Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[NH:3][C:4](=[O:11])[C:5]2[NH:6][CH:7]=[N:8][C:9]=2[N:10]=1.[CH2:12]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)[CH2:13][CH2:14][CH3:15]>COCCO.O>[CH2:12]([C:16]1[CH:17]=[CH:18][C:19]([NH:20][C:2]2[NH:3][C:4](=[O:11])[C:5]3[NH:6][CH:7]=[N:8][C:9]=3[N:10]=2)=[CH:21][CH:22]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCc1ccc(N)cc1
Reactant: O=c1[nH]c(Br)nc2nc[nH]c12
Solvent: COCCO
Solvent: O
Product: CCCCc1ccc(Nc2nc3nc[nH]c3c(=O)[nH]2)cc1
Reaction time: 2.5 h
Yield: 84.7 %

Procedure:
A stirred solution of 2-bromohypoxanthine (10.8 g, 50 mmol) and p-n-butylaniline (23.5 mL, 150 mmol) in a mixture of 2-methoxyethanol (300 mL) and water (100 mL) was heated at reflux. After 2.5 h, the mixture was chilled in an ice bath, and the fine precipitate was filtered, washed with concentrated aqueous ammonia (80 mL) and methanol (3×25 mL). The product was purified by dissolving the slightly yellow precipitate in hot N sodium hydroxide (300 mL) and treatment with activated charcoal. The hot mixture was filtered, acidified with glacial acetic acid and chilled. The product was isolated by filtration, washed with methanol and dried over phosphorus pentoxide to yield 12.0 g (85%) of fine colorless crystals, identical with an authentic sample. NMR (250 MHz; Me2SO-d6) 10.45 δ(s, 1-H), 8.60 δ(s, 2-NH), 8.00 δ(s, 8-H), 7.50 δ(d, J+8.5 Hz, 2',6'-H), 7.14 δ(d, J=8.5 Hz, 3',5'-H), 2.55 δ(t, CH2), 1.56 δ(quin, CH2), 1.33 δ(sext, CH2), 0190 δ(t, CH3).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Br:8][C:9]1[C:18]([CH3:19])=[CH:17][C:12]([C:13]([NH:15]O)=[NH:14])=[CH:11][C:10]=1[CH3:20]>N1C(C)=CC(C)=CC=1C>[Br:8][C:9]1[C:18]([CH3:19])=[CH:17][C:12]([C:13]2[N:14]=[C:5]([CH3:6])[O:7][N:15]=2)=[CH:11][C:10]=1[CH3:20]
Reactant: Cc1cc(C(=N)NO)cc(C)c1Br
Reactant: CC(=O)OC(C)=O
Solvent: Cc1cc(C)nc(C)c1
Product: Cc1nc(-c2cc(C)c(Br)c(C)c2)no1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Acetic anhydride (0.35 mL) is added to a solution of 4-bromo-N-hydroxy-3,5-dimethyl-benzamidine (0.30 g) in collidine (3 mL) at room temperature. The solution is stirred at room temperature for 1 h and then at 120° C. for 3 h. After cooling to room temperature, the mixture is concentrated, the residue is taken up in water and acetonitrile, and the resulting mixture is filtered. The filtrate is chromatographed on reversed phase (HPLC; acetonitrile/water/trifluoroacetic acid) to give the title compound. LC (method 11): tR=1.20 min; Mass spectrum (ESI+): m/z=267/269 (Br) [M+H]+.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5]([C:7]1[CH:8]=[CH:9][N:10]2[C:15]=1[C:14](=[O:16])[N:13]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]([CH:24]([N:27]([CH2:37][CH2:38][CH2:39][NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C:28](=[O:36])[C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1)[CH2:25][CH3:26])=[N:11]2)=[O:6]>CO.C1COCC1>[CH2:17]([N:13]1[C:14](=[O:16])[C:15]2=[C:7]([C:5]([OH:6])=[O:4])[CH:8]=[CH:9][N:10]2[N:11]=[C:12]1[CH:24]([N:27]([CH2:37][CH2:38][CH2:39][NH:40][C:41]([O:43][C:44]([CH3:45])([CH3:47])[CH3:46])=[O:42])[C:28](=[O:36])[C:29]1[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=1)[CH2:25][CH3:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCC(c1nn2ccc(C(=O)OC)c2c(=O)n1Cc1ccccc1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(c1nn2ccc(C(=O)O)c2c(=O)n1Cc1ccccc1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Reaction time: 4 h

