Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:10])[CH:7]=[CH:8][CH:9]=1)=[O:4].[CH3:11][C:12]#[N:13].CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[CH3:10][N:6]1[CH:7]=[CH:8][CH:9]=[C:5]1[C:3](=[O:4])[CH2:11][C:12]#[N:13]
Reactant: CC#N
Reactant: COC(=O)c1cccn1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cn1cccc1C(=O)CC#N
Reaction time: 8 h

Procedure:
1-Methyl-1H-pyrrole-2-carboxylic acid methyl ester (5 g, 35.9 mmol) and CH3CN (2.5 mL) were premixed and added into a suspension of potassium tert-butoxide (5.3 g, 47.2 mmol) in 150 mL of dry toluene at 90° C. The mixture was stirred at this temperature overnight. The solid precipitate was collected by filtration, washed with EtOAc and redissolved in 20 mL of water. The resulting solution was acidified with 1 N HCl to approximately pH 1 and was then extracted with EtOAc. The product 3-(1-methyl-1H-pyrrol-2-yl)-3-oxopropionitrile was obtained after removal of the solvent (1.9 g).
Reaction SMILES: S([NH:11]/[N:12]=[CH:13]/[C:14]([OH:16])=[O:15])(C1C=CC(C)=CC=1)(=O)=O.O[N:18]1[C:22](=[O:23])[CH2:21][CH2:20][C:19]1=[O:24].C1(N=C=NC2CCCCC2)CCCCC1>O1CCOCC1>[O:24]=[C:19]1[CH2:20][CH2:21][C:22](=[O:23])[N:18]1[O:16][C:14](=[O:15])[CH:13]=[N+:12]=[N-:11]
Reactant: Cc1ccc(S(=O)(=O)N/N=C/C(=O)O)cc1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Product: [N-]=[N+]=CC(=O)ON1C(=O)CCC1=O
Reaction time: 17 h
Yield: 53.9 %

Procedure:
Under argon atmosphere, to a solution of (E)-2-(2-tosylhydrazono)acetic acid (1.42 g) in 1,4-dioxane (14 ml) were sequentially added N-hydroxysuccinimide (677 mg) and dicyclohexylcarbodiimide (1.21 g) at room temperature, and the mixture was stirred for 17 hours. This reaction mixture was filtered through Celite, and eluted with 1,4-dioxane. This filtrate was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent: n-hexane/diethyl ether=1/3) to give the titled compound (579 mg).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[CH:17]1[CH2:21][O:20][C:19]([NH2:22])=[N:18]1.[Br:23]CCBr>C1COCC1>[Br:23][C:15]1[C:10]([F:9])=[C:11]([CH:17]2[CH2:21][O:20][C:19]([NH2:22])=[N:18]2)[CH:12]=[CH:13][C:14]=1[F:16]
Reactant: NC1=NC(c2ccc(F)cc2F)CO1
Reactant: BrCCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: NC1=NC(c2ccc(F)c(Br)c2F)CO1
Temperature: -55 °C
Reaction time: 2 h

