Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:20])[CH2:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)=[O:6].O.CO.[Cl-].[Li+]>O1CCCC1>[C:16]([O:15][C:13]([N:10]1[CH2:9][CH2:8][N:7]([C:5](=[O:6])[CH2:4][C:3]([OH:20])=[O:2])[CH2:12][CH2:11]1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: COC(=O)CC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-[4-(tert-Butoxycarbonyl)piperazin-1-yl]-3-oxopropionic acid methyl ester (35) (3.30 g; 11.5 mmol) is dissolved in 2:2:2 tetrahydrofuran: water: methanol. Lithium chloride (2.76 g; 115.3 mmol) is added and the mixture is stirred for 1 hour at ambient temperature. The solution is concentrated in vacuo to remove the tetrahydrofuran and methanol. The concentrate is poured onto citric acid solution (115 mL) and extracted with ethyl acetate (230 mL). The organic layer is washed with water (3×115 mL) and brine (1×115 mL), then dried over magnesium sulfate, filtered and concentrated in vacuo to afford the desired product as a solid. ESMS: MH+ 273.0
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH:18]=O)[CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1.[CH2:20]([S:22]([NH2:25])(=[O:24])=[O:23])[CH3:21].C1(C)C=CC=CC=1.[BH4-].[Na+]>C(Cl)Cl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:12]3[CH:17]=[C:16]([CH2:18][NH:25][S:22]([CH2:20][CH3:21])(=[O:24])=[O:23])[CH:15]=[N:14][CH:13]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1c(-c2cncc(C=O)c2)cc2ccc(Cl)cc21
Reactant: CCS(N)(=O)=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCS(=O)(=O)NCc1cncc(-c2cc3ccc(Cl)cc3n2C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A flask is charged with 6-chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole (Example 126a, 1.2 g, 4.43 mmol), ethanesulfonamide (0.726 g, 6.65 mmol), titanium(IV) isopropoxide (2.60 mL, 8.87 mmol) and toluene (50 mL). The reaction mixture is refluxed overnight and then concentrated to dryness. The crude material (1.60 g) is dissolved in MeOH (24 mL) and DCM (24 mL), and sodium borohydride (0.335 g, 8.87 mmol) is added. The reaction mixture is stirred at room temperature for 2 h, then concentrated in vacuo. The residue is taken up in DCM and washed with water twice. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo. Purification is achieved by silica gel flash chromatography to give N-[5-(6-Chloro-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-ethanesulfonamide. 1H NMR (400 MHz, MeOD) δ ppm 1.38 (t, J=7.3 Hz, 3H), 3.14 (q, J=7.3 Hz, 2H), 3.80 (s, 3H), 4.43 (s, 2H), 6.72 (s, 1H), 7.12 (dd, J=8.5, 1.9 Hz, 1H), 7.54 (d, J=1.8 Hz, 1H), 7.59 (d, J=8.6 Hz, 1H), 8.10 (t, J=2.1 Hz, 1H), 8.63 (d, J=2.0 Hz, 1H), 8.71 (d, J=2.0 Hz, 1H). HRMS (ESI) m/z 364.0869 [(M+H)+ Calcd for C17H19ClN3O2S: 364.0887].
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[Li].[Cl:7][C:8]1[CH:24]=[CH:23][C:11]([CH2:12][C:13]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=O)=[CH:10][CH:9]=1.Cl.CCCCCC>C1COCC1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:12][C:13]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[C:2]2[CH:1]=[CH:5][CH:4]=[CH:3]2)=[CH:23][CH:24]=1
Reactant: O=C(Cc1ccc(Cl)cc1)Cc1ccc(Cl)cc1
Reactant: C1=CCC=C1
Agent: Cl
Agent: [Li]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Clc1ccc(CC(Cc2ccc(Cl)cc2)=C2C=CC=C2)cc1
Temperature: -78 °C
Yield: 22.2 %

