Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C:6]([CH3:11])=[C:5]2[CH2:12][C:13]([OH:15])=[O:14].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH:21]=O.C[O-].[Na+].Cl>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:21]\[C:20]1[CH:23]=[C:24]([O:28][CH3:29])[C:25]([O:26][CH3:27])=[C:18]([O:17][CH3:16])[CH:19]=1)/[C:6]([CH3:11])=[C:5]2[CH2:12][C:13]([OH:15])=[O:14]
Reactant: CC1=C(CC(=O)O)c2cc(F)ccc2C1
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1cc(/C=C2/C(C)=C(CC(=O)O)c3cc(F)ccc32)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 6 h

Procedure:
5-fluoro-2-methyl-3-indenylacetic acid (15 g, 0.072 mol), 3,4,5-trimethoxybenzaldehyde (17.85 g, 0.091 mol) and sodium methoxide (13.0 g, 0.24 mol) are heated in methanol (200 ml) at 60° C. under nitrogen with stirring for 6 hours. After cooling, the reaction mixture is poured into 750 ml of ice-water, and is acidified with 2.5 N hydrochloric acid. The collected solid is triturated with a little ether to produce (Z)-5-fluoro-2-methyl-1-(3,4,5-trimethoxybenzylidene)-3-indenylacetic acid (M .P. 166-169° C.).
Reaction SMILES: [Na].[C:2]1([NH:8][NH2:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10](#[N:19])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[NH2:19][C:10]1[CH2:11][CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:9]=1
Reactant: N#CC=Cc1ccccc1
Reactant: NNc1ccccc1
Agent: [Na]
Solvent: CCO
Product: NC1=NN(c2ccccc2)C(c2ccccc2)C1
Reaction time: 0.08 h

Procedure:
A 2.0 g. amount of sodium metal is dissolved in 150 ml. of absolute ethanol, then 40.0 ml. of phenylhydrazine is added followed in 5 minutes by 48.0 ml. of cinnamonitrile. The reaction mixture is refluxed for 3 hours with exothermic crystallization of a product. The product is collected by filtration and washed with water. The material is recrystallized from absolute ethanol to give 56.0 g. of the desired product as a solid, m.p. 195°-197° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]=[CH:17][CH:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.[CH3:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][N:30]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[N:31]1.C([O-])([O-])=O.[K+].[K+]>COCCOC.CCOC(C)=O.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>[F:22][C:21]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][CH:17]=[N:18]2)=[CH:13][C:12]=1[CH2:11][C:8]1[N:6]2[N:7]=[C:2]([C:33]3[CH:32]=[N:31][N:30]([CH2:29][CH2:28][O:27][CH2:26][CH2:25][O:24][CH3:23])[CH:34]=3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: COCCOCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Fc1cc2ncccc2cc1Cc1cnc2ccc(Cl)nn12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COCCOCCn1cc(-c2ccc3ncc(Cc4cc5cccnc5cc4F)n3n2)cn1
Temperature: 95 °C
Reaction time: 1 h

Procedure:
A mixture of 6-(6-chloro-imidazo[1,2-b]pyridazin-3-ylmethyl)-7-fluoro-quinoline (Stage 173.1, 50 mg, 0.160 mmol), 1-[2-(2-methoxy-ethoxy)-ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (Stage 233.1, 47 mg, 0.160 mmol), Pd(PPh3)2Cl2 (6 mg, 0.008 mmol) and 2 M K2CO3 (216 μL, 0.432 mmol) in DME (1 mL) was stirred at 95° C. for 1 h. The mixture was diluted with EtOAc and washed with NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified twice by flash chromatography (CombiFlash® Companion System®, with a 4 g RediSep® silica gel column, DCM/(DCM/MeOH 19:1)=100:0→0:100) to afford the title compound as a foam (tR 3.56 min (conditions 3), MH+=447.1, 1H-NMR in DMSO-d6: 8.84 (m, 1H); 8.42 (s, 1H); 8.33 (d, 1H); 8.08 (m, 2H); 8.01 (d, 1H); 7.76 (d, 1H); 7.61 (s, 1H); 7.52 (d, 1H); 7.46 (dd, 1H); 4.55 (s, 2H); 4.31 (t, 2H); 3.79 (t, 2H); 3.50 (m, 2H); 3.36 (m, 2H); 3.15 (s, 3H)).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1.O>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Reactant: Clc1ccnc(Cl)n1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ccnc(Cl)n2)C1
Temperature: 90 °C
Yield: 68.5 %