Procedure:
A solution of lithium diisopropylamide in THF (2 M, 5.05 ml) was cooled to −55° C. and treated with (RS)-4-(2,4-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine (667 mg, example 7) in THF (6 ml). The reaction mixture was stirred at −55° C. for 2 hrs, then treated dropwise with 1,2-dibromoethane (0.58 ml). The reaction mixture was warmed to r.t., then stirred overnight at r.t. It was quenched with H2O and extracted with EtOAc. The organic layer was dried over MgSO4, filtrated and concentrated. The crude product was purified by column chromatography (SiO2; gradient: CH2Cl2->CH2Cl2/MeOH 95:5) to give (RS)-4-(3-bromo-2,4-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine (61 mg) as light yellow solid.
Reaction SMILES: [CH3:1][Si:2]([CH3:51])([CH3:50])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH2:29][CH:30]2[CH2:35][CH2:34][CH:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:32][CH2:31]2)[C:9]=1Br.C([Sn](CCCC)(CCCC)[C:57]([O:59][CH2:60][CH3:61])=[CH2:58])CCC>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.O1CCOCC1>[CH3:1][Si:2]([CH3:51])([CH3:50])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH2:29][CH:30]2[CH2:35][CH2:34][CH:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:32][CH2:31]2)[C:9]=1[C:57]([O:59][CH2:60][CH3:61])=[CH2:58]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)C1CCC(Cc2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=C(OCC)c1c(CC2CCC(C(=O)OCC)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N(COCC[Si](C)(C)C)COCC[Si](C)(C)C
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a 2-5 mL microwave vessel was charged ethyl 4-((7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)methyl)cyclohexanecarboxylate (Int-4m, 150 mg, 0.19 mmol), Pd(PPh3)4 (33 mg, 0.029 mmol), tributyl (1-ethoxyvinyl)tin (190 μL, 0.56 mmol), and 1,4-dioxane (2 mL). The vial was flushed with argon and sealed. The reaction was heated to 100° C. for 18 hours. After 18 hours, the solvent was removed in vacuo and the residue was purified via silica gel chromatography to yield the title compound. Yield=113 mg.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([OH:10])=[CH:8][N:7]=[C:6]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:12]=2)[N:5]=1.[N:28]1([C:33](Cl)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1>C1COCC1>[N:28]1([C:33]([O:10][C:9]2[C:4]([NH2:3])=[N:5][C:6]([C:11]3[C:19]4[C:14](=[N:15][CH:16]=[CH:17][CH:18]=4)[N:13]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[F:27])[N:12]=3)=[N:7][CH:8]=2)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)ncc1O
Reactant: O=C(Cl)N1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)ncc1OC(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3.5 mg (0.15 mmol) of sodium hydride were added to a suspension of 50.0 mg (0.15 mmol) of 4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinol from example IV in 2 ml of THF at RT. After the mixture had been stirred at RT for 30 min, 21.8 mg (0.16 mmol) of 1-pyrrolidinecarbonyl chloride were added and the mixture was stirred at RT overnight. The product was purified by thin-layer chromotography (silica gel, CH2Cl2/MeOH 10:1).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=1[CH3:17].O=P(Cl)(Cl)Cl>>[CH3:10][C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][C:16]=1[CH3:17])[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:9]
Reactant: O=C(O)c1ccccc1
Reactant: Cc1ccccc1C
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(C(=O)c2ccccc2)cc1C
Temperature: 140 °C

Procedure:
Synthesis of the novel compounds was carried out according to the following method. Benzoic acid (1.68 moles) was added to 3.96 moles of o-xylene and 0.6 mole POCl3 and refluxed at 140° C. for 11 hours. The reaction product was cooled to room temperature, washed once with 500 ml. of water, twice with 300 ml. of 5% of Na2C03 and twice again with 500 ml. of water. After washing, the xylene was distilled and the residue was vacuum distilled to obtain 3,4-dimethylbenzophenone. A mixture of 3,4-dimethylbenzophenone (1.0 mole), benzoyl peroxide (5 grams), chlorobenzene (800 ml.) and 3.0 moles of sulfuryl chloride was heated at 90° C. for 31/2 hours. During the last 30 minutes of the reaction nitrogen was passed through the reactor to remove the excess sulfuryl chloride. The resultant mixture was cooled and 50 grams of carbon black was added and the mixture stirred for 30 minutes, after which the carbon black was removed by filtration. The product 3,4-bis(chloromethyl)benzophenone was isolated by stripping of the solvent. Analysis found: 62.1% C, 4.3% H, and 27.1% Cl. Theoretical: 64.5% C, 4.3% H, and 25.5% Cl.
Reaction SMILES: [N+]([C:4]1[CH:21]=[C:20]([NH:22][CH2:23][C:24]2[N:35]=[C:34]3[C:27]([N:28]=[C:29]([NH:31][C:32]3=[O:33])[NH2:30])=[N:26][CH:25]=2)[CH:19]=[CH:18][C:5]=1[C:6](=[O:17])[NH:7][C@H:8]([C:14]([OH:16])=[O:15])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])([O-])=O.NC1C=CC(C(O)=O)=C([F:46])C=1>>[F:46][C:4]1[CH:21]=[C:20]([NH:22][CH2:23][C:24]2[N:35]=[C:34]3[C:27]([N:28]=[C:29]([NH:31][C:32]3=[O:33])[NH2:30])=[N:26][CH:25]=2)[CH:19]=[CH:18][C:5]=1[C:6](=[O:17])[NH:7][C@H:8]([C:14]([OH:16])=[O:15])[CH2:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: Nc1ccc(C(=O)O)c(F)c1
Reactant: Nc1nc2ncc(CNc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)c([N+](=O)[O-])c3)nc2c(=O)[nH]1
Product: Nc1nc2ncc(CNc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)c(F)c3)nc2c(=O)[nH]1

