Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([CH:21]=O)=[CH:13][CH:12]=2)[CH:3]=1.CN.[C:25]([BH3-])#[N:26].[Na+].[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33]>C(O)(=O)C.CO>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([CH2:21][NH:26][CH3:25])=[CH:13][CH:12]=2)[CH:3]=1
Reactant: [BH3-]C#N
Reactant: N#Cc1ccc(Cl)cc1Oc1ccc(C=O)c2ccccc12
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNCc1ccc(Oc2cc(Cl)ccc2C#N)c2ccccc12
Yield: 74.7 %

Procedure:
4-Chloro-2-(4-formylnaphthalen-1-yloxy)benzonitrile (0.34 g, 1.1 mmol), methylamine (2M in methanol, 2.0 mL, 4.0 mmol) and sodium cyanoborohydride (80 mg, 1.3 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (30 mL) for 18 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (0.12 g, 1.0 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 4-chloro-2-[4-(methylaminomethyl)naphthalen-1-yloxy]benzonitrile fumarate (328 mg, 68%) as an off-white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:14]3[N:15]=C[CH:17]=[CH:18][C:13]3=[N:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.NN.[CH2:21](O)[CH3:22]>[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[CH:17]=[CH:18][C:13]3[N:12]([C:21]([CH3:22])=[N:15][N:14]=3)[N:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(-c2nnc3cccnn23)c1
Reactant: CCO
Agent: [Pd]
Agent: NN
Product: Cc1nnc2ccc(-c3cccc(N)c3)nn12
Temperature: 20 °C

Procedure:
A 103.0 g portion of 3-methyl-6-(3-nitrophenyl-1,2,4-triazolo[4,3-b-]pyridazine and 1.0 g of 10% palladium on carbon were suspended in 2 liters of ethanol. The mixture was heated to reflux and 140 ml of anhydrous hydrazine added via a syringe pump over 24 hours. The solution was cooled to 20° C., filtered and the filtrate concentrated in vacuo. The residue was dissolved in 3 liters of hot dichloromethane and passed through a short column (200 g) of hydrous magnesium silicate with dichloromethane as the eluent. The fractions containing product were combined and evaporated, giving 83 g of the desired compound as yellow needles, mp 206°-208° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]2)=[CH:4][C:5]([NH:8][C:9]2[CH:14]=[N:13][C:12]([C:15]#[N:16])=[CH:11][N:10]=2)=[N:6][CH:7]=1.[O-]CC.[Na+].Br[CH2:37][CH2:38][CH2:39][CH2:40]Br>C(O)C>[NH:21]1[CH2:22][CH2:23][CH2:24][CH:19]([CH2:18][NH:17][C:3]2[C:2]([N:1]3[CH2:40][CH2:39][CH2:38][CH2:37]3)=[CH:7][N:6]=[C:5]([NH:8][C:9]3[N:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=3)[CH:4]=2)[CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCCC(CNc2cc(Nc3cnc(C#N)cn3)ncc2N)C1
Reactant: BrCCCCBr
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1cnc(Nc2cc(NCC3CCCNC3)c(N3CCCC3)cn2)cn1
Yield: 29 %

Procedure:
tert-Butyl 3-((5-amino-2-(5-cyanopyrazin-2-ylamino)pyridin-4-ylamino)methyl)piperidine-1-carboxylate (40 mg, 0.094 mmol) (Synthesis 101-C) was dissolved in ethanol (2 mL) and treated with sodium ethoxide (34 mg, 0.509 mmol) and 1,4-dibromobutane (44 mg, 0.208 mmol) at between 70 and 80° C. for 96 h. The reaction was quenched with water and the aqueous phase extracted with dichloromethane. The combined organic phases were evaporated and the residue was treated with a 20% solution of TFA in dichloromethane for 20 min. The solution was evaporated and the residue was purified by HPLC to give 5-(4-(piperidin-3-ylmethylamino)-5-(pyrrolidin-1-yl)pyridin-2-ylamino)pyrazine-2-carbonitrile (10.3 mg, 29%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=O.[NH2:14][C@@H:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][OH:17]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([NH:14][C@@H:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][OH:17])=[O:7]
Reactant: N[C@H](CO)Cc1ccccc1
Reactant: Cc1cc(C(=O)O)ccc1[N+](=O)[O-]
Product: Cc1cc(C(=O)N[C@H](CO)Cc2ccccc2)ccc1[N+](=O)[O-]
Yield: 81.8 %

