Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:35][CH:36]([CH3:39])[CH2:37][OH:38]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:35][CH:36]([CH3:39])[CH2:37][OH:38])=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O
Reactant: CC(N)CO
Product: CC(CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-(2-oxo-1-piperidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-amino-1-propanol using methods similar to Example 563 to provide a white solid: 1H NMR (CDCl3) δ 10.28 (1H, d, J=7 Hz), 8.55 (1H, s), 8.28 (1H, s), 7.25 (2H, dd, J=6, 8 Hz), 6.99 (2H, t, J=8 Hz), 4.38 (2H, t, J=8 Hz), 4.25-4.34 (1H, m), 4.16 (2H, s), 3.80 (1H, dd, J=4, 11 Hz), 3.68 (1H, dd, J=6, 11 Hz), 3.53 (2H, t, J=7 Hz), 3.37 (2H, b), 2.36 (2H, b), 1.76 (4H, b), 1.33 (3H, d, J=7 Hz); ES+ MS: 497 (M+H+).
Reaction SMILES: C1COCC1.[BH4-].[Na+].[OH:8][C@@:9]([C:42]1[CH:51]=[CH:50][C:49]2[C:44](=[CH:45][CH:46]=[C:47]([C:52]([NH:54][CH3:55])=[O:53])[CH:48]=2)[CH:43]=1)([C:18]1[N:19]=[CH:20][N:21]([C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=1)[CH2:10][C:11](OC(C)(C)C)=[O:12].[Cl-].[NH4+]>C(OCC)(=O)C.C(O)C.O.[Cl-].[Zn+2].[Cl-]>[OH:8][C@@:9]([C:42]1[CH:43]=[C:44]2[C:49](=[CH:50][CH:51]=1)[CH:48]=[C:47]([C:52]([NH:54][CH3:55])=[O:53])[CH:46]=[CH:45]2)([C:18]1[N:19]=[CH:20][N:21]([C:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=1)[CH2:10][CH2:11][OH:12]
Reactant: CNC(=O)c1ccc2cc([C@@](O)(CC(=O)OC(C)(C)C)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)c1ccc2cc([C@@](O)(CCO)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Reaction time: 0.25 h
Yield: 53.9 %

Procedure:
15 mL of THF was added to 0.47 g (12.5 mmol, 8 eq) of sodium borohydride. 0.85 g (6.27 mmol, 4 eq) of zinc chloride was added at 30° C., and the mixture was stirred at 35˜37° C. for 15 minutes. 1 g (1.57 mmol) of tert-butyl (3S)-3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-trityl-1H-imidazol-4-yl)propanoate was added at 35° C. The mixture was stirred at 45˜49° C. for 24 hours and 30 minutes. 5 mL of water was added dropwise at 35° C. or lower. 15 mL of water and 5 mL of an aqueous saturated ammonium chloride solution were added, and the mixture was stirred at 20˜25° C. for 6 hours. After diluted with 50 mL of ethyl acetate, 10 mL of ethanol and 10 mL of water, insoluble materials were filtered. The filtrate was separated, and the organic layer was washed successively with 20 mL of water and 20 mL of an aqueous saturated sodium chloride solution. After concentrated under reduced pressure, 1 mL of ethyl acetate and 2 mL of IPE were added to the concentration residue, crystals were loosened, filtered, and washed with 1.25 mL of ethyl acetate/IPE=1/1 two times. Vacuum drying (40° C.) to a constant weight afforded 0.48 g of 6-[(1S)-1,3-dihydroxy-1-(1-trityl-1H-imidazol-4-yl)propyl]-N-methyl-2-naphthamide (yield 58%).
Reaction SMILES: C(S[C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:7]=2[N:8]=1)C.[CH3:16][NH:17][CH:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1>>[CH3:16][N:17]([CH:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1)[C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:7]=2[N:8]=1
Reactant: CCSc1nc2cc([N+](=O)[O-])ccc2o1
Reactant: CNC1CCN(C)CC1
Product: CN1CCC(N(C)c2nc3cc([N+](=O)[O-])ccc3o2)CC1