Procedure:
The synthesis was done in analogy to the synthesis of 2′-nitrofolic acid following examples 1 to 4. In example 1 4-amino-2-fluoro-benzoic acid was used instead of 4-amino-2-nitrobenzoic acid. (HPLC purity: 97.5% area, m/z=460 [M+1]+, 1H-NMR (200 MHz, DMSO-d6) [ppm]: 8.65 (s, C(7)-H, 1H); 7.75 (t, N(8′)-H, 1H, exchangeable with D2O); 7.51 (t, C(3′H), 1H); 7.20 (t, N(10)-H, 1H, exchangeable with D2O); 7.03 (bs, NH2, 2H, exchangeable with D2O); 6.50 (m, C(5′)-H, (C(6′)-H, 2H); 4.48 (d, C(6)H2, 2H); 4.31 (m, C(α)-H, 1H); 2.28 (m, C(β)-H2, 2H); 1.96 (m, C(γ)-H2, 2H).
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O.O>C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.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>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccccc1B(O)O
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
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: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccccc1-c1cccc2c1OCCN(C(=O)OC(C)(C)C)C2
Yield: 83.7 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.605 mmol), a solution of 2-methoxyphenylboronic acid (139 mg, 0.912 mmol) in ethanol (0.7 ml), 2N aqueous sodium carbonate solution (2.5 ml), and tetrakis(triphenylphosphine)palladium(0) (84.0 mg, 0.0730 mmol) in toluene (5 ml) was stirred under a nitrogen atmosphere at 95° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (180 mg, 83.7%) as an oil.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]#[N:22])[CH:19]=2)[NH:14][CH:13]=1.[BH4-].[Na+]>C(O)C>[C:2]1([CH2:1][NH:9][CH2:10][CH2:11][C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]#[N:22])[CH:19]=3)[NH:14][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc2[nH]cc(CCN)c2c1
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1ccc2[nH]cc(CCNCc3ccccc3)c2c1
Reaction time: 2 h
Yield: 51.1 %