Procedure:
A solution of 2,4-dichloropyrimidine (2.0 g, 13.4 mmol), (R)-tert-butyl 3-aminopiperidine-1-carboxylate (2.7 g, 13.5 mmol) and NN-diisopropylethylamine (2.3 mL, 13.4 mmol) in N,N′-dimethylformamide (15 mL) was stirred and heated overnight at 90° C. After cooling to ambient temperature, water was added and the resulting mixture was extracted with ethyl acetate. The organic phase was washed with water and brine, dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography (2:1 hexanes/ethyl acetate) to give the title compound (2.87 g, 68%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][CH:19]=2)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:10])=[O:9].[OH:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[CH2:33][CH2:32][CH2:31][CH2:30]2>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17]([C:18]2[CH:19]=[CH:20][C:21]([CH2:24][O:26][C:27]3[CH:36]=[CH:35][C:34]4[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=4[CH:28]=3)=[CH:22][CH:23]=2)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:9])=[O:10]
Reactant: Oc1ccc2c(c1)CCCC2
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1Cl
Product: O=S(=O)(Nc1nccnc1-c1ccc(COc2ccc3c(c2)CCCC3)cc1)c1ccccc1Cl
Yield: 69 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from 2-chloro-N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}benzenesulfonamide (Intermediate 8), and 6-hydroxy-1,2,3,4-tetrahydronaphtalene, the title compound was isolated as a yellow solid in 69% yield (99% purity by HPLC).
Reaction SMILES: [Cl:1][C:2]1[C:3]([SH:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[C:12](OC(=O)C)(=[O:14])[CH3:13].Cl>C(O)(=O)C>[C:12]([S:11][C:3]1[C:2]([Cl:1])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1cccc(Cl)c1S
Agent: Cl
Solvent: CC(=O)O
Product: CC(=O)Sc1c(Cl)cccc1C(=O)O

Procedure:
3-Chloro-2-mercaptobenzoic acid (9.8 g, 52 mmol), acetic anhydride (6.3 g, 62 mmol) and glacial acetic acid (22 ml) were heated at 80° C. for 4 hours, then cooled and mixed with dilute hydrochloric acid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)(=O)=O)[N:3]=1.[CH2:19]([OH:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:27][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:3]=1
Reactant: OCCc1ccccc1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(OCCc2ccccc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, phenethyl alcohol and DBU in DME. EI-MS m/e (%): 306 (M+, 4), 202 ([M—C6H5CH═CH2]+, 48), 104 (21).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:19](=[O:24])C(F)(F)F)=[CH:7][N:8]2[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=2)=[CH:4][CH:3]=1.[OH-:25].[Na+]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:19]([OH:24])=[O:25])=[CH:7][N:8]2[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=2)=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: O=C(c1cn(-c2cc(F)cc(F)c2)c2cc(Cl)ccc12)C(F)(F)F
Agent: [Na+]
Product: O=C(O)c1cn(-c2cc(F)cc(F)c2)c2cc(Cl)ccc12
Temperature: 70 °C
Reaction time: 48 h
Yield: 70 %

Procedure:
A suspension of 1-[6-chloro-1-(3,5-difluoro-phenyl)-1H-indol-3-yl]-2,2,2-trifluoro-ethanone in 3N aqueous NaOH was stirred at 70° C. for 48 h. After washing with CH2Cl2, the aqueous phase was acidified to pH 1 and extracted with CH2Cl2. Concentration in vacuo gave the title compound in 70% yield.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][C@H:3]([CH2:7][NH:8][C:9]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][N:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:21][CH:20]=3)[N:10]=2)[CH2:2]1.Br[C:32]1[N:37]=[CH:36][CH:35]=[CH:34][N:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[O:28]1[CH2:29][CH2:30][N:25]([C:22]2[CH:21]=[CH:20][C:19]([C:11]3[N:10]=[C:9]([NH:8][CH2:7][C@H:3]4[O:4][CH2:5][CH2:6][N:1]([C:32]5[N:37]=[CH:36][CH:35]=[CH:34][N:33]=5)[CH2:2]4)[C:18]4[C:13](=[N:14][CH:15]=[CH:16][N:17]=4)[CH:12]=3)=[CH:24][CH:23]=2)[CH2:26][CH2:27]1
Reactant: Brc1ncccn1
Reactant: c1cnc2c(NC[C@@H]3CNCCO3)nc(-c3ccc(N4CCOCC4)cc3)cc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: c1cnc(N2CCO[C@H](CNc3nc(-c4ccc(N5CCOCC5)cc4)cc4nccnc34)C2)nc1