Procedure:
Under a nitrogen atmosphere, a 100-mL three-necked flask was charged with 0.66 g (9.22 mmol) of lithium cyclopentadiene and 10 mL of dehydrated THF, and the mixture was stirred. This solution was cooled (to −78° C.) in a dry ice/methanol bath, and 2.50 g (8.96 mmol) of bis(4-chlorobenzyl)ketone dissolved in 15 mL of dehydrated THF was added dropwise. Subsequently, the mixture was stirred for 17 hours while gradually warming to room temperature. Then, 1 N hydrochloric acid was added to the resulting brown-black solution to terminate the reaction. Thereafter, hexane was added to perform liquid-liquid phase separation, and the aqueous layer was subjected to extraction with hexane twice. The resultant was combined with the organic layer obtained previously. The resultant liquid was then washed two times with a saturated aqueous solution of sodium hydrogen carbonate, two times with water, and once with saturated brine, and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography to obtain a target product as a yellow powder (yield 0.65 g (22%)). The target product was identified by 1H-NMR.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([O:18][CH3:19])[CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH2:4][C@H:3]1[O:20][CH3:21].[Cl:22][C:23]1[N:24]=[C:25]([C:30](O)=[O:31])[NH:26][C:27]=1[CH2:28][CH3:29].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CC(N(C)C)=O.ClCCl>[Cl:22][C:23]1[N:24]=[C:25]([C:30]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[CH:9]=[C:10]([CH:15]=[C:16]([O:18][CH3:19])[CH:17]=3)[C:11]([O:13][CH3:14])=[O:12])[CH2:4][C@H:3]2[O:20][CH3:21])=[O:31])[NH:26][C:27]=1[CH2:28][CH3:29]
Reactant: COC(=O)c1cc(OC)cc(N2CC[C@H](N)[C@H](OC)C2)c1
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3cc(OC)cc(C(=O)OC)c3)C[C@H]2OC)nc1Cl
Yield: 87.7 %

Procedure:
The same operation as in Example (1g) was performed using methyl cis(±)-3-(4-amino-3-methoxypiperidin-1-yl)-5-methoxybenzoate obtained in Example (257c) (about 0.25 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (48 mg, 0.22 mmol), WSC hydrochloride (139 mg, 0.73 mmol), HOBT (49 mg, 0.36 mmol), dichloromethane (2 mL) and DMA (2 mL), to obtain 87 mg of the title compound (88%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[N:8][O:9][C:10]=1[CH:11]([CH3:13])[CH3:12])=[O:5])C.O[Li].O>C1COCC1.O>[CH:11]([C:10]1[O:9][N:8]=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[C:6]=1[C:4]([OH:5])=[O:3])([CH3:13])[CH3:12]
Reactant: CCOC(=O)c1c(-c2cccc(F)c2)noc1C(C)C
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1onc(-c2cccc(F)c2)c1C(=O)O

Procedure:
A mixture of 15 g crude 5-isopropyl-3-(3-fluoro-phenyl)-isoxazole-4-carboxylic acid ethyl ester and 10.08 g (240 mmol) LiOH.H2O in 75 mL THF, 50 mL water was heated under reflux for 15 h. The mixture was concentrated, acidified and extracted with ethyl acetate. The combined organic extracts were dried with Na2SO4 and evaporated to yield 4.1 g (33% in two steps) of the title compound as a light yellow solid. (m/e): 250.1 (MH+; 100%).
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:12]([CH:26]2[CH2:31][CH2:30][N:29]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:28][CH2:27]2)[C:11]1=[O:39].C(N1CCC(N2C(C3C=CC=CC=3)C3C(=CC=CC=3)NC2=O)CC1)C1C=CC=CC=1.O1CCCCC1OCCBr.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CO>[OH:7][CH2:8][CH2:9][N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:12]([CH:26]2[CH2:31][CH2:30][N:29]([CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:28][CH2:27]2)[C:11]1=[O:39]
Reactant: O=C1N(CCOC2CCCCO2)c2ccccc2C(c2ccccc2)N1C1CCN(Cc2ccccc2)CC1
Agent: BrCCOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Solvent: CO
Solvent: O
Product: O=C1N(CCO)c2ccccc2C(c2ccccc2)N1C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In similar way as in Preparation example 3, 1-[2-(tetrahydropyran-2-yl)oxyethyl]-3-(1-benzylpiperidin-4-yl)-4-phenyl-3,4-dihydro-2(1H)-quinazolinone was prepared from 99.4 mg (0.25 mmol) of 3-(1-benzylpiperidin-4-yl)-4-phenyl-3,4-dihydro-2(1H)-quinazolinone and 157 mg (0.75 mmol) of 2-(tetrahydropyran-2-yl)oxyethyl bromide as colorless oil. To a solution of the obtained oil in 4 ml of methanol, 57 mg (0.30 mmol) of p-toluenesulfonic acid monohydrate were added and stirred at room temperature for one hour. The reaction liquid was poured into aqueous saturated sodium bicarbonate solution and extracted with ethyl acetate. It was washed with saturated brine and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate, 1/1 to 1/4) to give 100 mg (0.23 mmol) of the title compound as colorless amorphous.
Reaction SMILES: CC(N)COCC(OCC(OCC([NH2:16])C)C)C.[C:18]([O-:23])(=[O:22])[C:19]([CH3:21])=[CH2:20].C([C:27]([CH3:29])=O)CC>>[NH2:16][C:18]([O:23][CH2:27][CH3:29])=[O:22].[C:18]([O-:23])(=[O:22])[C:19]([CH3:21])=[CH2:20]
Reactant: CC(N)COCC(C)OCC(C)OCC(C)N
Reactant: CCCC(C)=O
Agent: C=C(C)C(=O)[O-]
Product: CCOC(N)=O
Temperature: 25 °C