Procedure:
Freshly distilled benzaldehyde (2.96 g) was added to a solution of 3-(2-aminoethyl)-1H-indole-5-carbonitrile (5 g) in absolute ethanol (120 ml). The mixture was heated at reflux for 2 h before cooling to 10°. Sodium borohydride (1 g) was added and the suspension stirred for 2 h. The mixture was reduced to dryness and the residue recrystallised from a mixture of toluene and petroleum ether (b.p. 60°-80°). The solid was washed well with water and dried to give the title compound as a powder (3.8 g), m.p 99°-101°.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=2[C:17]2[C:18]3[NH:25][C:24]([CH3:26])=[C:23]([C:27]([NH:29][CH:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)=[O:28])[C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:4][CH2:3]1.[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([N:33]1[CH2:32][CH2:31][CH:30]([NH:29][C:27]([C:23]2[C:19]3[N:20]=[CH:21][N:22]=[C:17]([C:8]4[CH:9]=[C:10]([C:13]([F:15])([F:14])[F:16])[CH:11]=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:3][CH2:4]4)[C:18]=3[NH:25][C:24]=2[CH3:26])=[O:28])[CH2:35][CH2:34]1)(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(F)(F)F)ccc3OCC3CC3)ncnc2c1C(=O)NC1CCNCC1
Agent: Cl
Product: CC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)(F)F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(trifluoromethyl)phenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f31) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(=O)([O-])[O-].[Cs+].[Cs+].[Br:18][CH2:19][CH2:20][CH2:21]Br>CC(C)=O>[Br:18][CH2:19][CH2:20][CH2:21][O:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: Nc1ccc(OCCCBr)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A 500 mL flask was charged with 4-amino-3-nitrophenol (15.4 g, 100 mmol, commercially available from Aldrich). Acetone (300 mL), cesium carbonate (39.09 g, 120 mmol) and 1,3-dibromopropane (40.84 mL, 400 mmol) were added to the flask and stirred at refluxed temperature. The reaction was monitored by LCMS and was complete in 6 hours. The reaction mixture was cooled to room temperature, filtered and washed with excess acetone. The organic layer was removed on a rotary evaporator under reduced pressure and the resulting brown gelatin was purified by silica column chromatography using 40% hexane in dichloromethane as eluent. 20.0 g of 4-(3-bromopropoxy)-2-nitroaniline was obtained as a dark orange liquid which was used without any further purification. MS (EI: 276 (MH+).
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2N=NN(CC)C=2N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][C:39]([F:42])([F:41])[C:38]([F:44])([F:43])[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].Cl.Cl[CH2:47][C:48]1[N:52]([CH3:53])[N:51]=[N:50][CH:49]=1>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][C:39]([F:41])([F:42])[C:38]([F:43])([F:44])[CH2:37]2)[C:30]2[N:35]=[N:34][N:33]([CH2:47][C:48]3[N:52]([CH3:53])[N:51]=[N:50][CH:49]=3)[C:31]=2[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1nc(N2CC(F)(F)C(F)(F)C2)c2nn[nH]c2n1
Reactant: Cn1nncc1CCl
Agent: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: Cl
Product: Cn1nncc1Cn1nnc2c(N3CC(F)(F)C(F)(F)C3)nc(C(C)(C)C)nc21

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-Butyl-7-(3,3,4,4-tetrafluoro-pyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 5-(chloromethyl)-1-methyl-1H-1,2,3-triazole hydrochloride and isolated as light-yellow gum. MS(m/e): 414.3 (MH+).
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH3:21])[N:13]=[C:12]([NH:22][CH3:23])[N:11]=2)[CH:7]=[C:6]([O:24][CH3:25])[C:3]=1[C:4]#[N:5].CCO.CCN(C(C)C)C(C)C.[NH2:38][NH2:39]>O>[CH3:23][NH:22][C:12]1[N:11]=[C:10]([C:8]2[CH:9]=[C:2]3[C:3]([C:4]([NH2:5])=[N:38][NH:39]3)=[C:6]([O:24][CH3:25])[CH:7]=2)[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C@H:17]2[CH3:21])[N:13]=1
Reactant: CNc1nc(-c2cc(F)c(C#N)c(OC)c2)cc(N2CCC[C@H]2C)n1
Reactant: NN
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCO
Product: CNc1nc(-c2cc(OC)c3c(N)n[nH]c3c2)cc(N2CCC[C@H]2C)n1
Temperature: 110 °C
Reaction time: 8 h
Yield: 22.9 %