Procedure:
A solution of (S)—N-(morpholin-2-ylmethyl)-7-(4-morpholinophenyl)pyrido[4,3-b]pyrazin-5-amine (100 mg, 0.246 mmol), 2-bromopyrimidine (59 mg, 0.37 mmol) and cesiumcarbonate (193 mg, 0.592 mmol) in DMF (2 mL) was heated at 100° C. in a sealed tube for overnight. Then the mixture was extracted with EA, washed with brine, concentrated and purified by flash column chromatography, eluting with DCM/MeOH to give product as light yellow solid. MS (m/z): 485 (M+H)+
Reaction SMILES: [CH2:1]([N:19]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:20](Cl)=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH:41][CH2:42][CH2:43][N:44]([CH2:48][CH2:49][OH:50])[CH2:45][CH2:46][NH2:47]>C1C=CC=CC=1>[CH2:1]([N:19]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:20]([NH:47][CH2:46][CH2:45][N:44]([CH2:48][CH2:49][OH:50])[CH2:43][CH2:42][OH:41])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)Cl
Reactant: NCCN(CCO)CCO
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)NCCN(CCO)CCO
Reaction time: 3 h
Yield: 95.5 %

Procedure:
A mixture of N,N-dioctadecylcarbamyl chloride (2.9 g.), N,N-bis-(2-hydroxyethyl)-1,2-ethanediamine (4.0 g.) and benzene (50 ml.) is refluxed and stirred for three hours. The mixture is then cooled, concentrated in vacuo and the residue taken up on chloroform (100 ml.). The chloroform solution is washed successively with water (2×50 ml.), aqueous sodium hydroxide (1×50 ml. of 1N) and water (2×50 ml.), then dried (Na2SO4). Removal of the chloroform in vacuo leaves the crude product as an oil (3.3 g.).
Reaction SMILES: [F:1][C:2]1([F:25])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH:16]=[CH:15][C:14](=[O:17])[C:13]([C:18](=O)/[CH:19]=[CH:20]/N(C)C)=[N:12]3)=[CH:10][C:4]=2[O:3]1.[F:26][C:27]1([F:38])[O:31][C:30]2[CH:32]=[CH:33][CH:34]=[C:35]([NH:36][NH2:37])[C:29]=2[O:28]1.N([O-])=O.[Na+].[Sn](Cl)Cl>>[F:25][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH:16]=[CH:15][C:14](=[O:17])[C:13]([C:18]4[N:36]([C:35]5[C:29]6[O:28][C:27]([F:26])([F:38])[O:31][C:30]=6[CH:32]=[CH:33][CH:34]=5)[N:37]=[CH:20][CH:19]=4)=[N:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: NNc1cccc2c1OC(F)(F)O2
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc3c(c2)OC(F)(F)O3)ccc1=O
Agent: Cl[Sn]Cl
Agent: O=N[O-]
Agent: [Na+]
Product: O=c1ccn(-c2ccc3c(c2)OC(F)(F)O3)nc1-c1ccnn1-c1cccc2c1OC(F)(F)O2

Procedure:
The product was obtained starting from 1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-11) and 2,2-difluoro-benzo[1,3]dioxol-4-yl-hydrazine (prepared from the corresponding amino derivative using sodium nitrite and tin(II) chloride as described in J. Med. Chem. 2003, 46, 4676-4686) according to the method described for example 91. MS: M=475.0 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH:4](Br)[CH2:5][CH2:6][CH2:7][CH3:8].[F:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][C:13]=1[CH3:19].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3](=[O:10])[CH:4]([S:18][C:15]1[CH:16]=[CH:17][C:12]([F:11])=[C:13]([CH3:19])[CH:14]=1)[CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: Cc1cc(S)ccc1F
Reactant: CCCCC(Br)C(=O)OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(Sc1ccc(F)c(C)c1)C(=O)OC
Temperature: 25 °C
Reaction time: 46 h
Yield: 91.7 %