Procedure:
The title compound is prepared according to the procedure described in General Method A, using 2-ethylsulfanyl-5-nitrobenzooxazole (1.17 g, 5.23 mmol) and methyl-(1-methyl-piperidin-4-yl)-amine (1.37 mL, 9.42 mmol) in anhydrous THP (10 mL) at 100° C.: (0.608 g, 40%). mass spectrum (m/e): 291.0 (M+1).
Reaction SMILES: [C:1]1([CH:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16](O)[CH2:17][CH3:18])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:27].C(=O)([O-])O.[Na+]>C1C=CC=CC=1.CCOCC>[Br:27][CH:16]([CH2:17][CH3:18])[CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][N:8]([CH:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:9][CH2:10]1
Reactant: CCC(O)CCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCC(Br)CCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
1-(4-(diphenylmethyl)piperazinyl)pentane-3-ol (940 mg) was dissolved in benzene (10 ml) and ether (10 ml), and then phosphorus tribromide (0.2 ml) was added thereto, followed by stirring the mixture overnight at room temperature. To the reaction mixture, saturated aqueous sodium hydrogen carbonate solution was added and the resultant was extracted 3 times with ethyl acetate. Organic layers were combined and washed with brine. The resultant was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2) to obtain 340 mg of 1-(3-bromopentyl)-4-(diphenylmethyl)piperazine. Yield: 31%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[C:10](#[N:13])[CH:11]=[CH2:12].[O-]CC.[Na+].BrN1C(=O)CCC1=O>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([NH2:13])=[N:9]2)=[CH:4][CH:3]=1
Reactant: NNc1ccc(Br)cc1
Reactant: C=CC#N
Agent: CC[O-]
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: CCO
Product: Nc1ccn(-c2ccc(Br)cc2)n1

Procedure:
The title compound was prepared by the reaction of 4-bromophenylhydrazine with acrylonitrile in the presence of a suitable base such as sodium ethoxide in refluxing ethanol followed by oxidation with N-bromosuccinimide; 1H NMR (300 MHz, DMSO-d6) δ 3.81 (br s, 2H), 5.84 (s, 1H), 7.41 (d, J=8.7 Hz, 2H), 7.47 (d, J=8.7 Hz, 2H), 7.63 (s, 1H).
Reaction SMILES: C1(S(O[CH2:11][CH2:12][N:13]2[CH2:17][C@H:16]([CH:18]([CH3:20])[CH3:19])[N:15]([C:21]3[CH:26]=[CH:25][N:24]4[N:27]=[CH:28][C:29]([C:30]5[CH:35]=[CH:34][C:33]([C:36]6[N:40]=[CH:39][N:38]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[N:37]=6)=[CH:32][CH:31]=5)=[C:23]4[N:22]=3)[C:14]2=[O:49])(=O)=O)C=CC=CC=1.[NH:50]1[CH2:54][CH2:53][CH2:52][CH2:51]1>>[CH:18]([C@H:16]1[CH2:17][N:13]([CH2:12][CH2:11][N:50]2[CH2:54][CH2:53][CH2:52][CH2:51]2)[C:14](=[O:49])[N:15]1[C:21]1[CH:26]=[CH:25][N:24]2[N:27]=[CH:28][C:29]([C:30]3[CH:31]=[CH:32][C:33]([C:36]4[N:40]=[CH:39][N:38]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[N:37]=4)=[CH:34][CH:35]=3)=[C:23]2[N:22]=1)([CH3:19])[CH3:20]
Reactant: C1CCNC1
Reactant: CC(C)[C@H]1CN(CCOS(=O)(=O)c2ccccc2)C(=O)N1c1ccn2ncc(-c3ccc(-c4ncn(COCC[Si](C)(C)C)n4)cc3)c2n1
Product: CC(C)[C@H]1CN(CCN2CCCC2)C(=O)N1c1ccn2ncc(-c3ccc(-c4ncn(COCC[Si](C)(C)C)n4)cc3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To the crude (S)-2-(4-isopropyl-2-oxo-3-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)imidazolidin-1-yl)ethyl benzenesulfonate from step 1 (5 mL, 0.051 g, 0.071 mmol) was added pyrrolidine (2 mL) and the reaction stirred overnight at ambient temperature. The reaction was concentrated in vacuo and the material taken up in dichloromethane and washed with 1N NaOH. The combined organic layers were concentrated in vacuo and the residue chromatographed using 2% MeOH/dichloromethane to 5% MeOH/dichloromethane to yield (S)-4-isopropyl-1-(2-(pyrrolidin-1-yl)ethyl)-3-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)imidazolidin-2-one (0.041 g, 95%).
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].Br[C:21]1[S:22][CH:23]=[CH:24][C:25]=1[CH3:26].C([O-])([O-])=O.[Cs+].[Cs+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN1C(=O)CCC1>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:21]3[S:22][CH:23]=[CH:24][C:25]=3[CH3:26])=[C:14]([C:16]([F:18])([F:19])[F:17])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)c1cc(C)nn2cc(C(F)(F)F)nc12
Reactant: Cc1ccsc1Br
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCC(CC)c1cc(C)nn2c(-c3sccc3C)c(C(F)(F)F)nc12
Temperature: 130 °C
Reaction time: 8 h
Yield: 7.8 %