Procedure:
A mixture of lithium hydroxide (2 N, 0.122 mL, 0.24 mmol) and 3-benzyl-2-{1-[(3-tert-butoxycarbonylamino-propyl)-(4-methyl-benzoyl)-amino]-propyl}-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazine-5-carboxylic acid methyl ester, (Example 20 I, 0.003 g, 0.0049 mmol) in MeOH/THF (1:1, 0.20 mL) at 0° C. was stirred for 4 h. The reaction mixture was quenched with 1 N HCl (5 mL), extracted with EtOAc (3×10 ml), the combined organic extracts dried (Na2SO4), filtered and concentrated in vacuo to give the crude product as a solid. This crude product (0.0029 g, 60%) was used without further purification: MS (ESI+) 602 (M++H).
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[C@H:3]([CH3:5])[OH:4].C([O-])([O-])=O.[K+].[K+].Br[CH2:16][CH2:17][C:18]1[C:19]([Cl:27])=[C:20]([CH:23]=[CH:24][C:25]=1F)[C:21]#[N:22]>CS(C)=O>[Cl:27][C:19]1[C:18]([CH:17]=[CH2:16])=[C:25]([NH:1][CH:2]([CH:3]([OH:4])[CH3:5])[C:6]([OH:8])=[O:7])[CH:24]=[CH:23][C:20]=1[C:21]#[N:22]
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Reactant: N#Cc1ccc(F)c(CCBr)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C=Cc1c(NC(C(=O)O)C(C)O)ccc(C#N)c1Cl
Temperature: 85 °C
Reaction time: 18 h
Yield: 97.1 %

Procedure:
To a suspension of D-Threonine (0.299 g, 2.51 mmol) and K2CO3 (1.21 g, 8.72 mmol) in DMSO (24 mL) was added 3-(2-Bromo-ethyl)-2-chloro-4-fluoro-benzonitrile (572 mg, 2.18 mmol) at room temperature. The reaction mixture was heated to 85° C. and stirred for 18 h. The reaction mixture was allowed to cool to room temperature and quenched with H2O (20 mL) and extracted with EtOAc (3×60 mL). The aqueous layer was then acidified with solid citric acid and extracted with EtOAc (2×80 mL). The later organic extracts were combined, washed with H2O (3×30 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provided the title compound as a pale yellow solid (594 mg, 97%): 1H NMR (400 MHz, d6-acetone, δ in ppm) 7.48 (d, J=9 Hz, 1H), 6.74 (d, J=9 Hz, 1H), 6.63 (dd, J=12 and 18 Hz, 1H), 5.97 (d, J=9 Hz, 1H), 5.88 (dd, J=2 and 12 Hz, 1H), 5.78 (dd, J=2 and 18 Hz, 1H), 4.51-4.42 (m, 2H), 4.23-4.21 (m, 1H), and 1.24 (d, J=7 Hz, 3H).
Reaction SMILES: [OH:1][C:2]([CH3:13])([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:3]#[CH:4].N1C=CC=CC=1>[H][H].[Pd]>[OH:1][C:2]([CH3:13])([CH2:5][CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:3]=[CH2:4]
Reactant: C#CC(C)(O)CCCCCCCC
Reactant: [H][H]
Agent: [Pd]
Solvent: c1ccncc1
Product: C=CC(C)(O)CC=CCCCCC

