Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])[C@H:2]([C:12]([NH:14][C@H:15]([C:21]([NH:23][C@H:24]([C:35]([N:37]1[CH2:80][CH2:79][CH2:78][C@H:38]1[C:39]([NH:41][C@H:42]([C:47]([NH:49][C@H:50]([C:54]([NH:56][C@H:57]([C:68](OCC1C=CC=CC=1)=[O:69])[C@@H:58]([CH3:67])[O:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)=[O:55])[CH:51]([CH3:53])[CH3:52])=[O:48])[CH2:43][CH:44]([CH3:46])[CH3:45])=[O:40])=[O:36])[C@@H:25]([CH3:34])[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:22])[CH2:16][CH2:17][C:18](=[O:20])[NH2:19])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:88][NH2:89]>CN(C=O)C.CO>[NH:1]([C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])[C@H:2]([C:12]([NH:14][C@H:15]([C:21]([NH:23][C@H:24]([C:35]([N:37]1[CH2:80][CH2:79][CH2:78][C@H:38]1[C:39]([NH:41][C@H:42]([C:47]([NH:49][C@H:50]([C:54]([NH:56][C@H:57]([C:68]([NH:88][NH2:89])=[O:69])[C@@H:58]([CH3:67])[O:59][CH2:60][C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1)=[O:55])[CH:51]([CH3:53])[CH3:52])=[O:48])[CH2:43][CH:44]([CH3:46])[CH3:45])=[O:40])=[O:36])[C@@H:25]([CH3:34])[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:22])[CH2:16][CH2:17][C:18](=[O:20])[NH2:19])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)C[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C)[C@@H](C)OCc1ccccc1)C(=O)N[C@H](C(=O)N[C@H](C(=O)OCc1ccccc1)[C@@H](C)OCc1ccccc1)C(C)C
Reactant: NN
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C)[C@@H](C)OCc1ccccc1)C(=O)N[C@H](C(=O)N[C@H](C(=O)NN)[C@@H](C)OCc1ccccc1)C(C)C

Procedure:
Compound XIV (1.6 g, 1.32 mmol) was dissolved in DMF/MeOH (5:3; 16 ml) and treated with H2NNH2 (0.78 ml) for 72 hrs at 25° C. The white solid was filtered and washed with MeOH and water, yield 1.05 g (70.5%); mp 210°-210.5° C; [α]D25 -22.5° (c 1, DMF). Anal. Calcd for C58H84N10O13 (1129.37): C, 61.68; H, 7.50; N, 12.40. Found: C, 61.72; H, 7.26; N, 12.30.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11](=[O:15])[C:12]([O-:14])=O.[K+].[CH3:17][C@H:18]1[NH:23][CH2:22][CH2:21][N:20]([C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:19]1>>[N:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:24]([N:20]1[CH2:21][CH2:22][N:23]([C:12](=[O:14])[C:11]([C:7]2[C:6]3[C:10](=[C:2]([Br:1])[N:3]=[CH:4][CH:5]=3)[NH:9][CH:8]=2)=[O:15])[C@H:18]([CH3:17])[CH2:19]1)=[O:31]
Reactant: O=C([O-])C(=O)c1c[nH]c2c(Br)nccc12
Reactant: C[C@@H]1CN(C(=O)c2ccccn2)CCN1
Agent: [K+]
Product: C[C@@H]1CN(C(=O)c2ccccn2)CCN1C(=O)C(=O)c1c[nH]c2c(Br)nccc12

Procedure:
Precursor 5m, (R)-1-picolinoyl-3-methyl-4-[(7-bromo-6-azaindol-3-yl)-oxoacetyl]piperazine was prepared by the same method as Precursor 5a starting from Potassium (7-bromo-6-azaindol-3-yl)oxoacetate, Precursor 4g, and (R)-3-methyl-1-picolinoyl-piperazine. MS m/z: (M+H)+ Calc'd for C20H19BrN5O3: 456.07; Found 456. 11. HPLC retention time: 1.12 minutes (column A).
Reaction SMILES: [C:1]([CH2:4]/[CH:5]=[CH:6]/[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][CH2:17][CH3:18])[CH:11]=[C:10]2[CH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][C:21]=1[O:30][CH3:31])([OH:3])=[O:2]>[Pd].C(OCC)(=O)C.O1CCCC1>[C:1]([CH2:4][CH2:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][CH2:17][CH3:18])[CH:11]=[C:10]2[CH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][C:21]=1[O:30][CH3:31])([OH:3])=[O:2]
Reactant: CCCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(/C=C/CC(=O)O)ccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(CCCC(=O)O)ccc21
Reaction time: 6 h
Yield: 80.4 %