Procedure:
59.95 g-(0.010 m) α,β-di(1-methyl-aminoethyl) poly-(ethylene oxide-co-propyleneoxide) of MW 5995 (Jeffamine-ED 5000, TEXACO Corp.) and 59.95 g of anhydrous methyl propyl ketone are charged into a 3-necked round bottomed flask equipped with a stirrer, nitrogen inlet, condenser, thermometer and dropping funnel. The solution is stirred at room temperature under dry nitrogen. Then 3.10 g (0.020 mole) of 2-isocyanotoethyl methacrylate (MW 155) dissolved in 3.1 g of anhydrous methyl propyl ketone are added slowly from the dropping funnel. The mildly exothermic reaction is maintained at 35° C. and below by water bath cooling for 1 hour at which time an IR analysis shows the reaction to be complete.
Reaction SMILES: [CH2:1]([O:5][P:6]([C:13]1[CH:17]=[C:16]([Sn:18]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[S:15][C:14]=1[Sn](CCCC)(CCCC)CCCC)(OCCCC)=[O:7])[CH2:2][CH2:3][CH3:4].C([Li])CCC.P([O-])([O-])(O)=O.[Na+].[Na+].P([O-])(O)(O)=O.[Na+]>C1COCC1>[CH2:1]([O:5][P:6](=[C:13]1[CH:17]=[C:16]([Sn:18]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[S:15][CH2:14]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOP(=O)(OCCCC)c1cc([Sn](CCCC)(CCCC)CCCC)sc1[Sn](CCCC)(CCCC)CCCC
Agent: O=P([O-])(O)O
Agent: O=P([O-])([O-])O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCO[P+]([O-])=C1C=C([Sn](CCCC)(CCCC)CCCC)SC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
In THF, 8.48 g (9.90 mmols) of 3-(dibutoxyphosphoryl)-2,5-bis(tributylstannyl)thiophene was dissolved and cooled down to −78° C. Commercially available n-butyl lithium (1.59 M hexane solution, 10.9 mmols) was slowly dropped, followed by stirring for 1 hour at a standing temperature. Thereafter, a disodium hydrogen phosphate/sodium dihydrogen phosphate buffer solution, adjusted to pH=7, was added, followed by extraction with ethyl acetate. The organic phase was washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was removed by distilling off under reduced pressure, and the resulting crude product was purified with a silica gel column (gradiated from ethyl acetate:hexane=1:10 with ethyl acetate:hexane=1:2) to obtain the specified substance in the form of a transparent oil at a yield of 4.64 g (yield: 83%). The thus obtained substance was used as it is for reaction in Example 12(18).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])=[O:4].S(Cl)(Cl)=O.O.[NH2:22][NH2:23]>>[N+:14]([C:6]1[CH:7]=[C:8]([C:9]([NH:22][NH2:23])=[O:10])[CH:12]=[CH:13][C:5]=1[C:3]([O:2][CH3:1])=[O:4])([O-:16])=[O:15]
Reactant: COC(=O)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: NN
Solvent: O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C(=O)NN)cc1[N+](=O)[O-]

Procedure:
From 4-methoxycarbonyl-3-nitrobenzoic acid, thionyl chloride and hydrazine monohydrate, 758 mg of the desired product was obtained in the same manner as in Reference Synthetic Example 39 as a white solid (yield 79%).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][CH:2]=1.Cl[C:10]1[O:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1>CN1C(=O)CCC1.O>[O:11]1[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=[C:10]1[NH:7][C:4]1[CH:5]=[CH:6][C:1]([NH2:8])=[CH:2][CH:3]=1
Reactant: Nc1ccc(N)cc1
Reactant: Clc1nc2ccccc2o1
Solvent: CN1CCCC1=O
Solvent: O
Product: Nc1ccc(Nc2nc3ccccc3o2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104 %