Procedure:
A mixture of 20.0 g. of 3-hydroxy-3-methyl-undec-1-yne, 200 ml. of pyridine, and 500 mg. of 5% palladium on barium sulfate is shaken in hydrogen at an initial pressure of 45 lb./sq. in. The hydrogenation is stopped when the calculated amount for one mole uptake per mole of compound has been absorbed. The mixture is poured into water and extracted with ether. The ether extract is washed with water, dilute hydrochloric acid, aqueous sodium bicarbonate, dried, and evaporated under reduced pressure to give a residue which is distilled through a Vigreaux column to give a distillate comprising 3-hydroxy-3-methyl-1,5-undecadiene.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][C:11]2[CH2:10][CH:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH2:8][CH2:7][C:6]=2[NH:5][C:4]1=O.C(O)(=O)C.Cl>C1COCC1>[OH:1][CH2:2][CH:3]1[CH2:12][CH:11]2[CH:6]([CH2:7][CH2:8][CH:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH2:10]2)[NH:5][CH2:4]1
Reactant: COc1ccc(CC2CCC3=C(C2)CC(CO)C(=O)N3)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc(CC2CCC3NCC(CO)CC3C2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 34 %

Procedure:
3,4,5,6,7,8-Hexahydro-3-hydroxymethyl-6-((4-methoxyphenyl)methyl)quinolin-2[1H]-one (24.7 g) (prepared according to step c) in THF (200 ml) was treated with borane-dimethylsulphide complex (25 ml) and stirred at room temperature under argon for 18 hours. The reaction mixture was then treated with aqueous acetic acid (20%) until pH 5 and then stirred for an hour. HCl was added until the mixture was strongly acidic and then the solvent removed in vacuo. The residue was dissolved in methanol, concentrated to remove borate esters then converted to the hydrochloride salt (28 g). This salt was recrystallised from ethyl acetate-methanol (200 ml-15 ml) to yield a fraction (15.7 g) containing 34% of the title compound. This fraction was triturated with ethyl acetate, converted to the free base and fractionally crystallised from t-butylmethyl ether, yielding a fraction containing 84% of the title compound. Further recrystallisation was carried out from t-butylmethyl ether diethylether (1:1) and the product converted to the hydrochloride salt (1.8 g), mp 288°-289.5° C.
Reaction SMILES: CCN=C=NCCCN(C)C.[Cl:12][C:13]1[CH:36]=[CH:35][C:16]([C:17]([N:19]2[CH2:23][CH2:22][CH:21]([NH:24][C:25]3[S:26][CH:27]=[C:28](/[CH:30]=[CH:31]/[C:32](O)=[O:33])[N:29]=3)[CH2:20]2)=[O:18])=[CH:15][CH:14]=1.[O:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH:38]1[O:43][NH2:44].C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O.CCOC(C)=O>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([N:19]2[CH2:23][CH2:22][CH:21]([NH:24][C:25]3[S:26][CH:27]=[C:28](/[CH:30]=[CH:31]/[C:32]([NH:44][O:43][CH:38]4[CH2:39][CH2:40][CH2:41][CH2:42][O:37]4)=[O:33])[N:29]=3)[CH2:20]2)=[O:18])=[CH:35][CH:36]=1
Reactant: O=C(O)/C=C/c1csc(NC2CCN(C(=O)c3ccc(Cl)cc3)C2)n1
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(/C=C/c1csc(NC2CCN(C(=O)c3ccc(Cl)cc3)C2)n1)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 20 h
Yield: 87.1 %

Procedure:
EDCI (0.30 g) was added to the solution of (2E)-3-(2-{[1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-1,3-thiazol-4-yl)acrylic acid (0.6 g), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.22 g), and HOBT (0.26 g) in DMF (10 ml) under ice-cooling and the mixture was stirred at ambient temperature for 20 hours. The reaction mixture was poured into a mixture of AcOEt and water. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo to give (2E)-3-(2-{[1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-1,3-thiazol-4-yl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (0.66 g).
Reaction SMILES: C(OC([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11]([OH:21])([C:16]1[O:17][CH:18]=[CH:19][N:20]=1)[CH2:12]2)=O)(C)(C)C.[ClH:22]>O1CCOCC1>[ClH:22].[O:17]1[CH:18]=[CH:19][N:20]=[C:16]1[C:11]1([OH:21])[CH2:12][CH:13]2[NH:8][CH:9]([CH2:15][CH2:14]2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(O)(c1ncco1)C2
Agent: Cl
Solvent: C1COCCO1
Product: OC1(c2ncco2)CC2CCC(C1)N2
Reaction time: 1 h