Procedure:
Palladium on carbon (1.1 g, 10% w/w) was added to a solution of methyl E-4-[5-(3-carboxyprop-1-enyl)-1-propylindol-3-ylmethyl]-3-methoxybenzoate (10.8 g) in ethyl acetate (300 ml) and tetrahydrofuran (100 ml), and the mixture hydrogenated at atmospheric pressure for 6 hr. The catalyst was removed by filtration through diatomaceous earth, the filter cake washed with ethyl acetate, and the combined filtrate evaporated. The residue was stirred in 1:4 ethyl acetate:hexane (150 ml) and the product isolated by filtration to give methyl 4-[5-(3-carboxypropyl)-1-propylindol-3-ylmethyl]-3-methoxybenzoate (8.72 g, 80%) as an off-white powder; mp 106°-109°; NMR (300 MHz, DMSO-d6): 0.81(t, 3H, CH3), 1.68-1.83(m, 4H), 2.20(t, 2H), 2.61(t, 2H), 3.83(s, 3H, OCH3), 3.91(s, 3H, OCH3), 4.02(m, 4H, NCH2, ArCH2Ar'), 6.92(d, 1H), 7.08(s, 1H), 7.23(m, 2H), 7.32(d, 1H), 7.44(m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH:9][C:10](=[O:20])[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=1[NH2:19])[CH2:5][CH2:6][CH2:7][CH3:8].Cl[C:23](OC(Cl)(Cl)Cl)=[O:24]>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:21])[C@@H:4]([N:9]1[C:10](=[O:20])[C:11]2[C:12](=[CH:13][CH:14]=[C:15]([O:17][CH3:18])[CH:16]=2)[NH:19][C:23]1=[O:24])[CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CCCC[C@H](NC(=O)c1cc(OC)ccc1N)C(=O)OC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC[C@@H](C(=O)OC)n1c(=O)[nH]c2ccc(OC)cc2c1=O
Temperature: 90 °C
Reaction time: 4 h
Yield: 136 %

Procedure:
To a solution of (S)-2-(2-amino-5-methoxy-benzoylamino)-hexanoic acid methyl ester (410 mg, 1.39 mmol) in THF (30 mL) is added trichloromethyl chloroformate (200 mg, 1.01 mmol). The mixture is stirred at 90° C. for 4 hours. The reaction mixture is allowed to cool to room temperature, diluted with EtOAc (100 mL) and washed with H2O (50 mL×3). The organic layer is dried over sodium sulfate and is concentrated to give (S)-2-(6-methoxy-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-hexanoic acid methyl ester (440 mg, 98%).
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]([CH3:29])=[C:11]([CH3:28])[C:12]=1[C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21]C)=[C:17]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:16]=1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.C(Cl)Cl>C(Cl)Cl>[CH2:1]([C:8]1[O:9][C:10]([CH3:29])=[C:11]([CH3:28])[C:12]=1[C:13]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:16]=1)=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)c2c(Cc3ccccc3)oc(C)c2C)cc1C1CCCC1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1oc(Cc2ccccc2)c(C(=O)c2ccc(O)c(C3CCCC3)c2)c1C
Yield: 36.1 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 3 using (2-benzyl-4,5-dimethyl-furan-3-yl)-(3-cyclopentyl-4-methoxy-phenyl)-methanone (17.7 g, 45.5 mmol) and 1M boron tribromide/CH2Cl2 (34.8 mL) in CH2Cl2. Purification on Biotage KP-Sil eluting with a 2, 5 & 10% EtOAc/pet. ether step gradient gave 6.15 g (36%) of the title compound. 1H NMR (DMSO-d6) δ1.40-1.46 (m, 2H), 1.59-1.72 (m, 4H), 1.78 (s, 3H), 1.90-1.94 (m, 2H), 2.16 (s, 3H), 3.18 (quintet, 1H), 3.81 (s, 2H), 6.87 (d, 1H), 7.06 (d, 2H), 7.16-7.25 (m, 3H), 7.46 (dd, 1H), 7.55 (s, 1H), 10.33 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Br[CH2:31][C:32]1[CH:33]=[CH:34][C:35]([Cl:38])=[N:36][CH:37]=1>>[Cl:38][C:35]1[N:36]=[CH:37][C:32]([CH2:31][O:1][C:2]2[CH:3]=[C:4]([C:8]3[C:17]4[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=4)[N:11]=[CH:10][C:9]=3[C:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:23])[CH:5]=[CH:6][CH:7]=2)=[CH:33][CH:34]=1
Reactant: Clc1ccc(CBr)cn1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(OCc2ccc(Cl)nc2)c1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 5-Bromomethyl-2-chloropyridine following the procedure of Example 478: MS (ES) m/z 519.1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:7][CH2:8][OH:9])[S:5][CH:6]=1.C(N(C(C)C)CC)(C)C.[CH3:19][C:20]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])[CH3:21]>C(Cl)Cl>[C:20]([Si:23]([CH3:25])([CH3:24])[O:9][CH2:8][CH2:7][C:4]1[S:5][CH:6]=[C:2]([CH3:1])[CH:3]=1)([CH3:22])([CH3:21])[CH3:19]
Reactant: Cc1csc(CCO)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1csc(CCO[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Yield: 94.2 %

