Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.[Br-].[CH2:7]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[CH:37]([C:39]1[CH:40]=[N:41][N:42]([CH:44]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH:43]=1)=O>C1COCC1>[CH:37]([C:39]1[CH:40]=[N:41][N:42]([CH:44]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH:43]=1)=[CH:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH3:7]
Reactant: CCOC(=O)C(c1ccccc1)n1cc(C=O)cn1
Reactant: CCCCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCC=Cc1cnn(C(C(=O)OCC)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of n-BuLi (127 mL, 254 mmol, 2.0M in hexanes) was added dropwise to a suspension of n-undecyl-triphenylphosphonium bromide (121.6 g, 244 mmol, obtained from triphenylphosphine and undecylbromide) in 500 mL THF at -78° C. under an atmosphere of N2. The resulting orange solution was stirred for 1 hour before a solution of ethyl (±)-4-formyl-α-phenyl-1H-pyrazole-1-acetate in 250 mL THF was added dropwise. Warmed to room temperature and stirred for 16 hours. Quenched by adding 150 mL water and concentrating in vacuo. The residue was partitioned between water and dichloromethane. The organic layer was dried over MgSO4, filtered, and concentrated to give an oily tan solid. Triturated with boiling hexanes and filtered to remove triphenylphosphine oxide. The filtrate was concentrated and chromatographed (10% EtOAc/hexanes on silica) to give the title compound as a yellow oil, a 1:2 E/Z mixture (44.4 g, 50%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[CH3:15][N:16](C)C=O.C(N)CN>O>[C:15]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)#[N:16]
Reactant: CN(C)C=O
Reactant: O=c1ccc(-c2ccc(Br)cc2)n[nH]1
Solvent: NCCN
Solvent: O
Product: N#Cc1ccc(-c2ccc(=O)[nH]n2)cc1
Reaction time: 0.5 h

Procedure:
A 19.20 g. portion of 6-(p-bromophenyl)-3(2H)-pyridazinone is mixed with 9.10 g. of cuprous cyanide in 70 ml. of dimethylformamide and stirred at reflux temperature for 12 hours. The hot mixture is poured into a solution of 46 ml. of ethylenediamine in 230 ml. of water. The mixture is stirred at ice-bath temperature for 30 minutes and the solid is separated by filtration. A second crop forms in the filtrate which is collected and added to the first crop which is then washed with water yielding 6-(p-cyanophenyl)-3(2H)-pyridazinone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](O)=[O:11])=[CH:5][C:4]=1[S:13][CH3:14].C(Cl)(=O)C([Cl:18])=O.CN(C)C=O>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([Cl:18])=[O:11])=[CH:5][C:4]=1[S:13][CH3:14]
Reactant: COc1ccc(CC(=O)O)cc1SC
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(CC(=O)Cl)cc1SC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-methoxy-3-(methylthio)phenylacetic acid (10.2 g, 47.3 mmol) in THF (300 mL) was added oxalyl chloride (6.6 g, 52 mmol, 1.1 equivalent) followed by a catalytic amount of N,N-dimethylformamide (DMF) (~0.5 mL). The reaction mixture was stirred at ambient temperature for 3 h and then concentrated under reduced pressure to give the title compound as a yellow oil. The product was used without purification.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][NH:18][C:19](=[O:31])[C:20]([C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][CH:23]=3)=[O:21])[N:13]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)[CH2:12][C:11]=2[S:10][C:9]=1[NH2:41])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:42]([O:46][C:47](=[O:55])[C:48](N1C=CN=C1)=[O:49])([CH3:45])([CH3:44])[CH3:43]>ClCCl>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][NH:18][C:19](=[O:31])[C:20]([C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][CH:23]=3)=[O:21])[N:13]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)[CH2:12][C:11]=2[S:10][C:9]=1[NH:41][C:48](=[O:49])[C:47]([O:46][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:55])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(CN2Cc3sc(N)c(C(=O)OC(C)(C)C)c3CC2CNC(=O)C(=O)c2c[nH]c3ccccc23)cc1
Reactant: CC(C)(C)OC(=O)C(=O)n1ccnc1
Solvent: ClCCl
Product: COc1ccc(CN2Cc3sc(NC(=O)C(=O)OC(C)(C)C)c(C(=O)OC(C)(C)C)c3CC2CNC(=O)C(=O)c2c[nH]c3ccccc23)cc1
Reaction time: 24 h
Yield: 57.5 %