Procedure:
3-Hydroxy-3-oxazol-2-yl-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.3 g) was dissolved in a solution of hydrogen chloride in dioxane (4 N, 4 mL). The mixture was stirred for 1 hour and the solvent removed by evaporation under vacuum. The solid was triturated from ether to afford the title compound (0.28 g). LCMS m/z 195.2 [M+H]+. R.T.=0.35 min (Analytical Method 3).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:6]=[C:5](NC)[N:4]=1.[K+].C1(S([NH-])(=O)=O)C=CC=CC=1.CNC1N=C([Cl:40])C=C(Cl)N=1>CN1CCCC1=O.[OH-].[Na+]>[CH3:1][NH:2][C:3]1[N:8]=[C:7]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:6]=[C:5]([Cl:40])[N:4]=1
Reactant: CNc1cc(NS(=O)(=O)c2ccccc2)nc(NC)n1
Reactant: CNc1nc(Cl)cc(Cl)n1
Agent: [K+]
Agent: [NH-]S(=O)(=O)c1ccccc1
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CNc1nc(Cl)cc(NS(=O)(=O)c2ccccc2)n1
Temperature: 150 °C
Reaction time: 24 h
Yield: 46.1 %

Procedure:
N-(2,6-Bis-methylamino-pyrimidin-4-yl)-benzenesulfonamide 5.38 g (0.0275 mol) of benzenesulfonamide potassium salt and 2.45 g (0.0138 mol) of 2-methylamino-4,6-dichloro-pyrimidine were suspended in 22 ml of 1-methyl-2-pyrrolidone and stirred at 150° C. for 24 hours. The solvent was removed in a high vacuum and the residue was suspended in 250 ml of water. The mixture was extracted three times with 100 ml of ethyl acetate each time and the combined organic phases were washed with 200 ml of saturated NaHCO3. The combined aqueous phases were made acid with 3N HCl and the precipitate which thereby separated was filtered off under suction. It was chromatographed on silica gel with dichloromethane/methanol 99:1→98:2. The yellowish crystals obtained after the chromatography were suspended in 70 ml of 1N NaOH, the suspension was filtered and the clear filtrate was adjusted to pH 3.5 with 1N HCl. The precipitate which thereby separated was isolated and dried. There were obtained 1.9 g (46%) of N-(2-methylamino-6-chloro-pyrimidin-4-yl)-benzenesulfonamide as colorless crystals; m.p.: 186-187° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][CH:8]=[C:7]2[C:12]([O:14][CH3:15])=[O:13].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.BrN1C(=O)CCC1=O.C(Cl)(Cl)(Cl)[Cl:43]>[W]>[Cl:43][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][CH:8]=[C:7]2[C:12]([O:14][CH3:15])=[O:13]
Reactant: ClC(Cl)(Cl)Cl
Reactant: COC(=O)c1cnnc2c(C)cccc12
Agent: [W]
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Product: COC(=O)c1cnnc2c(CCl)cccc12
Temperature: 25 °C