Procedure:
To a solution of 2-(4-methylthiophen-2-yl)ethanol (3.0 g, 21.1 mmol) and diisopropylethylamine (4.1 g, 31.7 mmol) in dry DCM (50 mL) at 0° C. was added TBSCl (4.8 g, 32.0 mmol) in dry DCM (20 mL) dropwise and the mixture was then warmed to room temperature gradually. After the alcohol was consumed completely, water (10 mL) was added. The resulting mixture was extracted with DCM (3×100 mL), washed with brine, and dried over anhydrous Na2SO4. After filtration and concentration, the crude product was purified by column chromatography to give the title compound (5.1 g, 94%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([C:9]([NH2:12])([CH3:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:21][CH2:22][C:23](Cl)=[O:24].Cl>ClCCl.O>[Cl:21][CH2:22][C:23]([NH:12][C:9]([CH3:11])([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:13])([F:14])[F:1])[CH:4]=1)[CH3:10])=[O:24]
Reactant: CC(C)(N)c1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(NC(=O)CCl)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.5 g (12.3 mmol) of the compound from Example 1A and 1.70 g (12.3 mmol) of potassium carbonate are placed in 30 ml dichloromethane and slowly treated at RT with a solution of 1.46 g (12.9 mmol) of chloroacetyl chloride in 5 ml dichloromethane. The mixture is stirred for 3 hrs at RT and then treated with 150 ml water and slowly with 30 ml 1 N hydrochloric acid. It is extracted three times with dichloromethane. The combined organic phases are dried over magnesium sulphate and freed of solvent on the rotary evaporator. 2.65 g (77% of theory) of the title compound are thus obtained.
Reaction SMILES: [Cl:1][C:2]1(Cl)[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[N:4]([CH3:14])[CH2:3]1.C([O-])(=O)C.[Na+].[H][H]>[Pd].C(O)(=O)C>[Cl:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[N:4]([CH3:14])[CH2:3]1
Reactant: [H][H]
Reactant: CN1CC(Cl)(Cl)C(=O)Nc2ccccc21
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CN1CC(Cl)C(=O)Nc2ccccc21

Procedure:
A mixture of 3.06 g of 3,3-dichloro-5-methyl-1,3,4,5-tetrahydro-1,5-benzodiazepin-2-one, 30 ml of glacial acetic acid, 2.2 g of anhydrous sodium acetate and 86 mg of 5% palladium on charcoal is hydrogenated at atmospheric pressure until the theoretical amount of hydrogen has been absorbed. The suspension is filtered through celite and the solids are washed with 5 ml of acetic acid. Concentration of the filtrate and treatment of the residue with 17 ml of water for 30 min. affords 3-chloro-5-methyl-1,3,4,5-tetrahydro-1,5-benzodiazepin-2-one.
Reaction SMILES: [CH3:1][C:2]([OH:7])([CH2:5][CH3:6])[C:3]#[CH:4].C([Li])CCC.[CH3:13][C:14](=[O:17])[CH2:15][CH3:16]>O1CCCC1>[CH3:13][C:14]([OH:17])([C:4]#[C:3][C:2]([CH3:1])([OH:7])[CH2:5][CH3:6])[CH2:15][CH3:16]
Reactant: CCC(C)=O
Reactant: C#CC(C)(O)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(C)(O)C#CC(C)(O)CC
Temperature: -78 °C
Reaction time: 1 h
Yield: 52.9 %