Procedure:
To a dry 10 ml round bottom flask with reflux condenser containing 8-(1-ethyl-propyl)-6-methyl-2-trifluoromethyl-imidazo[1,2-b]pyridazine (300 mg, 1.11 mmol), 2-bromo-3-methyl-thiophene (216 mg, 1.22 mmol), and Cs2CO3 (760 mg, 2.33 mmol) is added NMP (1.7 ml). The mixture is degassed with bubbling N2 for 15 min and Pd2(dba)3 (50.8 mg, 0.055 mmol) and PPh3 (58.2 mg, 0.222 mmol) are added. The reaction mixture is stirred at 130° C. overnight. The mixture is cooled to rt, diluted with H2O; and extracted with EtOAc (3×20 ml). The organic layers are dried (Na2SO4), filtered and purified by HPLC to give title compound (32 mg, 0.087 mmol, 8%). 1H-NMR (CDCl3), δ 0.93 (t, J=7.2 Hz, 6H), 1.91 (m, 4H), 2.15 (s, 3H), 2.58 (s, 3H), 3.36 (m, 1H), 6.91 (s, 1H), 7.08 (d, J=5.3 Hz, 1H), 7.55 (d, J=5.5 Hz, 1H) ppm. ES-MS (m/z): calcd for C19H20F3N3S (M+H)+: 367.44; found: 368.1.
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]O)=[CH:20][CH:19]=2)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:10])=[O:9].S(Cl)([Cl:28])=O>ClCCl>[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:28])=[CH:20][CH:19]=2)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:10])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CO)cc1)c1ccccc1Cl
Solvent: ClCCl
Product: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1Cl
Temperature: 0 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
2-chloro-N-{3-[4-(hydroxymethyl)phenyl]pyrazin-2-yl}benzene sulfonamide (3.15 g; 8.4 mmol; 1.00 eq.) was dissolved in dichloromethane (80 mL) and thionyl chloride (8.5 mL, 117 mmol, 14 eq.) was added dropwise. The reaction mixture was stirred overnight. The reaction mixture was poured carefully into ice/water (200 mL) and stirred until clear layers were formed. The mixture was separated and the organic layer was dried over MgSO4 and evaporated down to give the crude solid which was recrystallised in AcOEt/cyclohexane to give the pure 2-chloro-N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}benzenesulfonamide as a white solid (3.02 g, 95% yield, 99% HPLC purity).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][N:11]=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:14].[Na+]>C(O)(=O)C>[C:2]1([C:1]([C:8]2[CH:13]=[CH:12][N:11]=[N:10][CH:9]=2)=[O:14])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Cc2ccnnc2)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(c1ccccc1)c1ccnnc1
Temperature: 100 °C