Procedure:
5 g (27.6 mmol) of 3-methyl-4-nitrobenzoic acid were reacted with 4.2 g (27.6 mmol) of (S)-2-amino-3-phenyl-1-propanol by the method of procedure 3c. 7.1 g (82%) of the product were obtained.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][NH:6][CH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)[CH3:2].[CH:21]1[C:33]2[CH:32]([CH2:34][O:35][C:36]([NH:38][C@@H:39]([CH2:43][C:44]3[CH:49]=[CH:48][C:47]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:46][CH:45]=3)[C:40](O)=[O:41])=[O:37])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]=2[CH:24]=[CH:23][CH:22]=1>>[C:51]([O:50][C:47]1[CH:46]=[CH:45][C:44]([CH2:43][C@H:39]([NH:38][C:36](=[O:37])[O:35][CH2:34][CH:32]2[C:33]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[C:26]3[C:31]2=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:40]([N:6]([CH2:5][CH:4]([O:3][CH2:1][CH3:2])[O:18][CH2:19][CH3:20])[CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)=[O:41])=[CH:49][CH:48]=1)([CH3:54])([CH3:52])[CH3:53]
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Reactant: CCOC(CNCc1cccc2ccccc12)OCC
Product: CCOC(CN(Cc1cccc2ccccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21)OCC
Yield: 90.4 %

Procedure:
According to the procedure described in the synthesis method of Compound III-1, 2,2-diethoxy-N-(naphthalen-1-ylmethyl)ethanamine (Compound IX-2) (2.73 g, 10 mmol) was coupled with (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-tert-butoxyphenyl)propanoic acid (6.89 g, 15 mmol) and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=8:2 to 6:4) to obtain the title compound (6.46 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][N:11]([C:13]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[O:14])[CH2:10][C@H:9]2[N:21]([CH3:32])[C:22](=[O:31])[O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:57]1([C:61](O)=[O:62])[CH2:60][CH2:59][CH2:58]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:30][C:27]1[CH:26]=[CH:25][C:24]([O:23][C:22](=[O:31])[N:21]([C@H:9]2[C@H:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH2:12][N:11]([C:13]([CH:15]3[CH2:20][CH2:19][N:18]([C:61]([CH:57]4[CH2:60][CH2:59][CH2:58]4)=[O:62])[CH2:17][CH2:16]3)=[O:14])[CH2:10]2)[CH3:32])=[CH:29][CH:28]=1
Reactant: O=C(O)C1CCC1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCNCC2)C[C@H]1c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(C(=O)C3CCC3)CC2)C[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 38.4 %