Procedure:
To a solution of 2-amino-5-((2-(1H-indol-3-yl)-2-oxo-acetylamino)methyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (143 mg, 0.25 mmol) in dichloromethane (5 ml) was added imidazol-1-yl-oxo-acetic acid tert-butyl ester (144 mg, 0.75 mmol) and the flask was purged with nitrogen. After 24 hours an additional portion of imidazol-1-yl-oxo-acetic acid tert-butyl ester (169 mg, 0.86 mmol) was added and the reaction mixture allowed stirred for an additional 24 hours. The mixture was then concentrated in vacuo. The residue was purified by flash chromatography using a mixture of ethyl acetate/hexanes (2:5) as eluent, which afforded 101 mg (58%) of 2-(tert-butyoxyoxalyl-amino)-5-((2-(1H-indol-3-yl)-2-oxo-acetylamino)methyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as a oil.
Reaction SMILES: [CH2:1]([NH:10][C:11](=O)[CH3:12])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:23]2)=CC=1>C1(C)C=CC=CC=1>[CH3:12][C:11]1[S:23][C:2]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:1][N:10]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(=O)NCC(=O)c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1ncc(-c2ccccc2)s1
Yield: 31.4 %

Procedure:
A mixture of N-phenacylacetamide (0.70 g, 4 mmol), 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulphide (Lawesson's reagent) (0.80 g, 2 mmol) and toluene (10 ml) was heated for 1.5 h at reflux and then evaporated under reduced pressure. The residue was purified by chromatography (10 g silica, dichloromethane) to give 2-methyl-5-phenylthiazole as a yellowish solid (0.11 g, 16%) m.p. 72°-4° C.; δH (CDCl3) 7.85 (1H, S, CH), 7.3-7.7 (5H, m, C6H5), 2.7 (3H, S, CH3).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:32]([O:34]C)=[O:33])[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH-].[Na+]>O1CCCC1.CO>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:32]([OH:34])=[O:33])[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=3)(=[O:22])=[O:23])[CH2:17][CH2:16]2)(=[O:13])=[O:14])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCN(S(=O)(=O)c3ccc(OC)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(S(=O)(=O)c3ccc(OC)cc3)CC2)cc1

Procedure:
4-(4-But-2-ynyloxybenzenesulfonyl)-1-[(4-methoxyphenyl)sulfonyl]-4-piperidine carboxylic acid was prepared following the procedure of Example 64 (step 5). Starting from methyl 4-(4-but-2-ynyloxybenzenesulfonyl)-1-[(4-methoxyphenyl)sulfonyl]-4-piperidinecarboxylate (545 mg, 1.04 mmol) in 8 ml of tetrahydrofuran:methanol (1:1), and 1N sodium hydroxide (2.09 ml, 2.09 mmol) to obtain 446 mg (85%) of the acid. HR-MS: m/z Calculated for C23H25NO8S2 508.1094; Found 508.1073.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][C:17]([S:20][C:21]2[CH:26]=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:24]([OH:31])=[C:23]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:22]=2)([CH3:19])[CH3:18])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[CH2:36]([O:38][CH:39]1[O:43][C@H:42]([CH2:44]O)[C@@H:41]([CH2:46][OH:47])[O:40]1)[CH3:37]>>[C:12]([C:9]1[CH:8]=[C:7]([S:16][C:17]([S:20][C:21]2[CH:22]=[C:23]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:24]([O:31][CH2:44][C@@H:42]3[C@@H:41]([CH2:46][OH:47])[O:40][CH:39]([O:38][CH2:36][CH3:37])[O:43]3)=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:26]=2)([CH3:18])[CH3:19])[CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:13])([CH3:14])[CH3:15]
Reactant: CCOC1O[C@H](CO)[C@@H](CO)O1
Reactant: CC(C)(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Product: CCOC1O[C@H](CO)[C@@H](COc2c(C(C)(C)C)cc(SC(C)(C)Sc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)cc2C(C)(C)C)O1