Procedure:
To a 100° C. suspension of SeO2 (4.75 g, 0.043 mole) in acetic acid (216 mL) was added dropwise to a solution of 4-benzylpyridazine (11; 7.6 g, 0.044.6 mole) in acetic acid (216 mL). The mixture was heated for 1 hour at 100° C. The reaction mixture was cooled to room temperature and was neutralized to a pH ˜6-7 with 50% NaOH. The neutralized mixture was extracted twice with CH2Cl2. The combined extracts were dried over MgSO4 and were evaporated to dryness. The crude product was purified by crystallization in refluxing isopropyl alcohol (10 vol). The yield of phenylpyridazin-4-yl-methanone (12) obtained was 5.8 g or 66%. MS (ESI+): [M+H]+=185.33; 1H NMR (300 MHz, CDCl3), δ ppm: 7.5-7.60(m, 2H), 7.64-7.83 (m, 4H), 9.42-9.51 (m, 2H).
Reaction SMILES: [C:1]1([CH3:35])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.O.[OH-].[Li+]>C1COCC1.O>[C:1]1([CH3:35])[CH:2]=[CH:3][C:4]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCCCCCN1CCCc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(CCCCCCC(=O)O)CCC3)cc1
Temperature: 50 °C
Reaction time: 7.5 h

Procedure:
Ethyl 7-(2,3-di-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoate (step 1) was dissolved in THF (94 ml) and lithium hydroxide monohydrate (7.79 g, 186 mmol) in water (94 ml) was added dropwise. The reaction mixture was warmed to 50° C. and stirred for 7.5 hours. The reaction mixture was concentrated in vacuo to remove the THF and diluted with water (500 ml). The pH of the aqueous layer was adjusted to pH 2 with 1 N HCl (100 ml) and extracted with EtOAc (3×500 ml). The combined organic layers were washed with brine (200 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. The crude solid was suspended in TBME/hexane (1:1, 100 ml) and rotated on the rotary evaporator (no vacuum) at RT until crystals formed. The solid was removed by filtration, washed with heptane (50 ml) and dried at RT overnight. The solid was re-crystallized from a hot mixture of EtOH (211 ml) and water (159 ml). After seeding and stirring for 1 h at 5° C., the crystals were filtered off and the product dried overnight at 40° C. in a vacuum oven to afford the title compound;
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][PH:18]([CH2:20]O)=[O:19])=[CH:14][CH:15]=2)[C:10]([C:22]2[N:23](C(OC(C)(C)C)=O)[C:24]3[C:29]([CH:30]=2)=[CH:28][C:27]([O:31][CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][N:37](C(OC(C)(C)C)=O)[CH2:36][CH2:35]2)=[CH:26][CH:25]=3)=[N:9]1)=O)(C)(C)C.FC(F)(F)C(O)=[O:57]>ClCCl>[N:34]1([CH2:33][CH2:32][O:31][C:27]2[CH:28]=[C:29]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22]([C:10]2[C:11]4[C:16](=[CH:15][CH:14]=[C:13]([O:17][P:18]([CH3:20])(=[O:19])[OH:57])[CH:12]=4)[NH:8][N:9]=2)=[CH:30]3)[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCN(CCOc2ccc3c(c2)cc(-c2nn(C(=O)OC(C)(C)C)c4ccc(O[PH](=O)CO)cc24)n3C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Product: CP(=O)(O)Oc1ccc2[nH]nc(-c3cc4cc(OCCN5CCNCC5)ccc4[nH]3)c2c1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
A solution of 39 mg of the preceding mixture containing mainly 3-{1-tert-butoxycarbonyl-5-[2-(4-tert-butoxycarbonylpiperazin-1-yl)ethoxy]-1H-indol-2-yl}-5-(hydroxymethylphosphinoyloxy)indazole-1-carboxylic acid tert-butyl ester in 1 ml of dichloromethane and 200 μl of trifluoroacetic acid is stirred at 20° C. for 4 hours and the reaction mixture is then evaporated under reduced pressure. The crude compound obtained is purified by preparative LCMS, and the fractions containing the compound of molecular mass 455 are combined and evaporated under reduced pressure to yield 4 mg of methylphosphonic acid mono-{3-[5-(2-piperazin-1-ylethoxy)-1H-indol-2-yl]-1H-indazol-5-yl}ester, which is characterized.
Reaction SMILES: [CH:1]([CH:3]([CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=1)[C:4](OCC)=O)=[O:2].[N+:22]([NH:25][C:26]([NH2:28])=[NH:27])([O-:24])=[O:23].C[O-].[Na+]>CO>[N+:22]([NH:25][C:26]1[NH:28][C:1](=[O:2])[C:3]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)=[CH:4][N:27]=1)([O-:24])=[O:23]
Reactant: N=C(N)N[N+](=O)[O-]
Reactant: CCOC(=O)C(C=O)Cc1cc(OC)c(OC)c(OC)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cc(OC)c1OC
Yield: 13 %