Procedure:
A mixture of 27.6 mg (0.06 mmol) 4-fluorophenyl (3S,4R)-4-(4-chlorophenyl)-1-(piperidine-4-carbonyl)pyrrolidin-3-yl(methyl)carbamate, 0.52 mL (0.072 mmol) HATU (0.136 M in DMF), 12 mg (0.072 mmol) cyclobutanecarboxylic acid and 46.5 mg (0.36 mmol) DIPEA in 1.5 mL DMF was shaken at room temperature over night. The mixture was subjected to preparative HPLC chromatography on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. The product containing fractions were evaporated to yield 12.5 mg (39%) of the title compounds as off-white solid. MS m/e: 542.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([NH:11][S:12]([C:15]2[C:16]3[N:17]=[CH:18][CH:19]=[N:20][C:21]=3[CH:22]=[CH:23][CH:24]=2)(=[O:14])=[O:13])[CH:3]=1.Cl.[Cl:26][C:27]1[CH:28]=[C:29]([CH:34]([CH3:37])[CH2:35][NH2:36])[CH:30]=[CH:31][C:32]=1[Cl:33]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:36][CH2:35][CH:34]([C:29]2[CH:30]=[CH:31][C:32]([Cl:33])=[C:27]([Cl:26])[CH:28]=2)[CH3:37])=[O:8])=[C:4]([NH:11][S:12]([C:15]2[C:16]3[N:17]=[CH:18][CH:19]=[N:20][C:21]=3[CH:22]=[CH:23][CH:24]=2)(=[O:13])=[O:14])[CH:3]=1
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12
Reactant: CC(CN)c1ccc(Cl)c(Cl)c1
Agent: Cl
Product: CC(CNC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from 4-chloro-2-(quinoxaline-5-sulfonylamino)-benzoic acid and (±)-2-(3,4-dichloro-phenyl)-propylamine hydrochloride as in EXAMPLE 1, Part C. HPLC: RT=10.78 min. MS (ESI+): mass calcd. for C24H19Cl3N4O3S, 548.02; m/z found, 551/553 [M+H]+; m/z found, 571/575 [M+Na]+. 1H NMR (400 MHz, CDCl3): 11.21 (s, 1H), 9.04 (d, J=1.7, 1H), 8.96 (d, J=1.7, 1H), 8.57 (dd, J=7.3, 1.3, 1H), 8.33 (dd, J=8.5, 1.2, 1H), 7.91-7.87 (m, 1H), 7.71 (d, J=1.9, 1H), 7.39 (d, J=8.2, 1H), 7.29 (d, J=2.0, 1H), 7.04 (dd, J=8.2, 2.0, 1H), 6.99 (d, J=8.4, 1H), 6.88 (dd, J=8.4, 2.0, 1H), 5.82 (s, 1H), 3.70-3.63 (m, 1H), 3.33-3.26 (m, 1H), 3.02-2.98 (m, 1H), 1.30 (d, J=7.0, 3H).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH3:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]#[N:7]
Reactant: OB(O)c1ccccc1
Reactant: Cc1cc(C#N)ccc1Br
Product: Cc1cc(C#N)ccc1-c1ccccc1

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 2 using 4-bromo-3-methylbenzonitrile instead of tert-butyl N-(4-bromobenzyl)carbamate and phenylboronic acid instead of 3-benzyloxyphenylboronic acid.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([O:6][CH3:7])[CH3:5].[Mg].[Cl:9][C:10]1[CH:11]=[CH:12][C:13]2[C:14](=[O:23])[C:15]3[N:16]([CH2:19][CH2:20][CH2:21][N:22]=3)[C:17]=2[CH:18]=1.[Cl-].[NH4+]>CCOCC.ClCCCl>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]2[C:14]([OH:23])([CH2:2][CH2:3][CH:4]([O:6][CH3:7])[CH3:5])[C:15]3[N:16]([CH2:19][CH2:20][CH2:21][N:22]=3)[C:17]=2[CH:18]=1
Reactant: COC(C)CCBr
Reactant: O=C1C2=NCCCN2c2cc(Cl)ccc21
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: ClCCCl
Solvent: CCOCC
Product: COC(C)CCC1(O)C2=NCCCN2c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-bromo-3-methoxybutane (2.0 g) in dry ether (20 ml) was added dropwise under a nitrogen atmosphere to magnesium turnings (0.3 g) at such a rate as to maintain gentle reflux. After 0.5 hour the reaction mixture was cooled and a solution of 7-chloro-3,4-dihydropyrimido[1,2-a]indol-10(2H)-one (1.0 g) in dry 1,2-dichloroethane (50 ml) was added dropwise. After stirring the reaction mixture for one hour at room temperature it was cooled and excess saturated ammonium chloride solution was added dropwise. The organic phase was separated and the aqueous phase was extracted with chloroform. The extracts were combined with the organic phase, dried (MgSO4) and the solution evaporated in vacuo to leave an oil which was triturated with ether to give a solid. Recrystallisation from ethyl acetate gave the title compound as crystals m.p. 146.5°-148°. A solution of these crystals in warm propan-2-ol was treated with ethereal hydrogen chloride. Evaporation in vacuo followed by recrystallisation from propan-2-ol gave the title compound as the hydrochloride, colourless needles, m.p. 226°-8°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11][NH:12]C(OC(C)(C)C)=O)[O:8][N:7]=1)=[O:5])[CH3:2].Cl>C(O)C.O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11][NH2:12])[O:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(CNC(=O)OC(C)(C)C)on1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(CN)on1
Temperature: 20 °C
Reaction time: 22 h
Yield: 91.7 %