Procedure:
To 4.3 g of 50 in 1900 ml of carbon tetrachloride a few milligrams of benzoyl peroxide was added, followed by 3.2 g of N-bromosuccinimide and the stirred mixture was refluxed and irradiated with a 200-watt tungsten lamp for 6 hours. The resulting mixture was cooled, washed with water, then with very dilute aqueous sodium bicarbonate solution, dried (MgSO4) and stripped of solvent. The residue (methyl 8-(bromomethyl)cinnoline-4-carboxylate) (58A) was dissolved in 80 ml of acetone, 2.11 g of lithium chloride was added, and the mixture was stirred at room temperature over a weekend. The mixture was stripped of solvent and the residue was dissolved in methylene chloride. The solution was washed with water, dried (MgSO4) and stripped of solvent. The residue was flash chromatographed over silica gel, first using methylene chloride as eluent, then a 1:99 v:v mixture of ethyl acetate and methylene chloride as eluent, to give methyl 8-(chloromethyl)cinnoline-4-carboxylate (58B), as a solid, m.p.: 111°-112° C. (with decomposition).
Reaction SMILES: [C:1]1([CH:7]([NH:9][C:10]([CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)=O)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B.C1COCC1>>[C:1]1([CH:7]([NH:9][CH2:10][CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(NC(=O)CC1CCN(Cc2ccc(F)cc2)CC1)c1ccccc1
Agent: B
Solvent: C1CCOC1
Product: CC(NCCC1CCN(Cc2ccc(F)cc2)CC1)c1ccccc1
Yield: 95 %

Procedure:
Compound 4-[(1-phenylethyl)aminocarbonyl]methyl-1-[(4-fluorophenyl)methyl]piperidine (0.33 g, 0.93 mmol) was reacted with 1M BH3/THF (5.0 ml) to produce a viscous oil, 0.23 g (95% yield)(procedure E). 1H NMR (CD3Cl) δ 7.34-=7.21 (5H, m, Ar—H), 7.01-6.95 (2H, t, J=8.4 Hz, Ar—H), 4.09-4.07 (1H, d, J=6.0 Hz, NH), 3.77-3.71 (1H, q, J=6.3 Hz, PhCHMe), 3.42 (2H, s, p-FPhCH2), 2.82-2.78 (2H, d, J=10.8 Hz, N(CH)2), 2.55-2.37 (2H, m, NCH2), 1.91-1.83 (2H, t, J=11.4 Hz, N(CH)2), 1.59-1.53 (4H, m), 1.44-1.38 (1H, m), 1.36-1.34 (3H, d, J=6.0 Hz, CH3), 1.25-1.14 (2H, m), The free base was converted into its oxalate salt, m.p.=172-173° C. Anal. [C22H29FN2.2(COOH)2] Calculated: C, 59.99; H, 6.39; N, 5.38; Found C, 59.84; H, 6.46; N, 5.29.
Reaction SMILES: Cl.C(OCC)(=O)C.[CH3:8][O:9][C:10]([C:12]1[N:13]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([O:39]C(C)(C)C)=[O:38])=[CH:33][CH:32]=2)[C:14](=[O:29])[C:15]2[C:20]([C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:19][C:18]([CH3:28])=[CH:17][CH:16]=2)=[O:11]>>[CH3:8][O:9][C:10]([C:12]1[N:13]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([C:37]([OH:39])=[O:38])=[CH:35][CH:36]=2)[C:14](=[O:29])[C:15]2[C:20]([C:21]=1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[CH:19][C:18]([CH3:28])=[CH:17][CH:16]=2)=[O:11]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(C)ccc2c(=O)n1Cc1ccc(C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1c(-c2ccccc2)c2cc(C)ccc2c(=O)n1Cc1ccc(C(=O)O)cc1
Reaction time: 6 h
Yield: 92.6 %

Procedure:
To a 4N-hydrochloric acid-ethyl acetate solution (6 ml) was added 2-(4-tert-butoxycarbonylbenzyl)-6-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (220 mg) at room temperature, and the mixture was stirred for 6 hrs. The reaction mixture was concentrated under reduced pressure, and the obtained residue was crystallized from ethyl acetate-hexane to give the title compound (180 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[CH2:10](C([Sn])=C(CCCC)CCCC)[CH2:11]CC>O1CCOCC1.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>[CH3:8][N:6]1[CH:7]=[C:2]([CH:10]=[CH2:11])[CH:3]=[CH:4][C:5]1=[O:9]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: Cn1cc(Br)ccc1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: C=Cc1ccc(=O)n(C)c1
Reaction time: 0.08 h
Yield: 746.1 %