Procedure:
Crude ethyl 2-formyl-3-(3,4,5-trimethoxyphenyl)propionate (7.41 g) was reacted with nitroguanidine (2.62 g) and sodium methoxide in refluxing methanol for 40 hours to give 2-nitroamino-5-(3,4,5-trimethoxybenzyl)-4-pyrimidone in 13% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][C:29](O)=[O:30])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:32].Cl.[NH:34]1[CH2:37][CH:36]([OH:38])[CH2:35]1.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][C:29]([N:34]3[CH2:37][CH:36]([OH:38])[CH2:35]3)=[O:30])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:32]
Reactant: Cc1cc(F)ccc1-c1nc(NCC(=O)O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: OC1CNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1cc(F)ccc1-c1nc(NCC(=O)N2CC(O)C2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reaction time: 16 h
Yield: 49.1 %

Procedure:
A mixture of [8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-acetic acid (100 mg, 0.23 mmol), azetidin-3-ol hydrochloride (37 mg, 0.34), o-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (129 mg, 0.34 mmol) and N-methyl-morpholine (0.12 mL, 1.13 mmol) in DMF (2 mL) was stirred at 23° for 16 h to give the crude material, which was purified by preparative hplc to afford the title compound 56 mg (49%). LC-MS: 496.2 (MH+, m/z), 1.69 (Rt, min).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[C:3]=1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:18]([F:29])[C:17]=1[F:30].O.[CH3:32][N:33](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([N:4]2[CH:5]=[CH:6][C:2]([C:32]#[N:33])=[C:3]2[CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:18]([F:29])[C:17]=2[F:30])=[CH:8][CH:9]=1
Reactant: CN(C)C=O
Reactant: CCOC(=O)CCc1ccc(OCc2c(Br)ccn2-c2ccc(Cl)cc2)c(F)c1F
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: CCOC(=O)CCc1ccc(OCc2c(C#N)ccn2-c2ccc(Cl)cc2)c(F)c1F

Procedure:
A solution of ethyl 3-(4-((3-bromo-1-(4-chlorophenyl)-1H-pyrrol-2-yl)methoxy)-2,3-difluorophenyl)propanoate (90 mg, 0.18 mmol, 1 eq), zinc cyanide (64 mg, 0.54 mmol, 3 eq), 1,1′-bis(diphenylphosphino)ferrocene (10 mg, 0.018 mmol, 0.1 eq), Pd2(dba)3 (16.5 mg, 0.018 mmol, 0.1 eq) in DMF (1.4 mL) under N2 was heated at 130° C. overnight in a vial. To the resulting mixture was added water, the aqueous was extracted with DCM, dried over MgSO4 and concentrated. The resulting residue was purified by flash chromatography (12 g column) eluting with 10 to 30% EtOAc/heptane to yield ethyl 3-(4-((1-(4-chlorophenyl)-3-cyano-1H-pyrrol-2-yl)methoxy)-2,3-difluorophenyl)propanoate.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.N1C2C(=CC=CC=2)C=CC=1.[C:16]([C:18]1[C:19](O)=[N:20][CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)#[N:17].C(=O)(O)[O-].[Na+]>O>[Cl:3][C:19]1[C:18]([C:16]#[N:17])=[CH:23][C:22]([C:24]([F:27])([F:26])[F:25])=[CH:21][N:20]=1
Reactant: N#Cc1cc(C(F)(F)F)cnc1O
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccc2ncccc2c1
Product: N#Cc1cc(C(F)(F)F)cnc1Cl
Temperature: 25 °C