Procedure:
To a stirred solution of 5-(tert-butoxycarbonylaminomethyl)-isoxazole-3-carboxylic acid ethyl ester (1.954 g) (EP 0451790) in ethanol (15 ml) was added a solution of 4.0M hydrogen chloride in 1,4-dioxane (23 ml). The mixture was stirred at 20° C. for 22 h and the solvent evaporated in vacuo to give the title compound (1.128 g) as a pale brown solid.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:37])[NH:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:14]=[C:15]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][C@H:30]4[CH3:35])[C:16]4[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][C:17]=4[N:18]=3)=[C:9]([F:36])[CH:8]=2)[CH2:3][CH2:2]1.[ClH:38]>CO.O1CCOCC1>[ClH:38].[CH:1]1([NH:4][C:5]([NH:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:14]=[C:15]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][C@H:30]4[CH3:35])[C:16]4[CH2:21][NH:20][CH2:19][C:17]=4[N:18]=3)=[C:9]([F:36])[CH:8]=2)=[O:37])[CH2:2][CH2:3]1
Reactant: C[C@@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2F)nc2c1CN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C[C@@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2F)nc2c1CNC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (R)-tert-butyl 2-(4-(3-cyclopropylureido)-2-fluorophenyl)-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (1.1 g, 2.1 mmol) in methanol (15 ml) was added 4M HCl in dioxane (4 ml) and the reaction was stirred at RT overnight. The reaction was concentrated in vacuo to yield the titled compound as a yellow solid which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH2:21][O:22][CH3:23])[C:17]([OH:19])=O)[C:10](=[O:24])[CH:9]=2)[CH:7]=1.[NH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][N:32]=[CH:31]2>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH2:21][O:22][CH3:23])[C:17]([NH:27][C:28]3[CH:29]=[C:30]4[C:34](=[CH:35][CH:36]=3)[NH:33][N:32]=[CH:31]4)=[O:19])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: COCCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: Nc1ccc2[nH]ncc2c1
Product: COCCC(C(=O)Nc1ccc2[nH]ncc2c1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
150 mg (398 μmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoic acid (racemate) and 58.3 mg (438 μmol, 1.1 eq.) of 5-aminoindazole were reacted according to General Method 1. The crude product was purified by preparative HPLC (column: Chromatorex 125 mm×30 mm, 10 μm, mobile phase: water and acetonitrile, gradient 10% acetonitrile to 90% acetonitrile). Yield: 88 mg (42% of theory)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].[Li]CCCC.Cl[Si](C)(C)C.[S:20]1[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]1.Cl>C1COCC1>[NH2:5][C:4]1[CH:3]=[C:2]([F:1])[C:8]([C:23]2([OH:26])[CH2:24][CH2:25][S:20][CH2:21][CH2:22]2)=[C:7]([F:9])[CH:6]=1
Reactant: O=C1CCSCC1
Reactant: Nc1cc(F)cc(F)c1
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Nc1cc(F)c(C2(O)CCSCC2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.3 %

Procedure:
3,5-Difluoroaniline (250 g, 1.94 mol) was dissolved in THF (3800 ml) and cooled to −78° C. nBuLi (1.59 M, 2560 ml) was added drop wise over 5 hours keeping the temperature below −70° C. and the resulting white slurry was stirred for 1 hour. Chlorotrimethylsilane (502 ml, 4.07 mol) in THF (2000 ml) was added drop wise over 2.5 hours keeping the temperature below −70° C. and the resulting yellow slurry was allowed to warm to room temperature overnight. The brown solution was recooled to −78° C., nBuLi (1340 ml) was charged drop wise over 1.5 hours keeping the temperature below −70° C. and the reaction mixture was stirred for 5 hours. Tetrahydrothiopyran-4-one (241 g, 2.07 mol) in THF (1500 ml) was added drop wise over 2 hours keeping the temperature below −70° C. during the addition and then the reaction allowed to warm to room temperature overnight. The reaction was acidified to pH<1 using 5M HCl (approx 2000 ml) and it was extracted with diethyl ether (2500 ml). The organic layer was washed with 5M HCl (1000 ml) and the combined aqueous layers were basified using 880 ammonia to pH 11 (1500 ml), then extracted with diethyl ether (2500 ml×2), washed with saturated aqueous sodium chloride (1000 ml), dried over MgSO4 and evaporated. The residue was taken up in dichloromethane (800 ml) evaporated to a low volume, isohexane (1000 ml) was added and it was cooled under ice. The yellow solid was filtered and dried in a vacuum oven at 40° C. overnight to provide 287 g of the title compound.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:26][C:27]1[CH:31]=[CH:30][N:29]([CH2:32][C:33]([CH3:36])([OH:35])[CH3:34])[N:28]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[CH:13]=[N:12]2)[C:8]([NH:26][C:27]2[CH:31]=[CH:30][N:29]([CH2:32][C:33]([OH:35])([CH3:34])[CH3:36])[N:28]=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: Cc1ccccc1Oc1cnn(C(CC2CCCC2)C(=O)O)c(=O)c1
Product: Cc1ccccc1Oc1cnn(C(CC2CCCC2)C(=O)Nc2ccn(CC(C)(C)O)n2)c(=O)c1
Yield: 58 %