Procedure:
To a solution of 2-bromo-hexanoic acid methyl ester (0.500 g, 2.404 mmol) and 4-fluoro-3-methyl-benzenethiol (0.340 g, 2.404 mmol) in 20 mL of dichloromethane, was added triethylamine (3.3 mL, 12.020 mmol). After stirring at room temperature under N2 for 46 h, the reaction mixture was diluted with dichloromethane and washed with 1N HCl and brine. The organic layer dried over anhydrous Na2SO4. After removing the solvent under reduced pressure, the product was isolated by Flash chromatography (silica gel) eluting with 0-20% ethyl acetate/hexanes to give the title compound as colorless oil (0.596 g, 92% yield). LC-MS: tR=11.2 min; m/z 271 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[CH:2]1.[Br-].[C:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:11])=[O:10]>>[S:1]1[CH:5]=[CH:4][C:3]([CH:6]=[CH:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:9]([OH:11])=[O:10])=[CH:2]1
Reactant: O=Cc1ccsc1
Reactant: O=C(O)CCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: O=C(O)CCCCCCCC=Cc1ccsc1

Procedure:
Reaction of 3-thiophenecarboxaldehyde with (8-carboxy-octyl)-triphenyl-phosphonium bromide, in analogy with example 34, step 2, produced 10-(thiophen-3-yl)-dec-9-enoic acid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[F:10][C:11]([F:22])([F:21])[C:12]([N:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1)=[O:13].C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][CH:17]2[CH2:18][CH2:19][N:14]([C:12](=[O:13])[C:11]([F:10])([F:21])[F:22])[CH2:15][CH2:16]2)=[CH:4][CH:3]=1
Reactant: NCc1ccc(F)cc1
Reactant: O=C1CCN(C(=O)C(F)(F)F)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(N1CCC(NCc2ccc(F)cc2)CC1)C(F)(F)F
Reaction time: 0.08 h
Yield: 36.9 %

