])=O)#[N:2].Cl.[NH2:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[C:7]([CH:11]=1)[C:8]([NH:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23])=[O:10])#[N:2]
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: N#Cc1ccc(Oc2cccc(F)c2)c(C(=O)O)c1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(C#N)ccc2Oc2cccc(F)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-cyano-2-(3-fluorophenoxy)benzoic acid (step 1) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3 of Example 5): 1H-NMR (CDCl3) δ 8.54 (1H, s), 7.97 (2H, d, J=8.4 Hz), 7.77–7.65 (2H, m), 7.47–7.34 (3H, m), 7.04–6.80 (4H, m), 5.35 (1H, m), 3.90 (3H, s), 1.54 (3H, d, J=7.8 Hz).
Reaction SMILES: [C:1]12([NH:6][C:7]3[C:12]([C:13]([NH2:15])=[O:14])=[CH:11][N:10]=[C:9]([S:16][CH3:17])[N:8]=3)[CH2:5][CH:3]([CH2:4]1)[CH2:2]2.C1(C2[O:26]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1>C(Cl)(Cl)Cl.C(OCC)(=O)C>[C:1]12([NH:6][C:7]3[C:12]([C:13]([NH2:15])=[O:14])=[CH:11][N:10]=[C:9]([S:16]([CH3:17])=[O:26])[N:8]=3)[CH2:2][CH:3]([CH2:5]1)[CH2:4]2
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: CSc1ncc(C(N)=O)c(NC23CC(C2)C3)n1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CS(=O)c1ncc(C(N)=O)c(NC23CC(C2)C3)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
To a stirring solution of 4-(bicyclo[1.1.1]pentan-1-ylamino)-2-(methylthio)pyrimidine-5-carboxamide (76 g, 0.304 mol) in chloroform (7 L) was added 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (143 g, 0.547 mol, 1.8 equiv.) and the resulting pale yellow solution was stirred at ambient temperature overnight. The reaction solution was concentrated under reduced pressure to give the crude product as a white solid, which was diluted with ethyl acetate (1.5 L) and the slurry was stirred at room temperature for 1 h. The resulting suspension was filtered, washed with ethyl acetate, and dried under vacuum to afford the desired compound (73 g, 0.274 mol, 90% yield) as a white solid; MS (ESI): m/z 267.0 [M+1]+.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:22][CH:5]2[C:6](=[O:21])[N:7]([C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)[C:8](=[O:9])[CH:4]2[CH2:3]1.[BH4-].[Na+].O>CCO.ClCCl>[OH:9][CH:8]1[N:7]([C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17]([F:18])([F:19])[F:20])=[CH:14][CH:15]=2)[C:6](=[O:21])[CH:5]2[CH2:22][C:2](=[CH2:1])[CH2:3][CH:4]12
Reactant: C=C1CC2C(=O)N(c3ccc(OC(F)(F)F)cc3)C(=O)C2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: C=C1CC2C(=O)N(c3ccc(OC(F)(F)F)cc3)C(O)C2C1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a cooled (−20° C.) solution of 5-Methylene-2-(4-trifluoromethoxy-phenyl)-tetrahydro-cyclopenta[c]pyrrole-1,3-dione (0.7 g, 2.25 mmol) in EtOH/dichloromethane (15/10 mL) were sequentially added CeCl3. 7H2O (1.0 g, 2.7 mmol) and NaBH4 (0.84 g, 22.5 mmol). The mixture was stirred for 0.5 h at −20° C., then poured into cold water (20 mL) and extracted with dichloromethane (2×15 mL). The solvent was removed by reduced pressure and the residue was purified by silica gel column (petroleum ether/ethyl acetate=5:1) to yield the title compound (0.55 g, 78%). H NMR (300 MHz, CDCl3): δ 7.64-7.60 (m, 2H), 7.25-7.22 (m, 2H), 5.67-5.61 (m, 1H), 5.07 (s, 1H), 4.98 (s, 1H), 3.21-3.09 (m, 2H), 2.81-2.56 (m, 5H); LC-MS: [M+1]+ 314.1.
Reaction SMILES: C(OO[C:7]1(OOC(C)(C)C)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)(C)(C)C.CC1(C)CC(C)CCC1.[C:28]([O:32][O:33][C:34]([O:38]OC(C)(C)C)(CC)C)([CH3:31])([CH3:30])[CH3:29].[C:44]([O:48][O:49][C:50]([O:56]OC(C)(C)C)(CCCC)[CH3:51])([CH3:47])([CH3:46])[CH3:45]>>[CH:12]1[C:7]([C:34]([O:33][O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:38])=[CH:8][CH:9]=[CH:10][CH:11]=1.[C:50]([O:49][O:48][C:44]([CH3:47])([CH3:46])[CH3:45])(=[O:56])[CH3:51]
Reactant: CCC(C)(OOC(C)(C)C)OOC(C)(C)C
Reactant: CC(C)(C)OOC1(OOC(C)(C)C)CCCCC1
Reactant: CCCCC(C)(OOC(C)(C)C)OOC(C)(C)C
Agent: CC1CCCC(C)(C)C1
Product: CC(=O)OOC(C)(C)C
Product: CC(C)(C)OOC(=O)c1ccccc1

Procedure:
Similar beneficial improvements in the conversion of monomer and physical properties of the polymer are obtained when the 1,1-bis(t-butyl peroxy)cyclohexane is replaced with 1,1-bis(t-butyl peroxy), 3,3,5-trimethylcyclohexane, 2,2-bis(t-butyl peroxy)butane and 2,2-bis(t-butyl peroxy)hexane. Slightly inferior results are obtained when t-butyl perbenzoate and t-butyl peracetate are employed.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].C([N:12]1[C:16]2=[N:17][CH:18]=[N:19][C:20]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:15]2[C:14]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:13]1)C1C=CC=CC=1>C1C=CC=CC=1.O>[C:29]1([NH:28][C:14]2[C:15]3[C:16](=[N:17][CH:18]=[N:19][C:20]=3[NH:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:12][N:13]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: c1ccc(Cn2nc(Nc3ccccc3)c3c(Nc4ccccc4)ncnc32)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: c1ccccc1
Product: c1ccc(Nc2ncnc3[nH]nc(Nc4ccccc4)c23)cc1
Temperature: 50 °C
Reaction time: 1.75 h

Procedure:
With the exclusion of air and moisture, there is added to a suspension of 203 mg of AlCl3 in 2.5 ml of absolute benzene a solution of 100 mg of 1-benzyl-3,4-diphenylamino-pyrazolo[3,4-d]pyrimidine in 2.5 ml of absolute benzene. The reaction mixture is stirred for 1.5-2 hours at 50° C. until, according to thin-layer chromatography, no starting material remains and is then stirred in approx. 30 ml of water. The precipitate is filtered off and dissolved in ethyl acetate. The ethyl acetate phase is washed several times with 5% aqueous sodium hydrogen carbonate solution and then with saturated sodium chloride solution, dried and concentrated to dryness by evaporation. The residue is crystallized from ethyl acetate/hexane, yielding 3,4-diphenylamino-1H-pyrazolo[3,4-d]pyrimidine in the form of colorless crystals, m.p. 263-264° C., FAB-MS: (M+H)+ =303 (C17H14N6).