Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([O:12]CC3C=CC(OC)=CC=3)[C:7]=2[C:22]2[CH:23]=[C:24]([CH:33]3[CH2:38][CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34]3)[C:25]3[CH2:30][O:29][C:28](=[O:31])[NH:27][C:26]=3[N:32]=2)[CH2:3][CH2:2]1.[ClH:46]>O1CCOCC1>[ClH:46].[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[C:7]=2[C:22]2[CH:23]=[C:24]([CH:33]3[CH2:38][CH2:37][CH2:36][NH:35][CH2:34]3)[C:25]3[CH2:30][O:29][C:28](=[O:31])[NH:27][C:26]=3[N:32]=2)[CH2:2][CH2:3]1
Reactant: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(C3CCCN(C(=O)OC(C)(C)C)C3)c3c(n2)NC(=O)OC3)cc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C1Nc2nc(-c3c(O)cccc3OCC3CC3)cc(C3CCCNC3)c2CO1
Reaction time: 3 h
Yield: 62 %

Procedure:
To a solution of tert-butyl 3-(7-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}-2-oxo-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl)-1-piperidinecarboxylate (2.0 g, 3.248 mmol) in dioxane (15 mL) was added 4N HCl in dioxane (30 mL) at room temperature. The stirring was continued for 3 hrs. After the solvent was removed by evaporation, the resulting solid was triturated with acetonitril, collected by filtration, and washed with acetonitrile. The solid was dried under reduced pressure to give 7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-(3-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one hydrochloride as a white solid (0.865 g, yield; 62%).
Reaction SMILES: [OH:1][CH:2]([CH3:14])[C@@H:3]([NH:10][C:11]([NH2:13])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(O)C>C(=O)=O>[OH:1][C@H:2]([CH3:14])[C@@H:3]([NH:10][C:11]([NH2:13])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(O)[C@@H](NC(N)=O)c1ccccc1
Agent: O=C=O
Solvent: CCO
Product: C[C@@H](O)[C@@H](NC(N)=O)c1ccccc1

Procedure:
The enantiomers of 1-((1S)-2-hydroxy-1-phenylpropyl)urea (2.86 g, 14.72 mmol) were separated by SFC (Thar 80, Column: Phenomenex Lux-4 21×250 (mm), UV wavelength: 220 nM, mobile phase: 25:75 Ethanol+0.25% dimethyl ethyl amine in CO2(l), flow rate: 70 mL/min, Run Time: 7.1 min). The fractions were collected and the solvent evaporated in vacuo to afford 1-((1S,2R)-2-hydroxy-1-phenylpropyl)urea (Intermediate 23B). MS: [M+H]+ m/z 195.
Reaction SMILES: [CH3:1][C@H:2]1[N:7]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][O:26]C4CCCCO4)=[CH:20][CH:19]=3)=[N:10][N:9]=2)[CH2:6][CH2:5][N:4]([C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:34])[CH2:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CO>[OH:26][CH2:25][CH2:24][C:21]1[CH:22]=[CH:23][C:18]([C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([N:7]3[CH2:6][CH2:5][N:4]([C:33]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)=[O:34])[CH2:3][C@H:2]3[CH3:1])=[N:9][N:10]=2)=[CH:19][CH:20]=1
Reactant: C[C@@H]1CN(C(=O)c2ccccc2)CCN1c1nnc(-c2ccc(CCOC3CCCCO3)cc2)c2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C[C@@H]1CN(C(=O)c2ccccc2)CCN1c1nnc(-c2ccc(CCO)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
((R)-3-methyl-4-(4-(4-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)phenyl)phthalazin-1-yl)piperazin-1-yl)(phenyl)methanone (122 mg, 0.227 mmol) 83 and p-toluenesulfonic acid (130 mg, 0.682 mmol) were dissolved in methanol (4 mL) and stirred at rt for 1.5 hours. The reaction was added to 35 mL aqueous K2CO3 (10%) and extracted three times with 30 mL portions of dichloromethane. The combined organic extracts were dried over MgSO4 and evaporated to give a pale yellow solid, compound 84. MS (M+H)+=453.2.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[C:5]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[S:6][C:7]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:20][C:19](=[O:21])[O:18][N:17]=2)=[C:12]([F:22])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[C:39](#[N:41])[CH3:40]>>[F:22][C:12]1[CH:11]=[C:10]([O:9][CH2:8][C:7]2[S:6][C:5]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[N:4][C:3]=2[CH2:2][N:41]2[CH2:24][CH2:25][CH:26]([C:29]([F:32])([F:31])[F:30])[CH2:40][CH2:39]2)[CH:15]=[CH:14][C:13]=1[C:16]1[NH:20][C:19](=[O:21])[O:18][N:17]=1