Procedure:
4-Fluorobenzylamine (3.14 g, 25.9 mmol) was dissolved in methanol (150 mL). 1-(trifluoroacetyl)-4-piperidone (5.07 g, 25.9 mmol) was added and the pH was adjusted to ˜5 with acetic acid. The reaction mixture was stirred for 5 min and NaBH3CN (2.46 g, 38.9 mmol) was added slowly under stirring. After 20 h at room temperature the reaction was concentrated 2 M NaOH (100 mL) was added and the aqueous phase was extracted with dichloromethane (2×100 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated to give N-(4-fluorobenzyl)-1-(trifluoroacetyl)piperidin-4-amine (50ELH85, 2.91 g, 37%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][C:8]([OH:10])=[O:9])[CH2:2]1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.Br[CH2:30][CH:31]([C:33]1[CH:38]=[CH:37][C:36]([C:39]2[N:43]=[C:42]([C:44]3[C:48]([CH2:49][CH2:50][CH3:51])=[C:47]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[O:46][N:45]=3)[O:41][N:40]=2)=[CH:35][CH:34]=1)[OH:32].CCN(C(N1N=NN(C2C(Cl)=CC=CC=2)C1=O)=O)C1CCCCC1>CS(C)=O.CO>[OH:32][CH:31]([C:33]1[CH:38]=[CH:37][C:36]([C:39]2[N:43]=[C:42]([C:44]3[C:48]([CH2:49][CH2:50][CH3:51])=[C:47]([C:52]4[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=4)[O:46][N:45]=3)[O:41][N:40]=2)=[CH:35][CH:34]=1)[CH2:30][N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][C:8]([OH:10])=[O:9])[CH2:2]1
Reactant: CCCc1c(-c2nc(-c3ccc(C(O)CBr)cc3)no2)noc1-c1ccccc1
Reactant: O=C(O)CC1CCCNC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN(C(=O)n1nnn(-c2ccccc2Cl)c1=O)C1CCCCC1
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CO
Product: CCCc1c(-c2nc(-c3ccc(C(O)CN4CCCC(CC(=O)O)C4)cc3)no2)noc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-(piperidin-3-yl)acetic acid (51 mg, 0.36 mmol) in 0.5 mL dry DMSO was added tetrabutylammonium hydroxide (0.360 mL, 360 μmol, 1M in THF) and the reaction mixture was stirred at room temperature for 15 min. 2-bromo-1-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethanol, Preparation 1C (30 mg, 0.066 mmol) was dissolved in 0.5 mL DMSO and added and the reaction mixture was agitated at 400 rpm on an INNOVA® platform shaker at 80° C. for 1.5 hours. The reaction was diluted with 250 μL of MeOH and purified by HPLC (MeOH—H2O-TFA) to give 2-(1-(2-hydroxy-2-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl)acetic acid. MS (m+1)=517. HPLC RT=2.08 min using a Waters Masslynx instrument equipped with a 19×100 mm 5 uM C18 column and a method of 0-100% B solvent over 15 min at a flow rate of 20 mL/min. Solvent A is 5:95 acetonitrile/water; solvent B is 95:5 acetonitrile/water and both contain 0.5% TFA.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[S:12]([CH2:15][CH2:16][NH:17][CH2:18][C:19]1O[CH:21]=[CH:22][CH:23]=1)(=[O:14])=[O:13].ClC1C2C(=CC=CC=2)C=CC=1[S:35]CCNCC1SC=CC=1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[S:12]([CH2:15][CH2:16][NH:17][CH2:18][C:19]1[S:35][CH:21]=[CH:22][CH:23]=1)(=[O:14])=[O:13]
Reactant: O=S(=O)(CCNCc1ccco1)c1ccc2ccccc2c1Cl
Reactant: Clc1c(SCCNCc2cccs2)ccc2ccccc12
Product: O=S(=O)(CCNCc1cccs1)c1ccc2ccccc2c1Cl
Yield: 68 %

Procedure:
Prepared as described for compound 25 from 2-[(1-chloronaphthalen-2-yl)sulfanyl]-N-(thiophen-2-ylmethyl)ethanamine in 68% yield as yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[CH:8][NH:9][C:10]([C:11]3[CH:15]=[CH:14][N:13]([CH3:16])[N:12]=3)=[C:6]2[C:5](=[O:17])[N:4]([CH3:18])[C:3]1=[O:19].Br[CH2:21][CH2:22][CH2:23][C:24]([N:26]([O:28][CH3:29])[CH3:27])=[O:25].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:1][N:2]1[C:7]2=[CH:8][N:9]([CH2:21][CH2:22][CH2:23][C:24]([N:26]([O:28][CH3:29])[CH3:27])=[O:25])[C:10]([C:11]3[CH:15]=[CH:14][N:13]([CH3:16])[N:12]=3)=[C:6]2[C:5](=[O:17])[N:4]([CH3:18])[C:3]1=[O:19]
Reactant: CON(C)C(=O)CCCBr
Reactant: Cn1ccc(-c2[nH]cc3c2c(=O)n(C)c(=O)n3C)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)CCCn1cc2c(c1-c1ccn(C)n1)c(=O)n(C)c(=O)n2C
Temperature: 25 °C
Reaction time: 22 h