Procedure:
A solution of 3-methyl-1-pentyn-3-ol (30 g, 0.3 mol) in tetrahydrofuran (250 ml) is cooled to −78° C. under a nitrogen atmosphere and n-butyl lithium (1.6 molar solution in hexanes, 383 ml, 0.611 mol) is added slowly over 1.5-2.0 hours. The reaction mixture is stirred for 1 hour at −78° C. and a solution of 2-butanone (41 ml, 0.458 mol) in tetrahydrofuran (50 ml) is added. The reaction mixture is stirred at −78° C. for one hour, allowed to come to ambient temperature and stirred for 2-3 hours. The reaction mixture is cooled to 10° C. and quenched with ice cold water. The aqueous phase is extracted with dichloromethane (3×200 ml). The organic phases are combined, washed with water, and dried over anhydrous sodium sulfate. The mixture is filtered, and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give 3,6-dimethyloct-4-yne-3,6-diol (27 g) as a colourless oil.
Reaction SMILES: C(O)(=O)C.C(O)(=O)C.[NH:9]1[C:18](=[O:19])[C:17]2[NH:16][CH:15]=[N:14][C:13]=2[N:12]=[C:10]1[NH2:11].C(OC[O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][C:32](=O)C1C=CC=CC=1)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[OH:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][N:14]1[CH:15]=[N:16][C:17]2[C:18](=[O:19])[NH:9][C:10]([NH2:11])=[N:12][C:13]1=2
Reactant: CC(=O)OCOCCOCCOC(=O)c1ccccc1
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Product: Nc1nc2c(ncn2COCCOCCO)c(=O)[nH]1
Temperature: 120 °C
Reaction time: 18 h
Yield: 6.2 %

Procedure:
A mixture of guanine diacetate (1.31 g), 2-(2-benzoyloxyethoxy)ethoxymethyl acetate (2.37 g), p-toluenesulfonic acid (32 mg) and mineral oil (5.2 g) was heated at 120° C. with stirring for 18 hours. The reaction mixture was cooled and the mineral oil decanted off. The residue was triturated with benzene and the benzene decanted off. To the residue was added 40% aqueous methylamine (10 ml), and the mixture was heated in a steam bath for 30 minutes. The water and methylamine were removed under reduced pressure and the residue extracted with hot ethanol. The ethanol-insoluble material was dissolved in boiling methanol, filtered, concentrated to 125 ml and cooled to room temperature, precipitating an impure product (166 mg) which was unmoved by filtration. The filtrate was chilled and 9-[2-(2-hydroxyethoxy)ethoxymethyl]guanine (80 mg, m.p. 184°-187° C.) was obtained.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[F:19])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[CH3:20][C:21]1[N:22]=[C:23]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][N:33]=2)[CH:29]=O)[S:24][CH:25]=1>>[F:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:29][C:28]2[CH:31]=[CH:32][N:33]=[C:26]([C:23]3[S:24][CH:25]=[C:21]([CH3:20])[N:22]=3)[CH:27]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: CCOC(=O)C(C)CC(N)c1c(F)cccc1OC
Reactant: Cc1csc(-c2cc(C=O)ccn2)n1
Product: COc1cccc(F)c1C1CC(C)C(=O)N1Cc1ccnc(-c2nc(C)cs2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2-fluoro-6-methoxyphenyl)-2-methylbutanoate with 2-(4-methylthiazol-2-yl)isonicotinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.81 min.; [M+H]+: 411.99 g/mol.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[Cl:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH:15]=[O:16])[CH2:10][C:9](=[CH:17]O)[C:8]2=O.C(O)(=O)C>CO>[Cl:4][C:5]1[CH:14]=[CH:13][C:12]2[N:11]([CH:15]=[O:16])[CH2:10][C:9]3[CH:17]=[N:3][N:2]([CH3:1])[C:8]=3[C:7]=2[CH:6]=1
Reactant: O=CN1CC(=CO)C(=O)c2cc(Cl)ccc21
Reactant: CNN
Solvent: CC(=O)O
Solvent: CO
Product: Cn1ncc2c1-c1cc(Cl)ccc1N(C=O)C2
Reaction time: 1.5 h
Yield: 61.7 %