Procedure:
The title compound was prepared using the same procedure as described in Ex-1A starting from probucol and 2-ethoxy-1,3-dioxolane-4(R),5(R)-dimethanol as a white solid (10.3 g, 35%), mp 60–62° C. 1H-NMR (300 MHz, CDCl3) δ 7.56 (s, 2H), 7.44 (s, 2H), 5.89 (s, 1H), 5.36 (s, 1H), 4.75–4.78 (m, 1H), 4.19–4.24 (m, 2H), 3.92–3.99 (m, 2H), 3.84 (dd, 1H, J=10.0, 4.2 Hz), 3.60–3.74 (m, 2H), 2.79 (dd, 1H, J=9.1, 3.3 Hz). 1.43–1.45 (m, 42H), 1.28 (t, 3H, J=7.2 Hz). HRMS (ESI) calcd for C38H60O6S2 (M+Na), 699.3729; found, 699.3756. Anal. calcd. for C38H60O6S2: C, 67.42, H, 8.93, S, 9.47; found: C, 67.04, H, 9.00, S, 8.86.
Reaction SMILES: [OH-].[NH4+:2].Cl[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)=[O:5]>>[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)(=[O:5])[NH2:2]
Reactant: CCOC(=O)C[C@H]1CC[C@H](c2ccc(C(=O)Cl)cc2)CC1
Reactant: [NH4+]
Agent: [OH-]
Product: CCOC(=O)C[C@H]1CC[C@H](c2ccc(C(N)=O)cc2)CC1

Procedure:
Ammonium hydroxide (large excess) was added to the product from Example 1C (8.43 g. 27.3 mmol) at room temperature. White solids precipitated out and were collected by filtration and washed with water to afford the title compound (7.9 g, 100%) as a white solid which was taken on to the next step-without further purification. MS (DCI) m/z 290.1 [M+H]+.
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][CH:7]([C:10]2[N:14]([CH3:15])[N:13]=[CH:12][C:11]=2[NH:16][C:17]([C:19]2[N:20]=[C:21]([C:32]3[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=3[F:39])[S:22][C:23]=2[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:18])[CH2:6][CH2:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[NH2:1][CH:4]1[CH2:5][CH2:6][CH:7]([C:10]2[N:14]([CH3:15])[N:13]=[CH:12][C:11]=2[NH:16][C:17]([C:19]2[N:20]=[C:21]([C:32]3[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=3[F:39])[S:22][C:23]=2[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:18])[CH2:8][CH2:9]1
Reactant: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1C1CCC(N=[N+]=[N-])CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1C1CCC(N)CC1
Temperature: 60 °C

Procedure:
tert-Butyl 4-(5-(4-azidocyclohexyl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-(2,6-difluorophenyl)thiazol-5-ylcarbamate (18 mg, 0.032 mmol) was dissolved in THF (2 mL) and water (0.5 mL). Triphenylphosphine (21.5 mg, 0.083 mmol) was added and the mixture was heated at 60° C. overnight. After cooling to room temperature, the reaction was quenched with water and extracted with methylene chloride three times to give the crude product tert-butyl 4-(5-(4-aminocyclohexyl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-(2,6-difluorophenyl)thiazol-5-ylcarbamate.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:7][C@H:8]1[CH2:15][C:14]2[C:9]1=[CH:10][C:11]([O:18][CH3:19])=[C:12]([O:16][CH3:17])[CH:13]=2)[CH3:6].[C:20]([OH:25])(=[O:24])[C:21]([OH:23])=[O:22]>C(OCC)(=O)C.C(O)C>[C:20]([OH:25])(=[O:24])[C:21]([OH:23])=[O:22].[Cl:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:7][C@H:8]1[CH2:15][C:14]2[C:9]1=[CH:10][C:11]([O:18][CH3:19])=[C:12]([O:16][CH3:17])[CH:13]=2)[CH2:6][CH3:20]
Reactant: COc1cc2c(cc1OC)[C@@H](CN(C)CCCCl)C2
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCN(CCCCl)C[C@H]1Cc2cc(OC)c(OC)cc21
Yield: 116.6 %