Procedure:
Into a sealable tube, 2-fluoro-4-{2-(methylamino)-6-[(2R)-2-methyl-1-pyrrolidinyl]-4-pyrimidinyl}-6-(methyloxy)benzonitrile (100 mg, 0.293 mmol), EtOH (5 mL), Hunig's base (0.05 mL, 0.29 mmol), and hydrazine anhydrous (0.055 mL, 1.76 mmol) were added, and the yellow suspension mixture was heated overnight at 110° C. in an oil bath. After overnight, there was yellow suspension as well as some black colored solid formed. LCMS showed mainly product. The reaction was cooled to room temperature. Water (20 mL) was added to the yellow solution, and a solid was formed. The solid was filtered, washed by water, and dried in vacuum. The solid was purified further by flash column chromatography. The fractions with product were combined, and the solvent was removed under reduced pressure to afford the title compound (23.7 mg) as a white solid. LC-MS (ES) m/z=354 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 1.30 (d, J=6.3 Hz, 3H), 1.75-2.18 (m, 4H), 3.02 (s, 3H), 3.50-3.63 (m, 2H), 4.02 (s, 3H), 4.34 (m, 1H), 4.50 (m, 2H), 6.07 (s, 1H), 6.93 (s, 1H), 7.44 (s, 1H).
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]2[N:12]=[C:13]([C:25]#[N:26])[C:14](C#N)=[N:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:5]1)([CH3:3])[CH3:2].N.[CH3:28][OH:29]>>[CH:1]([N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]2[N:12]=[C:13]([C:25]#[N:26])[C:14]([O:29][CH3:28])=[N:15][C:16]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[N:5]1)([CH3:2])[CH3:3]
Reactant: CO
Reactant: CC(C)n1nc(-c2nc(C#N)c(C#N)nc2-c2ccccc2)ccc1=O
Agent: N
Product: COc1nc(-c2ccccc2)c(-c2ccc(=O)n(C(C)C)n2)nc1C#N
Temperature: 30 °C
Reaction time: 30 h

Procedure:
A suspension of 5-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-6-phenyl-2,3-pyrazinedicarbonitrile (100 mg) in a 2M solution of ammonia in MeOH (3 ml) was stirred at 25-35° C. for 30 hours in a sealed tube. The mixture was concentrated under reduced pressure and subjected to column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (60:40 v/v) to give 6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-3-methoxy-5-phenyl-2-pyrazinecarbonitrile as a solid (32 mg).
Reaction SMILES: [C:1]1([C@@H](N)C)C=CC=CC=1.[Cl:10][C:11]1[C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([OH:28])([C:24]([F:27])([F:26])[F:25])[C:15]=2[CH:14]=[C:13]([C:29]([OH:31])=[O:30])[CH:12]=1>C(OCC)(=O)C>[CH3:1][O:30][C:29]([C:13]1[CH:12]=[C:11]([Cl:10])[C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([OH:28])([C:24]([F:26])([F:27])[F:25])[C:15]=2[CH:14]=1)=[O:31]
Reactant: O=C(O)c1cc(Cl)c2c(c1)C(O)(C(F)(F)F)c1ccccc1-2
Reactant: C[C@H](N)c1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Cl)c2c(c1)C(O)(C(F)(F)F)c1ccccc1-2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Under an argon atmosphere, (S)-(−)-1-phenylethylamine (0.392 ml) and a seed crystal of a salt of an optically active form of 4-chloro-9-hydroxy-9-trifluoromethyl-9H-fluorene-2-carboxylic acid and (S)-(−)-1-phenylethylamine were added to a mixture of 4-chloro-9-hydroxy-9-trifluoromethyl-9H-fluorene-2-carboxylic acid (1.000 g) and ethyl acetate (5 ml), and the mixture was stirred at room temperature for 3 days. This suspension was filtered, and the obtained solid was washed with ethyl acetate (3 ml). The solid was dried under reduced pressure to give the title compound (0.466 g). The solid was analyzed under HPLC analysis condition 4 to find that an isomer with a long retention time was the main component.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]3[CH:34]=[CH:33][C:23]([CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])=[CH:22][C:21]=3OC)[N:10]=2)=[C:4]([C:37](=[O:40])[NH:38][CH3:39])[CH:3]=1.Cl[C:42]1C(C(F)(F)F)=CN=C(NC2C=CC(CP(=O)(OCC)OCC)=CC=2)N=1.NC1C=CC=CC=1C(NCC)=O>>[CH2:39]([NH:38][C:37]([C:4]1[CH:3]=[CH:2][CH:7]=[CH:6][C:5]=1[NH:8][C:9]1[C:14]([C:15]([F:18])([F:16])[F:17])=[CH:13][N:12]=[C:11]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])=[CH:33][CH:34]=2)[N:10]=1)=[O:40])[CH3:42]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(F)cc3C(=O)NC)n2)c(OC)c1)OCC
Agent: CCNC(=O)c1ccccc1N
Product: CCNC(=O)c1ccccc1Nc1nc(Nc2ccc(CP(=O)(OCC)OCC)cc2)ncc1C(F)(F)F