Procedure:
1,3-Dimethyl-5-(1-methyl-1H-pyrazol-3-yl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (800 mg, 3.09 mmol), 4-bromo-N-methoxy-N-methylbutanamide (Intermediate P) (843 mg, 4.01 mmol) and cesium carbonate (2011 mg, 6.17 mmol) were suspended in DMF (11.100 ml) and the mixture was stirred at room temperature for 22 hours. The mixture was poured into water (50 ml) and extracted with DCM (3×100 ml). The combined organic extracts were washed with water (2×50 ml) and brine (50 ml), dried over sodium sulfate and evaporated under vacuum. Purification by mass-directed HPLC under the following conditions afforded the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[NH3:15].O>CS(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:6]([NH2:15])[CH:7]=1
Reactant: N
Reactant: Clc1cc(Cl)nc(-c2ccccc2)n1
Solvent: O
Solvent: CS(C)=O
Product: Nc1cc(Cl)nc(-c2ccccc2)n1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
An ice-cold suspension of pyrimidine 3 (44.34 g; 0.197 mol) in DMSO (366 mL) was saturated with ammonia, during which time a solution formed. After 24 h at rt, water (710 mL) was added dropwise. The suspension was cooled in an ice bath for 1 h then collected by filtration and washed with water (500 mL), yielding a light tan powder after drying in vacuo (37.84 g; 93%). LC (method B) tR=16.0 min; 1H NMR (200 MHz, CDCl3) δ 8.33 (m, 2H), 8.44 (m, 3H), 6.32 (s, 1H), 5.12 (brs, 2H); 13C NMR (50.3 MHz, CDCl3) δ 165.1, 164.0, 160.5, 136.7, 131.0, 128.4, 128.4, 101.4; ESIMS 205.9/207.8 (100/34) [MH+].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:14][C:9]2[N:10]=N[CH:12]=[CH:13][C:8]=2[C:7]=1[OH:15])=[O:5])[CH3:2].[CH2:16](OC(=O)C1C=CC(C)=NC=1Cl)[CH3:17]>>[CH2:1]([O:3][C:4]([C:6]1[O:14][C:9]2=[N:10][C:16]([CH3:17])=[CH:12][CH:13]=[C:8]2[C:7]=1[OH:15])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(C)nc1Cl
Reactant: CCOC(=O)c1oc2nnccc2c1O
Product: CCOC(=O)c1oc2nc(C)ccc2c1O

Procedure:
This compound was prepared using a method analogous to that of 5-hydroxyfuro[2,3-c]pyridazine-6-carboxylic acid ethyl ester (A.2.3.1), 2-chloro-6-methylnicotinic acid ethyl ester replacing 3-chloropyridazine-4-carboxylic acid ethyl ester;
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[CH3:17]O>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[CH:4][C:5]([C:6]([O:8][CH3:17])=[O:7])=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12]
Reactant: CO
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 89 %

Procedure:
4-Chloro-3,5-dinitrobenzoic acid (25.0 gm.) is dissolved in a cooled solution of methanol (125 ml.) and concentrated sulfuric acid (3.0 ml.). The reaction mixture is allowed to warm to room temperature and then heated to reflux for 18 hours. The product precipitated as light yellow needles on cooling, which are collected by filtration and washed with 15 ml. of methanol (24.0 gm., m. p. 102°-104.5°). Recrystallization from methanol gives light yellow needles (23.6 g., m.p. 104°-105.5°, 89% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:10])[CH:5]=[CH:6][C:7]=1[O:8]C.B(Br)(Br)Br.O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([SH:10])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc(S)cc1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Oc1ccc(S)cc1Cl
Temperature: 0 °C
Reaction time: 20 h
Yield: 97.9 %

Procedure:
324 mg of said di(3-chloro-4-methoxyphenyl)disulfide was dissolved in 10 ml of ethanol, followed by addition of 106 mg of sodium borohydride. The mixture was stirred over 2 hours at room temperature. The solution thus reacted was made weakly acidic by addition of dilute hydrochloric acid. The product was extracted twice with ethyl acetate. The organic layer was washed with saturated salt water and then dried over sodium sulfate anhydride. The solvent was distilled out under reduced pressure. The resulting crude product was purified by flash column chromatography (hexane:ethyl acetate=15:1), whereby 239 mg of 3-chloro-4-methoxybenzenethiol was obtained. 231 mg of the resulting 3-chloro-4-methoxybenzenethiol was dissolved in 4 ml dichloromethane, followed by cooling to 0° C. 4 ml of boron tribromide in dichloromethane was added dropwise under stirring. The mixture was stirred for 2 hours under cooling on ice and then for 20 hours at room temperature. Subsequently, under cooling on ice, water was added to the solution thus reacted, and the product was extracted twice with chloroform. The organic layer was washed with saturated salt water and dried over sodium sulfate anhydride. The solvent was distilled out, whereby 208 mg of crude 3-chloro-4-hydroxybenzenethiol was obtained.