Procedure:
Using the method described in Example 17, 3-cyclopentyl-2-(6-oxo-4-o-tolyloxy-6H-pyridazin-1-yl)-propionic acid (Intermediate 41) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(6-oxo-4-o-tolyloxy-6H-pyridazin-1-yl)-propionamide as a white solid (0.86 g, 58%); ES+-HRMS m/e calcd for C26H33N5O4 [M+H+] 480.2606 found 480.2605. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.05 (s, 3H), 1.06 (s, 3H), 1.09 (m, 1H), 1.27-1.75 (m, 8H), 1.92 (m, 1H), 2.16 (s, 3H), 2.27 (m, 1H), 3.89 (s, 2H), 4.67 (s, 1H), 5.45 (dd, J=4.3, J=10.9 Hz, 1H), 5.56 (d, J=2.8 Hz, 1H), 6.40 (d, J=2.3 Hz, 1H), 7.21 (dd, Jo=7.5 Hz, Jm=1.3 Hz, 1H), 7.28 (td, Jo=7.5 Hz, Jm=1.3 Hz, 1H), 7.34 (td, Jo=7.5 Hz, Jm=1.3 Hz, 1H), 7.41 (d, Jo=7.5 Hz, 1H), 7.53 (d, J=2.3 Hz, 1H), 8.15 (d, J=2.8 Hz, 1H), 10.80 (s, 1H).
Reaction SMILES: Cl[CH:2]([CH3:5])[C:3]#[N:4].Cl.[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+].C(#N)C>O>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH:16]2[CH2:21][CH2:20][N:19]([CH:2]([CH3:5])[C:3]#[N:4])[CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: CC(Cl)C#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C#N)N1CCC(C(=O)c2ccc(F)cc2)CC1
Temperature: 100 °C

Procedure:
A mixture of 25 parts of 2-chloropropanenitrile, 61 parts of (4-fluorophenyl)(4-piperidinyl)methanone hydrochloride, 63 parts of sodium carbonate and 160 parts of acetonitrile is stirred and refluxed (100° C.) overnight. The reaction mixture is cooled, water is added and the layers are separated. The aqueous phase is extracted with 4-methyl-2-pentanone. The combined organic phases are dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane, hexane and methanol (50:49:1 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The solid residue is crystallized from 2,2'-oxybispropane. The product is filtered off, and dried yielding 17 parts of 4-(4-fluorobenzoyl)-α-methyl-1-piperidineacetonitrile; mp. 126.7° C.
Reaction SMILES: II.[Mg].Br[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:18]([O:20][C:21](=[O:22])[C:13]=12)=[O:19]>C1COCC1>[CH3:11][C:8]1[CH:9]=[CH:10][C:5]([C:18]([C:14]2[C:13]([C:21]([OH:20])=[O:22])=[N:12][CH:17]=[CH:16][CH:15]=2)=[O:19])=[CH:6][CH:7]=1
Reactant: O=C1OC(=O)c2ncccc21
Reactant: Cc1ccc(Br)cc1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)c2cccnc2C(=O)O)cc1
Reaction time: 1 h