Reactant: O=c1[nH]c(-c2ccc(OCc3sc(-c4ccc(C(F)(F)F)cc4)nc3CBr)cc2F)no1
Reactant: CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=c1[nH]c(-c2ccc(OCc3sc(-c4ccc(C(F)(F)F)cc4)nc3CN3CCC(C(F)(F)F)CC3)cc2F)no1
Reaction time: 8 h

Procedure:
To a mixture of 136 mg of 3-{4-[4-bromomethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-fluoro-phenyl}-4H-[1,2,4]oxadiazol-5-one in 17 mL of acetonitrile was added 48.6 mg of 4-trifluoropiperidine hydrochloride and 70 mg of potassium carbonate. The resulting mixture was stirred overnight and then concentrated under reduced pressure. It was then taken into dichloromethane and washed with water. The aqueous layer was extracted with dichloromethane. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (dichloromethane 98/methanol 2) to give 51.6 mg of 3-{2-fluoro-4-[2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazol-5-ylmethoxy]-phenyl}-4H-[1,2,4]oxadiazol-5-one as a white solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:34])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22](=O)[C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[C:36]1([N:42]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)N)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH3:1][CH:2]([CH3:34])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]3[C:37]4[C:36](=[CH:41][CH:40]=[CH:39][CH:38]=4)[N:42]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[C:22]=3[C:23]3[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:32])[F:31])=[CH:27][CH:28]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: NN(c1ccccc1)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(C(F)(F)F)cc3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccc(C(F)(F)F)cc4)n(-c4ccccc4)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-[3-(1-{5-oxo-5-[4-(trifluoromethyl)phenyl]pentyl}-4-piperidinyl)phenyl]propanamide and 1,1-diphenylhydrazine hydrochloride: ESMS m/e: 624.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH:6]=1.[CH2:14]([O:16][CH:17]=[CH:18][C:19](Cl)=[O:20])[CH3:15]>N1C=CC=CC=1>[CH2:14]([O:16][CH:17]=[CH:18][C:19]([NH:11][C:10]1[CH:12]=[CH:13][C:7]([N:5]2[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]2)=[CH:8][CH:9]=1)=[O:20])[CH3:15]
Reactant: Cc1cn(-c2ccc(N)cc2)cn1
Reactant: CCOC=CC(=O)Cl
Solvent: c1ccncc1
Product: CCOC=CC(=O)Nc1ccc(-n2cnc(C)c2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
4-(4-methyl-1H-imidazol-1-yl)aniline (15 g, 138 mmol) was dissolved in dry pyridine (80 mL), freshly distilled 3-ethoxyacryloyl chloride (19 g, 140 mmol) was then added drop-wise at 5°/0° C. The resulting mixture was stirred at 0° C. for 1 hours and at r.t. overnight. The reaction mixture was quenched with water (500 mL), the pH was adjusted to pH=10, by adding K2CO3 and the resulting solid was filtered, washed with water and dried, to provide the title product as slight orange powder (18.6 g; 75%), m.p.: 214-216° C. C15H17N3O2, MW: 271.32.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:22])[CH2:7][NH:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=3)[NH:11][N:10]=2)[CH2:2]1.[C:23]([CH:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1)#[N:24]>>[C:23]([CH:25]1[CH2:30][CH2:29][CH:28]([N:1]2[CH2:2][CH:3]([NH:5][C:6](=[O:22])[CH2:7][NH:8][C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:20])([F:19])[F:21])[CH:16]=4)[NH:11][N:10]=3)[CH2:4]2)[CH2:27][CH2:26]1)#[N:24]