Procedure:
The title compound was prepared according to the procedure from Example 102 (Diethyl (4-{[4-{[4-fluoro-2-(methylcarbamoyl)-phenyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate) using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate and the commercially available 2-amino-N-ethylbenzamide. MS (ES+): m/z 552.51 (100) [MH+] HPLC: tR=1.05 min (UPLC, purity).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:12]=[O:13])[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].[NH4+].[Cl-]>C(O)C>[C:1]1([C:7]2[CH:8]=[C:9]([CH2:12][OH:13])[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1cc(-c2ccccc2)cs1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: OCc1cc(-c2ccccc2)cs1
Reaction time: 0.33 h
Yield: 96.2 %

Procedure:
A stirred suspension of 4phenyl-2-thiophenecarboxaldehyde (4.32 g) in absolute ethanol (85 ml) was cooled in an ice-bath and treated with NaBH4 (1.06g). After 20 min. the mixture was allowed to attain ambient temperature when stirring was continued for 6h. Saturated aqueous NH4Cl (30 ml) was then carefully added to the vigorously stirred mixture, and the resulting suspension extracted with ether (2×200 ml). The combined extracts were dried (Na2SO4 /K2CO3), filtered and evaporated to give the title compound (4.2 g) as crystals, m.p. 112°-113°.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=1)[C:22]([O:24][CH3:25])=[O:23].I[CH2:30][CH2:31][CH2:32][C:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O>[NH:35]1[C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:33]([CH2:32][CH2:31][CH2:30][N:9]2[CH2:10][CH2:11][C:6]3([N:5]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:4][N:3]([CH2:18][C:19]4[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=4)[C:22]([O:24][CH3:25])=[O:23])[C:2]3=[O:1])[CH2:7][CH2:8]2)=[CH:34]1
Reactant: ICCCc1c[nH]c2ccccc12
Reactant: COC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCc4c[nH]c5ccccc45)CC3)C2=O)c1
Temperature: 65 °C
Yield: 23.4 %

Procedure:
A mixture of methyl 3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (871 mg, 2.11 mmol, 1.05 equiv), 3-(3-iodopropyl)-1H-indole (574 mg, 2.01 mmol, 1 equiv), and potassium carbonate (833 mg, 6.03 mmol, 3 equiv) in N—N-dimethylformamide was heated at 65° C. for 16 h. The reaction was cooled to ambient temperature and worked up using ethyl acetate and water. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified using preparatory thin layer chromatography in 7% methanol in dichloromethane to afford the title compound as cream crystals (252 mg, 46%); 1H NMR (400 MHz, DMSO-d6): δ 1.62 (d, 2H, J=12 Hz), 1.84 (bs, 2H); 2.41 (bs, 2H); 2.57 (bs, 2H); 2.67 (bs, 2H); 2.71-2.75 (m, 4H); 3.85 (s, 3H); 4.59 (s, 2H); 4.63 (s, 2H); 6.77 (d, 1H, J=7.6 Hz); 6.85 (d, 2H, J=8 Hz); 6.96 (t, 1H, J=6.8 and 7.6 Hz); 7.03-7.07 (m, 1H); 7.13 (bs, 1H); 7.22 (t, 2H, J=8 Hz); 7.33 (d, 1H, J=8 Hz); 7.52-7.59 (m, 3H); 7.89-7.91 (m, 2H); 10.75 (s, 1H); MS for C33H36N4O3 m/z 537.06 (M+H)+.