Procedure:
The title compound was prepared by following general procedure 2. To a solution of 5-bromo-1-methylpyridin-2(1H)-one (2 g, 10.63 mmol) in 20 mL of 1,4-dioxane, dichlorobis(triphenylphosphine)palladium(II) (0.834 g, 1.19 mmol) was added at RT and stirred at the same temperature for 5 min. Tributylvinyltin (3.46 mL, 1.19 mmol) was added slowly at RT and stirred at 100-105° C. for 2 h. The reaction was monitored by TLC and LCMS. After completion of the starting material, the solvent was evaporated and the residue purified by column chromatography using 60% ethyl acetate-hexane to afford 1.2 g of 1-methyl-5-vinylpyridin-2(1H)-one.
Reaction SMILES: [I:1]I.[CH2:3]([NH:5][C:6](=[O:24])[C:7]1[CH:12]=[C:11]([C:13]2[CH:21]=[C:20]3[C:16]([CH:17]=[N:18][NH:19]3)=[CH:15][CH:14]=2)[C:10]([CH3:22])=[C:9]([F:23])[CH:8]=1)[CH3:4].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>O1CCOCC1.[OH-].[Na+].O>[CH2:3]([NH:5][C:6](=[O:24])[C:7]1[CH:12]=[C:11]([C:13]2[CH:21]=[C:20]3[C:16]([C:17]([I:1])=[N:18][NH:19]3)=[CH:15][CH:14]=2)[C:10]([CH3:22])=[C:9]([F:23])[CH:8]=1)[CH3:4]
Reactant: II
Reactant: CCNC(=O)c1cc(F)c(C)c(-c2ccc3cn[nH]c3c2)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCNC(=O)c1cc(F)c(C)c(-c2ccc3c(I)n[nH]c3c2)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 98.4 %

Procedure:
Iodine (0.153 g) was added to a stirred solution of N-ethyl-3-fluoro-5-(1H-indazol-6-yl)-4-methylbenzamide (Intermediate 18, 0.15 g) in 1,4-dioxan (4 ml) and aqueous sodium hydroxide (2M, 4 ml) then stirred at room temperature for 45 min. The reaction mixture was treated aqueous citric acid (20%, 20 ml) followed by sodium metabisulphite (2 g). The mixture was diluted with water then extracted with ethyl acetate (2×30 ml). The organic extracts were washed with water (30 ml) dried (Na2SO4) and concentrated under vacuum to give the title-compound as a pale yellow foam (0.21 g).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:8]=2[CH3:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:17]Br>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:8]=2[CH2:16][Br:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1c(-c2ccccc2)cccc1[N+](=O)[O-]
Reactant: BrBr
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: O=[N+]([O-])c1cccc(-c2ccccc2)c1CBr
Yield: 73 %

Procedure:
The procedure of Example 8 was employed, except that the starting material was 2 g of 2-phenyl-6-nitrotoluene which was reacted with 1.5 g of bromine and 0.110 g of benzoyl peroxide. In this way, 2 g (77% yield) of yellowish crystals were recovered.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:5]([OH:7])=[O:6].O[N:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=[O:22]>O1CCCC1>[CH3:14][O:13][C:11](=[O:12])[C:10]1[CH:9]=[CH:8][C:4]([C:5]([O:7][N:16]2[C:20](=[O:21])[CH2:19][CH2:18][C:17]2=[O:22])=[O:6])=[CH:3][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1O
Reactant: COC(=O)c1ccc(C(=O)O)cc1Cl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(=O)ON2C(=O)CCC2=O)cc1Cl
Temperature: 10 °C
Reaction time: 8 h
Yield: 112.3 %