Procedure:
To a solution of benzene-1,4-diamine (5.0 g) in NMP (30 mL) was added dropwise, over 0.5 h, a solution of 2-chlorobenzo[d]oxazole (6.03 g) in NMP (50 mL). After the addition was complete, the mixture was stirred at ambient temperature for 1 h. After this time, the reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with brine (150 mL), dried (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure. The residue obtained was purified by chromatography (silica, methylene chloride to 1:19 methanol/methylene chloride) to afford N-(1,3-benzoxazol-2-yl)benzene-1,4-diamine (9.20 g) as an off-white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].N1C=CC=CC=1.[Cl:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]([CH3:25])[C:16]=1[CH:26]([O:29][C:30]([CH3:36])([CH3:35])[C:31]([F:34])([F:33])[F:32])[CH2:27][OH:28]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:3]([O:28][CH2:27][CH:26]([C:16]1[C:17]([CH3:25])=[CH:18][C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]=1[Cl:14])[O:29][C:30]([CH3:36])([CH3:35])[C:31]([F:32])([F:33])[F:34])(=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1cc2ccccc2c(Cl)c1C(CO)OC(C)(C)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc2ccccc2c(Cl)c1C(COC(=O)C(C)(C)C)OC(C)(C)C(F)(F)F
Temperature: 25 °C

Procedure:
To a stirred solution of trimethylacetyl chloride (0.17 mL, 1.36 mmol) and 4-(Dimethylamino)pyridine (55 mg, 0.45 mmol) in pyridine (2.4 mL, 29.48 mmol), 2-(1-chloro-3-methylnaphthalen-2-yl)-2-(1,1,1-trifluoro-2-methylpropan-2-yloxy)ethanol (157 mg, 0.45 mmol) in CH2Cl2 (2.4 mL) was added at 0° C. The reaction mixture was allowed to warm to room temperature overnight. The mixture was quenched with water and concentrated and purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give 2-(1-chloro-3-methylnaphthalen-2-yl)-2-(1,1,1-trifluoro-2-methylpropan-2-yloxy)ethyl pivalate. 1H-NMR: 400 MHz, (CDCl3) δ 8.26 (d, J=8.4 Hz, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.58-7.48 (m, 3H), 6.05 (dd, J=8.4, 5.2 Hz, 1H), 4.50 (dd, J=11.2, 8.4 Hz, 1H), 4.21 (dd, J=11.2, 4.8 Hz, 1H), 2.73 (s, 3H), 1.43 (s, 3H), 1.19 (s, 3H), 1.16 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:16]=[C:15]([O:17][CH2:18][C@@H:19]([NH:21][C:22](=[O:24])[CH3:23])[CH3:20])[N:14]=[CH:13][C:12]=3[N:25]=2)[CH:5]=[CH:6][C:7]=1[OH:8].Br[CH2:27][C:28](=[O:31])[CH2:29][CH3:30]>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:16]=[C:15]([O:17][CH2:18][C@@H:19]([NH:21][C:22](=[O:24])[CH3:23])[CH3:20])[N:14]=[CH:13][C:12]=3[N:25]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:27][C:28](=[O:31])[CH2:29][CH3:30]
Reactant: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(O)c(F)c3)nc2cn1
Reactant: CCC(=O)CBr
Product: CCC(=O)COc1ccc(-c2nc3cnc(OC[C@H](C)NC(C)=O)cc3o2)cc1F