Reactant: N#CC1CCC(=O)CC1
Reactant: O=C(CNc1n[nH]c2ccc(C(F)(F)F)cc12)NC1CNC1
Product: N#CC1CCC(N2CC(NC(=O)CNc3n[nH]c4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide (as prepared in Example 41, Step A) and 4-cyano-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][N:12]([C:15]4[CH:16]=[N:17][CH:18]=[CH:19][C:20]=4Cl)[C:11]3=[O:22])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[OH-].[K+].C([O-])([O-])=O.[K+].[K+].[CH3:31][N:32]1[CH2:36][CH2:35][CH2:34][CH:33]1[CH2:37][OH:38]>C(Cl)(Cl)Cl.CO.C1(C)C=CC=CC=1>[S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][N:12]([C:15]4[CH:16]=[N:17][CH:18]=[CH:19][C:20]=4[O:38][CH2:37][CH:33]4[CH2:34][CH2:35][CH2:36][N:32]4[CH3:31])[C:11]3=[O:22])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C1N(c2ccc3ncsc3c2)CCN1c1cnccc1Cl
Reactant: CN1CCCC1CO
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CN1CCCC1COc1ccncc1N1CCN(c2ccc3ncsc3c2)C1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 4.8 %

Procedure:
1-Benzothiazol-6-yl-3-(4-chloro-pyridin-3-yl)-imidazolidin-2-one (I-180a: 100 mg, 0.3023 mmol) was added to a stirred mixture of KOH (68 mg, 1.2092 mmol), K2CO3 (42 mg, 0.3023 mmol) and toluene (3 mL) and the reaction mixture was stirred at RT for 5 mins. This was followed by the addition of (1-methyl-pyrrolidin-2-yl)-methanol (52 mg, 0.4534 mmol) and 18 crown ether (8 mg, 0.0302 mmol) and the resulting mixture was refluxed for 24 hrs. The reaction was monitored by TLC (10% MeOH in CHCl3). The reaction mixture was concentrated and the concentrate was partitioned between ethylacetate and water. The organic layer was washed with water, brine, dried over Na2SO4 and concentrated. Purification by preparative HPLC afforded 6 mg of the product (5% yield).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10](=O)[C:11]=1[C:12]([NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1)=[O:13])=[CH:8][CH:7]=[CH:6][N:5]=2.[Cl:27]C1C2C(=NC=CC=2)N=C(C)C=1C(OCC)=O>>[Cl:27][C:10]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([CH3:1])[C:11]=1[C:12]([NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1)=[O:13]
Reactant: CCOC(=O)c1c(C)nc2ncccc2c1Cl
Reactant: Cc1[nH]c2ncccc2c(=O)c1C(=O)NCc1cccc(C(F)(F)F)c1
Product: Cc1nc2ncccc2c(Cl)c1C(=O)NCc1cccc(C(F)(F)F)c1
Yield: 59 %

Procedure:
This substance was synthesized from 2-Methyl-4-oxo-N-(3-(trifluoromethyl)benzyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide (130.0 mg, 0.36 mmol) following the same procedure used for ethyl 4-chloro-2-methyl-1,8-naphthyridine-3-carboxylate. Purification was done by flash chromatography (EtOAc/MeOH 100:0→96:4) giving 80.0 mg (59%) of the title compound.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]#[N:15])=[C:4]1[C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[NH:21][C:20]=2[CH:26]=1)[CH3:2].[H-].[Na+].[CH3:29]I>C1COCC1>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]#[N:15])=[C:4]1[C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:29])[C:20]=2[CH:26]=1)[CH3:2]
Reactant: CCn1c(-c2ccc3c(c2)NC(=O)CO3)c(C#N)c2ccc(OC)cc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCn1c(-c2ccc3c(c2)N(C)C(=O)CO3)c(C#N)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 76 %

Procedure:
1-Ethyl-6-methoxy-2-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-1H-indole-3-carbonitrile (20 mg, 0.058 mmol), prepared as in example 1BH, is combined with NaH (14 mg, 60% suspension in oil, 0.35 mmol). THF (300 μL) is added. This is stirred at room temperature for 5 minutes. A solution of methyl iodide (4.4 μL) in THF (100 μL) is added. This is stirred at room temperature for 1 hour. The reaction mixture is partitioned between EtOAc and aqueous HCl. The organic layer is dried and concentrated. Purification by silica gel chromatography (9/1, CH2Cl2/EtOAc) yields 1-ethyl-6-methoxy-2-(4-methyl-3-oxo-3,4,-dihydro-2H-benzo[1,4]oxazin-6-yl)-1H-indole-3-carbonitrile (16 mg, 76%) as a white solid.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].CC(C)=O.C1(O)C=CC=CC=1.[OH:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][C:20]=1[CH3:27].Br[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][C:36]([O:38][CH3:39])=[O:37]>>[CH:23]([C:22]1[CH:25]=[CH:26][C:19]([O:18][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH2:35][C:36]([O:38][CH3:39])=[O:37])=[C:20]([CH3:27])[CH:21]=1)=[O:24]
Reactant: Cc1cc(C=O)ccc1O
Reactant: COC(=O)Cc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: Oc1ccccc1
Product: COC(=O)Cc1ccccc1Oc1ccc(C=O)cc1C
Yield: 95.6 %

Procedure:
Using the K2CO3 /acetone conditions for phenol alkylation described in Step A of Example 30, 0.50 g (3.68 mmol) of 4-hydroxy-3-methylbenzaldehyde was alkylated with 0.926 g (4.05 mmol) of methyl 2-bromophenylacetate to afford 1.00 g (96%) of the title compound.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C([O:13][C:14](=O)/[CH:15]=[CH:16]/[C:17]#[C:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)C>C1COCC1>[C:19]1([C:18]#[C:17]/[CH:16]=[CH:15]/[CH2:14][OH:13])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)/C=C/C#Cc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: OC/C=C/C#Cc1ccccc1
Reaction time: 1.5 h
Yield: 100 %

Procedure:
Diisobutylaluminium hydride (1.0 M solution in toluene, 42 mL, 42 mmol) was added, under a nitrogen atmosphere at −70° C., to a stirred solution of (E)-5-phenyl-pent-2-en-4-ynoic acid ethyl ester (1.2 g, 5.99 mmol) in dry THF (105 mL). After stirring for 1.5 h, the reaction mixture was quenched with methanol (5 mL) followed by saturated aqueous Rochelle's salt (90 mL) and 1N sodium hydroxide (40 mL). The organic phase was separated, and the aqueous phase extracted with ethyl acetate (250 mL, 2×). The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo to give 948 mg (100%) of (E)-5-phenyl-pent-2-en-4-yn-1-ol. 1H NMR (CDCl3, 300 MHz) δ: 2.20 (bs, 1H), 4.25 (d, 2H), 5.95 (dt, 1H, Jtrans=15 Hz), 6.35 (dt, 1H, Jtrans=15 Hz), 7.23-7.35 (m, 3H), 7.35-7.48 (m, 2H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][CH:35]=[C:9]23)[CH2:4][CH2:3]1.Br[CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39].Cl>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:12]2[C:13](=[O:14])[N:8]([C@H:5]3[CH2:4][CH2:3][C@H:2]([O:1][CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:7][CH2:6]3)[C:9]3[N:10]([N:33]=[CH:34][CH:35]=3)[C:11]=2[CH2:30][CH2:31][CH3:32])=[CH:17][CH:18]=1)#[N:29]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ccnn12
Reactant: CC(C)(C)OC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)OC(C)(C)C)CC2)c2ccnn12
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (21.1 g) and tetrabutylammonium hydrogen sulfate (1.5 g) in toluene (160 mL)-50% sodium hydroxide (160 mL) was added dropwise tert-butyl bromoacetate (20 mL) at 50° C., and the mixture was stirred at 50° C. for 1.5 hr. The mixture was allowed to cool to room temperature, diluted with ethyl acetate and then neutralized with 6M hydrochloric acid. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as an amorphous pale-yellow solid (24.4 g, 93%).