Procedure:
Iodine (catalytic amount) was added to a THF (30 ml) suspension of magnesium (2.4 g) in a nitrogen atmosphere at room temperature with stirring, and then a THF (20 ml) solution of 4-bromotoluene (17.1 g) was dropwise added thereto and stirred for 1 hour. The resulting mixture was added to a THF (50 ml) solution of 2,3-pyridinedicarboxylic acid anhydride (12.7 g) at 0-5° C. with stirring, and this was stirred for additional 30 minutes as it was and then for 1 hour at room temperature. The solvent was removed from the reaction mixture by distillation, and water (30 ml) was added to the residue, which was then adjusted the pH to 1.0 with hydrochloric acid. The mixture was extracted with dichloromethane, washed with water and dried. Then, the solvent was removed by distillation. Dichloromethane (about 10 ml) was added to the residue, and then isopropyl ether (about 70 ml) was added thereto. This was stirred for 16 hours at room temperature, and 3-(4-methylbenzoyl)-2-pyridinecarboxylic acid was obtained as colorless crystals (5.0 g).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[O:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:12][CH:9]1[CH2:10][CH2:11][O:6][CH2:7][CH2:8]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OC1CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CCOCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Methanesulphonyl chloride (1.82 ml, 23.5 mmol) was added dropwise over 10 minutes to an ice-cold solution of tetrahydro-2H-pyran-4-ol (2.0 g, 19.6 mmol) and triethylamine (3.56 ml, 25.5 mmol) in dichloromethane (20 ml), and the reaction then stirred at room temperature for 72 hours. The reaction was washed with saturated aqueous sodium bicarbonate solution (10 ml), dried (MgSO4) and evaporated under reduced pressure to give an orange oil, that solidified on standing, 3.1 g.
Reaction SMILES: [N:1]([C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)=[N:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C([O:20][CH2:21][CH3:22])(=O)C>ClCCl>[C:21]([NH:14][C:13]1[CH:15]=[CH:16][C:10]([N:1]=[N:2][C:3]2[CH:4]=[CH:5][C:6]([NH2:7])=[CH:8][CH:9]=2)=[CH:11][CH:12]=1)(=[O:20])[C:22]1[CH:8]=[CH:9][CH:3]=[CH:4][CH:5]=1
Reactant: Nc1ccc(N=Nc2ccc(N)cc2)cc1
Reactant: CCOC(C)=O
Solvent: ClCCl
Product: Nc1ccc(N=Nc2ccc(NC(=O)c3ccccc3)cc2)cc1
Yield: 54 %

Procedure:
Following the general monoacylation procedure, 4,4′-azodianiline (50 mg, 240 μmol) was treated with benzoyl choloride (26 μl, 240 μmol). Silica gel chromatography through a wide column (10% ethyl acetate in dichloromethane) provided S5 as an orange solid (44 mg, 130 μmol, 54% yield): 1H (DMSO, 400 MHz): 6.04 (s, 2H); 6.66 (d, 2H, J=8.4); 7.52-7.65 (m, 5H); 7.76 (d, 2H, J=8.8); 7.88-7.98 (m, 4H); 10.46 (s, 1H). 13C (DMSO, 100 MHz): 113.4, 120.5, 122.3, 124.9, 127.7, 128.4, 131.7, 134.8, 140.4, 142.9, 148.4, 152.5, 165.7. HRMS (ESI+): calc'd for C19H17N4O+—317.1397. found—317.1403 (MH+).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[CH:15]=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1([Mg]Br)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[OH:16][CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:9]=1[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:8]
Reactant: Br[Mg]c1ccccc1
Reactant: O=Cc1cnccc1C(=O)c1ccccc1
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1ccncc1C(O)c1ccccc1
Reaction time: 0.25 h

Procedure:
To a solution of 4-benzoyl-pyridine-3-carbaldehyde (97 mg, ol) in THF (5 mL) at −78° C. was added 1.0M phenylmagnesium bromide in THF (0.46 mL) and the reaction mixture stirred for 15 min. The reaction mixture was then quenched with aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by preparation TLC of silica gel with 10% methanol in dichloromethane to yield [3-(hydroxy-phenyl-methyl)-pyridin-4-yl]-phenyl-methanone as white crystals.