Procedure:
To a solution of 3-chloro-N-{[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}-N-methyl-1-propanamine (19.8 g, 69.8 mmoles) in 60 mL of ethyl acetate heated at reflux there is added a solution of oxalic acid (6.91 g, 76.7 mmoles) in 60 mL of ethanol. Precipitation from the mixture occurs during contact at reflux. After returning to ambient temperature, the mixture is filtered and washed with 20 mL of ethanol to obtain 17.35 g of a brown powder corresponding to the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[C:19]1([CH2:18][O:1][C:2]2[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:8][C:4]3[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=3)=[O:10])[CH:5]=[CH:6][CH:7]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Cc1cccc(OCc2ccccc2)c1)OCc1ccccc1
Reaction time: 8 h
Yield: 198.6 %

Procedure:
To a solution of 3-hydroxyphenyl acetic acid (5.0 g, 0.03 mol) in DMF (25 ml) was added potassium carbonate (12.4 g, 0.09 mol). The reaction was allowed to stir for twenty minutes at which time benzyl bromide (8.9 ml, 0.075 mol) was added to the flask. The reaction was allowed to stir overnight. Solvent was removed. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to yield the title compound (9.9 g, 99% yield): ES-MS (m/z) 243 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[C:7]([C:20]([OH:22])=O)=[CH:6]2.[OH:25][CH:26]1[CH2:29][N:28]([C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][N:31]=2)[CH2:27]1>>[OH:25][CH:26]1[CH2:29][N:28]([C:30]2[N:31]=[CH:32][C:33]([NH:36][C:20]([C:7]3[N:8]([CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=4)[C:9]4[C:5]([CH:6]=3)=[CH:4][C:3]([C:2]([F:23])([F:1])[F:24])=[CH:11][CH:10]=4)=[O:22])=[CH:34][CH:35]=2)[CH2:27]1
Reactant: Nc1ccc(N2CC(O)C2)nc1
Reactant: O=C(O)c1cc2cc(C(F)(F)F)ccc2n1Cc1cccc(F)c1
Product: O=C(Nc1ccc(N2CC(O)C2)nc1)c1cc2cc(C(F)(F)F)ccc2n1Cc1cccc(F)c1

Procedure:
The process is carried out according to the method described in example 2, using 5-trifluoromethyl-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid (WO 2006/072736) and 2-(3-hydroxyazetidin-1-yl)-5-aminopyridine, prepared in step 10.2 of example 10 (Compound Ve).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[O:11]1[CH2:16][CH2:15][CH:14]([CH:17]([C:20]2[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][CH:25]=2)[CH2:18][NH2:19])[CH2:13][CH2:12]1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:19][CH2:18][CH:17]([CH:14]1[CH2:15][CH2:16][O:11][CH2:12][CH2:13]1)[C:20]1[CH:21]=[N:22][C:23]([C:26]([F:28])([F:29])[F:27])=[N:24][CH:25]=1)=[O:6]
Reactant: O=C(O)c1ccccc1Cl
Reactant: NCC(c1cnc(C(F)(F)F)nc1)C1CCOCC1
Product: O=C(NCC(c1cnc(C(F)(F)F)nc1)C1CCOCC1)c1ccccc1Cl

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2-chlorobenzoic acid and 2-(tetrahydro-2H-pyran-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=414.1, tR (minutes, Method F)=2.54. [α]D20=+38.57 (c=2.80 mg/mL,CHCl3)
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[N:8]=1)=O.[F:22][C:23]1[CH:24]=[C:25]([NH:29]N)[CH:26]=[CH:27][CH:28]=1>>[F:20][C:16]1[CH:15]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:29]([C:25]4[CH:26]=[CH:27][CH:28]=[C:23]([F:22])[CH:24]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(F)c2)ccc1=O
Reactant: NNc1cccc(F)c1
Product: O=c1ccn(-c2cccc(F)c2)nc1-c1ccnn1-c1cccc(F)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-fluoro-phenyl)-1H-pyridazin-4-one (A-13) and 3-fluoro-phenylhydrazine according to the method described for example 91. MS: M=351.3 (M+H)+
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].CC[O-].[Na+].Br[CH:21]([CH2:27][CH2:28][CH2:29][CH3:30])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CCO>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[O:15][CH:21]([CH2:27][CH2:28][CH2:29][CH3:30])[C:22]([O:24][CH2:25][CH3:26])=[O:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCC(Br)C(=O)OCC
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCC(Oc1ccc(C(C)(C)C)cc1C(C)(C)C)C(=O)OCC
Temperature: 140 °C
Yield: 98 %