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([N:14]1[C:23]2[C:18](=[C:19]([CH2:25][CH:26]3[S:30][C:29](=[O:31])[NH:28][C:27]3=[O:32])[CH:20]=[CH:21][C:22]=2[OH:24])[CH2:17][CH2:16][C:15]1=[O:33])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.I[CH2:35][CH2:36][CH2:37][CH3:38].S([O-])(O)(=O)=O.[K+]>O.CS(C)=O>[CH2:7]([N:14]1[C:23]2[C:18](=[C:19]([CH2:25][CH:26]3[S:30][C:29](=[O:31])[NH:28][C:27]3=[O:32])[CH:20]=[CH:21][C:22]=2[O:24][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:17][CH2:16][C:15]1=[O:33])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCCCI
Reactant: O=C1NC(=O)C(Cc2ccc(O)c3c2CCC(=O)N3Cc2ccccc2)S1
Agent: CC(C)(C)[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCOc1ccc(CC2SC(=O)NC2=O)c2c1N(Cc1ccccc1)C(=O)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
55.5 mg of potassium tert-butoxide was added to a DMSO solution (1 ml) of 90 mg of 5-(1-benzyl-8-hydroxy-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl)thiazolidine-2,4-dione, followed by stirring at room temperature for 1 hour. 29.8 μl of 4-iodobutane was added thereto, followed by stirring at room temperature for 2 hours. Water was added to the reaction liquid, potassium hydrogensulfate was added to the mixture, and the mixture was extracted with ethyl acetate. After washing with water, the extract was dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by preparative silica gel thin layer chromatography (dichloromethane:methanol=20:1), giving 42 mg (41% yield) of 5-(1-benzyl-8-butoxy-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl)thiazolidine-2,4-dione as a colorless amorphous solid.
Reaction SMILES: [CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:15]([C:19]#[N:20])=[N:14][C:13]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=O)=[O:22])=[C:12]([OH:30])[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH2:46]([NH2:49])[CH2:47][CH3:48]>C(Cl)Cl>[CH2:46]([NH:49][C:27]([CH2:26][CH2:25][CH2:24][NH:23][C:21]([C:13]1[N:14]=[C:15]([C:19]#[N:20])[C:16]2[C:17](=[O:18])[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:9]=[CH:10][C:11]=2[C:12]=1[OH:30])=[O:22])=[O:29])[CH2:47][CH3:48]
Reactant: N#Cc1nc(C(=O)NCCCC(=O)O)c(O)c2ccn(Cc3ccccc3)c(=O)c12
Reactant: CCCN
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCNC(=O)CCCNC(=O)c1nc(C#N)c2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4-[(7-benzyl-1-cyano-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carbonyl)-amino]-butyric acid (30 mg, 0.074 mmol) and triethylamine (0.015 mL, 0.11 mmol) in CH2Cl2 (3 mL) was cooled in an ice bath. Isobutyl chloroformate (0.014 mL, 0.11 mmol) was added, and the mixture was stirred at 0° C. for 10 min. Propylamine (0.1 mL) was then added, and the mixture was slowly warmed to r.t. and stirred for 16 h. The mixture was diluted with CH2Cl2 (30 mL) and washed with 1 M HCl. The organic layer was dried over MgSO4 and concentrated. The crude product was purified twice by silica gel chromatography (0-30% EtOAc/CH2Cl2, then 10-80% EtOAc/hexanes+2% AcOH) to give 23 mg of the title compound as a white solid. MS: (+) m/z 448.35 (M+1).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.Br[C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:18]=1[Cl:19])[N:15]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:14]=[C:13]2[NH:28][C:29](=[O:33])[CH2:30][CH2:31][CH3:32].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C(OCC)(=O)C.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>[Cl:19][C:18]1[CH:17]=[C:16]2[C:12]([C:13]([NH:28][C:29](=[O:33])[CH2:30][CH2:31][CH3:32])=[N:14][N:15]2[CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:25])[CH3:26])=[CH:11][C:10]=1[C:3]1[CH:4]=[CH:5][O:1][CH:2]=1