Procedure:
To a mixture of phosphorous oxychloride (13.4 mL, 144 mmol) and quinoline (8.7 mL, 73 mmol) was added the product from Step C above (24.6 g, 131 mmol) and the resultant mixture was heated to reflux for 3 h. The reaction was cooled to 100° C. before water (70 mL) was slowly added. The mixture was further cooled to room temperature and neutralized by the cautious addition of saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with three portions of ethyl acetate and the organic layers were combined, dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography to afford the desired compound. 1H NMR (500 MHz, CDCl3) δ 8.88 (d, J=2.0 Hz, 1H), 8.26 (d, J=2.5 Hz, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[ClH:23]>>[ClH:23].[O:20]1[CH2:21][CH2:22][CH:17]([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[CH2:9][NH:8][CH2:16]3)[CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(C3CCOCC3)cc2C1
Agent: Cl
Product: c1cc2c(cc1C1CCOCC1)CNC2

Procedure:
Prepared in analogy to Example A3(e) from 5-(tetrahydro-pyran-4-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and hydrochloric acid. White solid. MS (m/e): 204.3 ([M+H]+, 100%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:20][C:19](=[O:21])[C:18]3[C:13](=[CH:14][C:15]([Cl:22])=[CH:16][CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])C.[Li+].[OH-]>C1COCC1>[Cl:22][C:15]1[CH:14]=[C:13]2[C:18]([C:19](=[O:21])[NH:20][C:11]([N:9]3[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]3)=[N:12]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Cl)ccc3c(=O)[nH]2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cnn(-c2nc3cc(Cl)ccc3c(=O)[nH]2)c1
Temperature: 0 °C
Reaction time: 6 h
Yield: 95.3 %

Procedure:
A mixture of 1-(7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (240 mg, 0.74 mmol), 1M aq. LiOH (4.0 mL), and THF (6 mL) was rapidly stirred for 6 h. The mixture was concentrated to remove the THF, and the aqueous residue was cooled to 0° C. and acidified to pH 2 with 1 M aq. HCl. The resulting precipitate was collected by filtration to provide the titled compound (205 mg, 71%). MS (Cl): mass calcd. for C12H7ClN4O3, 290.7; m/z found, 289.0 [M−H]−. 1H NMR (400 MHz, DMSO-d6): 12.99 (br s, 2H), 8.93 (d, J=0.7 Hz, 1H), 8.27 (s, 1H), 8.11 (d, J=8.5 Hz, 1H), 7.74 (d, J=1.9 Hz, 1H), 7.54 (dd, J=8.5, 2.1 Hz, 1H).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([NH:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CCCCCC>[CH2:10]([N:17]([CH2:18][CH2:19][CH2:20][CH3:21])[C:8]([NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCCCNCc1ccccc1
Reactant: O=C=Nc1ccccc1
Solvent: CCCCCC
Product: CCCCN(Cc1ccccc1)C(=O)Nc1ccccc1

Procedure:
A solution of 4.89 g. of phenylisocyanate in 100 ml. of hexane was added to a solution of 4.41 g. of N-benzyl-n-butylamine in 150 ml. of hexane and the solution was stirred at room temperature for 2 hours and then evaporated. The residual solid was recrystallized from pentane to yield 1-benzyl-1-(n-butyl)-3-(phenyl)urea.