Procedure:
206 g (1 mol) of 2,4-di-tert-butylphenol were melted and heated to 140° C. under nitrogen. 234 g (1.03 mol) of a 30% strength NaOEt solution in EtOH and 245 g (1.1 mol) of ethyl 2-bromocaproate were metered in simultaneously in the course of 1 hour. During the addition, EtOH was distilled off. After the addition, the reaction was ended. The mixture was cooled to 90° C. and 250 ml of water were added. After separation of the phases and washing with 200 ml of water, 347 g of a viscous yellow oil of the following composition (0.3% of ethyl bromocaproate, 0.5% of residual phenol and 98% of ethyl 2-(2,4-di-tert-butylphenoxy)caproate, remained. This corresponds to a yield of 98% of theory, based on the phenol employed.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:20]2([OH:26])[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]2)[CH:17]=[CH:18][CH:19]=1>>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([N:22]1[CH2:23][CH2:24][CH2:25][C:20]([OH:26])([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH3:12])[CH:15]=2)[CH2:21]1)=[O:5]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: COc1cccc(C2(O)CCCNC2)c1
Product: COc1cccc(C2(O)CCCN(C(=O)c3ccc(Cl)cc3Cl)C2)c1

Procedure:
The compound of Example 24 was prepared according to the general preparation protocol A from 2,4-dichlorobenzoyl chloride and 3-(3-methoxy-phenyl)-piperidine-3-ol.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7](=O)[NH:8][N:9]=1)([CH3:3])[CH3:2].P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:7]1[N:8]=[N:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)c1ccc(=O)[nH]n1
Product: CC(C)c1ccc(Cl)nn1

Procedure:
6-Isopropyl-3(2H)-pyridazinone (3.30 g) and phosphorus oxychloride (15.0 ml) were heated for 1 hour under reflux. After an excess of phosphorus oxychloride was distilled away, ice-water (200 ml) was added to the residues which were then adjusted to pH 6 with 20% aqueous sodium hydroxide solution. The reaction solution was extracted 3 times with ethyl acetate, and the extracts were combined, dried over anhydrous magnesium sulfate and concentrated. The residues were purified by silica gel column chromatography (ethyl acetate:chloroform=1:2) to give the title compound as pale red crystals. The yield was 1.60 g (40.8% based on 5-methyl-4-oxohexanoic acid).
Reaction SMILES: [O:1]1[CH:3]2[CH2:4][CH:5]([C:7]([O:9][CH3:10])=[O:8])[CH2:6][CH:2]12.C(=O)([O-])[O-:12].[Na+].[Na+].C(=O)([O-])O.[Na+]>O1CCCC1.O.S(=O)(=O)(O)O>[OH:1][C@@H:3]1[CH2:4][CH:5]([C:7]([O:9][CH3:10])=[O:8])[CH2:6][C@H:2]1[OH:12]
Reactant: COC(=O)C1CC2OC2C1
Reactant: O=C([O-])[O-]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C1C[C@@H](O)[C@H](O)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1,2-Epoxy-4-methoxycarbonylcyclopentane (37.7 g) was dissolved in a mixed solvent of tetrahydrofuran (500 ml) and water (500 ml), and sulfuric acid (13.3 ml) was added dropwise under ice cooling to stir the mixture at room temperature for 4 hours. Sodium carbonate and sodium hydrogencarbonate were added to the reaction mixture to make the mixture neutral or weakly alkaline, and the solvent was distilled off under reduced pressure. The residue was extracted with dichloromethane and ethyl acetate, insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound (35.5 g) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:24]3[CH:25]=[C:20]([Cl:19])[CH:21]=[CH:22][C:23]=3[Cl:26])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: OB(O)c1cc(Cl)ccc1Cl
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3cc(Cl)ccc3Cl)cccc2c1N
Yield: 46.7 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (150 mg, 0.485 mmol) and 2,5-dichloro-phenylboronic acid (190 mg, 1.00 mmol) were reacted to afford the title compound (85 mg, 47% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.52 (br, 1H), 7.99-7.91 (m, 1H), 7.78-7.67 (m, 2H), 7.48-7.31 (m, 3H), 3.45 (apparent quartet, J=7.0 Hz, 2H), 1.65 (apparent sextet, J=7.0 Hz, 2H), 1.00 (t, J=7.0 Hz, 3H). MS APCI, m/z=375 (M+H). HPLC 2.24 min.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#N)=[C:6]([C:12]([F:15])([F:14])[F:13])[CH:5]=1)([O-:3])=[O:2].CC(C[AlH]CC(C)C)C.CO.S(=O)(=O)(O)[OH:28]>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:28])=[C:6]([C:12]([F:15])([F:14])[F:13])[CH:5]=1)([O-:3])=[O:2]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C(F)(F)F
Reactant: O=S(=O)(O)O
Agent: CC(C)C[AlH]CC(C)C
Solvent: CO
Solvent: Cc1ccccc1
Product: O=Cc1ccc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3.75 h