Reactant: OB(O)c1ccoc1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)c(Br)cc12
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: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)c(-c3ccoc3)cc12
Yield: 82.4 %

Procedure:
377 mg of 3-furylboronic acid are added to 1 g of N-[5-bromo-6-chloro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in Example 58, in 90 cm3 of dioxane, followed by addition of 570 mg of sodium carbonate in 18 cm3 of water and finally 173 mg of tetrakis(triphenylphosphine)palladium, and the mixture is refluxed for 18 hours. The reaction medium is diluted with 75 cm3 of ethyl acetate and 50 cm3 of water. The organic phase is separated out after settling of the phases has taken place, washed with 50 cm3 of water and 50 cm3 of saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 50° C.). The crude product obtained is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with a cyclohexane/ethyl acetate mixture (85/15 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.); 800 mg of N-[6-chloro-5-(3-furyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide are obtained in the form of a colourless oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.[O:16]1[CH2:33][C@@H:17]1[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](OCC#N)=[O:28])=[CH:22][CH:21]=1>C1COCC1>[O:16]1[CH2:33][C@@H:17]1[CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][C:27]([NH:1][CH2:2][CH2:3][N:4]2[CH2:9][CH2:8][N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:6][CH2:5]2)=[O:28])=[CH:24][CH:25]=1
Reactant: N#CCOC(=O)Cc1ccc(OC[C@H]2CO2)cc1
Reactant: NCCN1CCN(c2ccccc2)CC1
Solvent: C1CCOC1
Product: O=C(Cc1ccc(OC[C@H]2CO2)cc1)NCCN1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
A mixture of 10.7 g (52.1 mmol) 1-(2-aminoethyl)-4-phenylpiperazine and 13.5 g (54.6 mmol) (R)-4-(2,3-epoxypropoxy)phenylacetic acid, cyanomethyl ester in 125 dry THF was stirred at room temperature for 40 hours: The solvent was removed in vacuo and the residue was triturated with ether to give the crude amide as a white solid. The solid was dissolved in 35 ml. CH2Cl2 and placed on a column of 170 g Woelm basic alumina (grade 3) made up in CHCl2. Elution with 1 liter CH2Cl2 furnished essentially pure material. Crystallization from acetone afforded the end product, m.p. 124°-125°. A second crop, m.p. 121°-123° was obtained from the mother liquors.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[N:11]1([CH2:17][CH2:18][CH2:19][NH2:20])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>>[N:11]1([CH2:17][CH2:18][CH2:19][NH:20][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1ccc(I)cc1
Reactant: NCCCN1CCOCC1
Product: O=[N+]([O-])c1ccc(NCCCN2CCOCC2)cc1

Procedure:
Using 1-iodo-4-nitro-benzene (500 mg) instead of 1-bromo-3-nitro-benzene, and 3-morpholin-4-yl-propylamine (353 mg) instead of morpholine, in the same manner as Step A in Example 1-D-105, the desired compound was obtained (219 mg, 41%).