Procedure:
Methylhydrazine (52.5 g) was dropwise to a mixture of 6-chloro-1-formyl-3-hydroxymethylene-4-oxo-1,2,3,4-tetrahydroquinoline (276 g) and acetic acid (13 ml) in methanol (2.76 liters) at 10° C. to 12° C. over a period of 10 minutes. After being stirred for 1.5 hours at the same temperature, the resulting precipitate was collected by filtration, washed with methanol and dried to give 8-chloro-4,5-dihydro-5-formyl-1-methyl-1H -pyrazolo[4,3-c]quinoline (174 g).
Reaction SMILES: C([N:8]([CH2:16][CH2:17][C:18]1[CH:41]=[CH:40][C:21]([C:22]([NH:24][C@@H:25]([CH2:29][CH2:30][CH2:31][NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[C:26]([OH:28])=[O:27])=[O:23])=[CH:20][CH:19]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)(OC(C)(C)C)=O.[ClH:42].O1CCOCC1>CO>[ClH:42].[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][NH:8][CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([NH:24][C@@H:25]([CH2:29][CH2:30][CH2:31][NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[C:26]([OH:28])=[O:27])=[O:23])=[CH:40][CH:41]=1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(C(=O)N[C@@H](CCCNCc2ccccn2)C(=O)O)cc1)Cc1ccccn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(N[C@@H](CCCNCc1ccccn1)C(=O)O)c1ccc(CCNCc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
The compound obtained in Example 10-1 (13.9 mg) was dissolved in methanol (0.28 ml) and 4 mol/l hydrochloric acid/dioxane solution (0.28 ml) was added to the solution. The mixture was stirred for 75 minutes at room temperature. After the completion of the reaction, the solvent was removed by distillation. The residue was purified by silica gel column chromatography (0.5 g, chloroform/methanol/water=7/3/0.5). The obtained product was added with aqueous solution of hydrochloric acid, concentrated and then azeotropically distilled with water. The resulting solid was washed with ether to obtain a hydrochloride of the title compound (13.8 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:12])=[C:4]([CH:8]=[CH:9][C:10]=1Cl)[C:5](O)=[O:6].O1CCCC1.B(F)(F)F.O1CCCC1.O.C(Cl)[Cl:29]>>[NH2:1][C:2]1[C:3]([Cl:12])=[C:4]([CH:8]=[C:9]([Cl:29])[CH:10]=1)[CH2:5][OH:6]
Reactant: Nc1c(Cl)ccc(C(=O)O)c1Cl
Reactant: ClCCl
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: O
Product: Nc1cc(Cl)cc(CO)c1Cl
Temperature: 8 °C
Reaction time: 1 h