Procedure:
To 4-nitro-2-(trifluoromethyl)benzonitrile (100 mg, 0.463 mmol) in toluene (3 mL) at 0° C. under argon was added DIBAL-H (0.51 mL, 1M in toluene, 0.51 mmol) and the reaction stirred for 3.75 h. MeOH and sulphuric acid were added and the reaction mixture was warmed to room temperature and stirred for 1 h. The mixture was concentrated and the residue was portioned between EtOAc (10 mL) and water (10 mL). The organic phase was dried and concentrated to give the crude product which was purified by column chromatography eluting with 0-15% EtOAc/petroleum ether to give the title compound as a yellow oil (91 mg), δH (CDCl3, 400 MHz) 10.47 (1H, s), 8.66 (1H, d), 8.56 (1H, dd), 8.33 (1H, d).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([O:13]CC)=O)[CH2:8][NH:7][C:6]=2[CH:16]=1.[CH2:17]([NH2:20])[CH:18]=[CH2:19]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([NH:20][CH2:17][CH:18]=[CH2:19])=[O:13])[CH2:8][NH:7][C:6]=2[CH:16]=1
Reactant: C=CCN
Reactant: CCOC(=O)C1CNc2cc(Cl)ccc2O1
Product: C=CCNC(=O)C1CNc2cc(Cl)ccc2O1

Procedure:
3 was prepared as white platelets, mp: 114°-114.5° C., by treating 3A with 2-propenamine by the procedure of Example 1.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=[C:9]3[N:16]([CH2:19][CH3:20])[N:17]=[CH:18][C:8]=23)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[C:35]([NH:38][NH2:39])(=[O:37])[CH3:36]>CN(C=O)C>[C:35]([NH:38][NH:39][C:13]([C:12]1[C:7]([NH:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[C:8]2[CH:18]=[N:17][N:16]([CH2:19][CH3:20])[C:9]2=[N:10][CH:11]=1)=[O:15])(=[O:37])[CH3:36]
Reactant: CCn1ncc2c(NC3CCCC3)c(C(=O)O)cnc21
Reactant: CC(=O)NN
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCn1ncc2c(NC3CCCC3)c(C(=O)NNC(C)=O)cnc21
Reaction time: 0.25 h
Yield: 54.1 %

Procedure:
Intermediate 3 (0.066 g), EDC (0.06 g) and HOBT (0.035 g) were suspended in DMF (2 ml) and the mixture was stirred for 15 minutes. Acetic hydrazide (0.02 g) was then added and the mixture stirred under nitrogen for 18 h. Solvents were removed by concentration in vacuo and the residue partitioned between DCM and water. The layers were separated and the organic phase was washed with saturated aqueous sodium bicarbonate solution, then concentrated and applied to an SPE cartridge (aminopropyl, 1 g) which was eluted with methanol. Concentration in vacuo afforded Intermediate 4 (0.043 g). LCMS showed MH+=331; TRET=2.38 min.