Procedure:
A 3-neck 1 L round-bottom flask equipped with a magnetic stirrer, ice cooling bath, thermometer and an argon inlet tube was set up and charged with 3-chloro-4-(methoxycarbonyl)benzoic acid (Example 72; 21.5 g, 0.1 mol) in tetrahydrofuran (250 mL). The solution was cooled to 10° C. under argon and was treated in succession with N-hydroxysuccinimide (12.66 g, 0.11 mol) and N,N-dicyclohexylcarbodiimide (21.66 g, 0.105 mol). These reagents were washed into the reaction flask with additional tetrahydrofuran (100 mL). A precipitate started to form immediately. The cooling bath was removed and the reaction mixture was stirred at ambient temperature overnight, then was diluted with diethyl ether (400 mL) and stirred for another 30 min. The precipitate was collected by filtration and the filter cake was washed with diethyl ether (3×50 mL). The dried solids (N,N-dicyclohexylurea) weighed 22.2 g (>99% of theory). The combined filtrates were diluted with hexane (100 mL) then were transferred to a 2 L separatory funnel and were washed in turn with cold saturated sodium bicarbonate solution (150 mL) and brine (150 mL). Each aqueous layer was back-extracted in turn with diethyl ether (200 mL), then the combined organic extracts were dried (MgSO4) and evaporated to give crude 2-chloro-4-[[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]benzoic acid methyl ester (˜35 g) as a colorless solid. This material was used directly in the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH:4]([CH3:22])[CH2:5][N:6]([C:12]1[C:17]([N+:18]([O-])=O)=[CH:16][N:15]=[C:14]([Cl:21])[N:13]=1)[CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:23])[CH:4]([CH3:22])[CH2:5][N:6]([C:12]1[C:17]([NH2:18])=[CH:16][N:15]=[C:14]([Cl:21])[N:13]=1)[CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: [H][H]
Reactant: COC(=O)C(C)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)C(C)CN(c1nc(Cl)ncc1N)C1CCCC1
Yield: 94.6 %

Procedure:
A mixture of 40.64 g (0.119 mole) of (rac)-3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-2-methyl-propanoic acid methyl ester (IV-1) in 1500 mL of ethyl acetate and 14 g of 5% palladium on carbon catalyst was stirred under an atmosphere of hydrogen until hydrogen uptake was complete. The mixture was filtered through a pad of Celite, washing the filter pad with dichloromethane. Concentration under reduced pressure gave 35.2 g of (rac)-3-[(5-amino-2-chloro-pyrimidin-4-yl)-cyclopentyl-amino]-2-methyl-propanoic acid methyl ester (V-1), which also contained a small amount of (rac-)-2-chloro-9-cyclopentyl-7-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one. This material was used directly in the next step without further purification.
Reaction SMILES: O=[C:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1.[C:14]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]=[CH:18][C:17]([CH2:20][Mg]Br)=[CH:16][CH:15]=1>[Pd]>[C:14]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:15]=[CH:16][C:17]([CH2:20][CH:2]2[C:9]3[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=3[CH2:4][CH2:3]2)=[CH:18][CH:19]=1
Reactant: COC(=O)c1cc2c([nH]1)CCC2=O
Reactant: Br[Mg]Cc1ccc(-c2ccccc2)cc1
Agent: [Pd]
Product: COC(=O)c1cc2c([nH]1)CCC2Cc1ccc(-c2ccccc2)cc1

Procedure:
The title compound was synthesized in two steps. First, methyl 4-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (200 mg, 1.12 mmol) was reacted with (biphenyl-4-ylmethyl)magnesium bromide (0.25 M in diethyl ether, 17.9 mL, 4.46 mmol) according to General Procedure 3. The resulting crude product was converted to the title compound by hydrogenation according to General Procedure 6 (with 10% Pd/C). The crude product was purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-40% EtOAc/heptane to afford the title compound, 122 mg. 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.08-2.19 (m, 1H), 2.51-2.72 (m, 3H), 2.75-2.87 (m, 2H), 3.26-3.35 (m, 1H), 3.76 (s, 3H), 6.34 (s, 1H), 7.24-7.28 (m, 2H), 7.28-7.33 (m, 1H), 7.38-7.44 (m, 2H), 7.51-7.56 (m, 2H), 7.59-7.63 (m, 2H); LCMS-MS (ESI+) 354.0 (M+Na).