Procedure:
Into a 1 liter three-neck flask was introduced 40 g (0.19 mole) of 3-amino-2,4-dichlorobenzoic acid and 150 ml of tetrahydrofuran. The solution was cooled to 8°-10° C. in an ice bath. A borontrifluoride-tetrahydrofuran (1M) solution (280 ml) was added dropwise over a period of 1 hr. After being stirred at 8° C. for an additional 1 hr. the solution was allowed to warm up slowly to room temperature. The reaction flask was then cooled again in an ice bath and 50 ml of water was added through a dropping funnel. The mixture was taken into 1 liter of methylene chloride and washed once with NaHCO3 and twice with water, then dried over calcium sulfate. The methylene chloride solution afforded 19.2 g of crude solid product, mp 111-121. Five grams of the crude solid was recrystallized from acetonitrile to yield 4.2 g of 3-amino-2,5-dichlorobenzyl alcohol; mp 121-127; nmr (DMSO-d6) δ4.50 (D, 2H), 5.34 (t, 1H), 5.52 (S, 2H), 6.73 (S, 2H); ir (CHCl3) 3490, 3380, 3240, 1630 and 1598 Cm-1.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])(C)(C)C.C(O[C:25](=[O:42])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[C:39]([CH3:41])[N:38]=[CH:37][N:36]=2)[CH:30]=1)=O)(C)(C)C>>[CH3:41][C:39]1[N:38]=[CH:37][N:36]=[C:35]([C:31]2[CH:30]=[C:29]([C:27]3[CH2:26][C:25](=[O:42])[NH:18][C:9]4[CH:10]=[C:11]([C:14]([F:15])([F:16])[F:17])[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:34]=[CH:33][CH:32]=2)[CH:40]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ncn1
Product: Cc1cc(-c2cccc(C3=Nc4ccc(C(F)(F)F)cc4NC(=O)C3)c2)ncn1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (138 mg, 0.5 mmol) and 3-[3-(6-methyl-pyrimidin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K41) (187 mg, 0.6 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (44 mg).
Reaction SMILES: [S:1](S([O-])=O)([O-:3])=[O:2].[Na+].[Na+].[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=1.O>CN(C=O)C>[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][S:1]([CH2:14][C:13]2[CH:16]=[CH:17][C:10]([F:9])=[CH:11][CH:12]=2)(=[O:3])=[O:2])=[CH:12][CH:11]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)(Cc1ccc(F)cc1)Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 45.9 %

Procedure:
To a well-stirred suspension of 6.95 grams (40 mmol) of sodium hydrosulfite in 100 ml DMF was added 5.10 grams (35.3 mmol) of 4-fluoro benzyl chloride. The mixture was stirred at room temperature for five hours, then brought to 85° C. for 20 hours. The warm mixture was poured into 400 ml ice, and the total volume brought to 700 ml with water. The solid precipitates were isolated to give 2.3 grams (8.1 mmol; 46% yield) of bis(4-fluoro benzyl) sulfone. Recrystallization from toluene gave the pure compound as white needles (top 193° C.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[NH2:12][CH2:13][CH2:14][OH:15]>C(O)CCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:12][CH2:13][CH2:14][OH:15])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: NCCO
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Solvent: CCCCO
Product: O=[N+]([O-])c1cc(Br)ccc1NCCO
Reaction time: 8 h
Yield: 101 %

Procedure:
A mixture of 4-bromo-1-fluoro-2-nitrobenzene (I-9, Aldrich, Wis.; 25 g, 0.11 mol) and 2-aminoethanol (13.9 g, 0.23 mol, 2.0 eq.) in n-butanol (300 mL) was heated under reflux for 1 hour. The reaction mixture was concentrated and the residue was dispersed in petrol ether (600 mL) and stirred overnight. The solids were iltered to give I-10 as a yellow powder (29 g, 98%). MS (ESI): m/z 262 (M+H+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][SH:9].[OH-].[K+].Cl[CH2:13][CH2:14][OH:15].Cl>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][S:9][CH2:13][CH2:14][OH:15]
Reactant: OCCCl
Reactant: SCCc1ccccn1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: OCCSCCc1ccccn1
Reaction time: 6 h
Yield: 22.4 %

Procedure:
2-Pyridineethanethiol (1.9 g) and potassium hydroxide (0.77 g) in methanol (15 ml) were stirred under nitrogen for 15 min. 2-Chloroethanol (1.10 g) was added and the solution stirred under nitrogen for 6 h. The mixture was acidified to pH5 with 2N hydrochloric acid and then left overnight. The methanol was evaporated in vacuo and the residue partitioned between water (150 ml) and diethyl ether (150 ml), separated and the aqueous phase re-extracted with diethyl ether (100 ml). The combined ethereal layers were dried and evaporated in vacuo to give an oil. Purification by FCC eluting with System G (98:2:1) gave the title compound (0.56 g) as a colourless oil. T.l.c. (diethyl ether) Rf 0.21
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](=[O:15])[N:6]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH:7]=1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5](=[O:15])[N:6]([CH:8]2[CH2:13][CH2:12][CH:11]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:10][CH2:9]2)[CH:7]=1
Reactant: Cc1ccc(=O)n(C2CCC(=O)CC2)c1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: Cc1ccc(=O)n(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)c1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 5-methyl-1-(4-oxo-cyclohexyl)-1H-pyridin-2-one (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in Example 2 Step C) using the procedure described in Step D of Example 1.