Procedure:
Using N-((2S)-1-((2-(3-fluoro-4-hydroxyphenyl)[1,3]oxazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)acetamide and 1-bromobutan-2-one, and in the same manner as in Example 5, the title compound was obtained.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH:12]([C:14]1[N:18]2[N:19]=[C:20]([C:23]3[CH:24]=[N:25][N:26]([CH2:28][CH2:29][O:30]C4CCCCO4)[CH:27]=3)[CH:21]=[CH:22][C:17]2=[N:16][CH:15]=1)[CH3:13].Cl>C(Cl)Cl.O1CCOCC1>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH:12]([C:14]1[N:18]2[N:19]=[C:20]([C:23]3[CH:24]=[N:25][N:26]([CH2:28][CH2:29][OH:30])[CH:27]=3)[CH:21]=[CH:22][C:17]2=[N:16][CH:15]=1)[CH3:13]
Reactant: CC(c1cc2cccnc2cc1F)c1cnc2ccc(-c3cnn(CCOC4CCCCO4)c3)nn12
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(c1cc2cccnc2cc1F)c1cnc2ccc(-c3cnn(CCO)c3)nn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (rac)-7-fluoro-6-[1-(6-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-imidazo[1,2-b]pyridazin-3-yl)-ethyl]-quinoline (Stage 255.1, 49 mg, 0.101 mmol) in DCM (3 mL) stirred at rt was added a solution of HCl in dioxane (4 M, 0.252 mL). The RM was stirred 1 h at rt, during this time the product precipitated as an oil. The residue was taken in DCM and water, then neutralized with a solution of 10% NaHCO3 and extracted with DCM. The combined organic phase was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (CombiFlash® Companion System®, with RediSep® silica gel column, EtOAc/MeOH (1% NH3)=100:0->80:20) to afford the title compound as a white crystalline powder (tR 3.40 min (conditions 3), MH+=403.3, 1H-NMR in DMSO-d6: 8.81 (d, 1H), 8.35-8.28 (m, 2H); 8.05 (d, 1H); 7.95-7.88 (m, 2H), 7.76 (d, 1H); 7.72 (s, 1H); 7.49 (d, 1H); 7.46-7.40 (m, 1H); 5.03 (q, 1H); 4.92 (t, 1H); 4.15 (t, 2H); 3.72 (q, 2H); 2.83 (d, 3H)).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[CH:4][C:3]=1[CH2:10][C:11]([OH:13])=[O:12].BrB(Br)Br.O>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:10][C:11]([OH:13])=[O:12]
Reactant: COc1ccc(CC(=O)O)c(Br)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=C(O)Cc1ccc(O)cc1Br
Temperature: 25 °C
Yield: 97.4 %

Procedure:
To a solution of (2-bromo-4-methoxyphenyl)acetic acid (0.49 g) in dichloromethane (5 mL) was added a solution of tribromoborane (5 mL) dropwise at room temperature. The mixture was refluxed for 3 hr. After cooling to room temperature, the mixture was poured into iced water. The organic layer was separated, and the water layer was extracted by ethyl acetate (30 mL×3). The combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The residue was washed with ether to give the title compound (0.45 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:4][CH:3]=1.[Li]CCCC.CN([CH:23]=[O:24])C.Cl.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])[C:5]([CH:23]=[O:24])=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: CC(C)(C)C(=O)Nc1cccc(Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1nc(Cl)ccc1C=O
Temperature: -20 °C
Reaction time: 3 h
Yield: 58.9 %

Procedure:
A solution of intermediate 5 (19.28 g, 90.6 mmol) in THF (181 mL) was treated with n-BuLi (108.8 mL, 272 mmol) and the resulting mixture was stirred at −20° C. for 3 h. After addition of DMF (20.81 mL, 271.86 mmol), the reaction was allowed to warm to rt. The reaction was poured into cold 6N HCl and stirred for 15 min. The mixture was then neutralized with anhydrous K2CO3 to pH=7 and extracted with Et2O. The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by recrystallization from EtOAc and hexanes to afford N-(6-chloro-3-formylpyridin-2-yl)pivalamide (intermediate 6) (12.84 g, 59%).
Reaction SMILES: [C:1]([C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1)#[N:2].C([O-])(=O)C.[K+].CC1(C)C(C)(C)OB([C:42]2[CH:43]=[CH:44][C:45]3[O:49][C:48](=[O:50])[NH:47][C:46]=3[CH:51]=2)O1>C(#N)C.O>[C:1]([C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:42]2[CH:43]=[CH:44][C:45]3[O:49][C:48](=[O:50])[NH:47][C:46]=3[CH:51]=2)=[CH:7][CH:6]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@H](C#N)Cc2ccc(I)cc2)CCOCC1
Reactant: CC1(C)OB(c2ccc3oc(=O)[nH]c3c2)OC1(C)C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@H](C#N)Cc2ccc(-c3ccc4oc(=O)[nH]c4c3)cc2)CCOCC1
Temperature: 90 °C
Yield: 52.6 %

Procedure:
(S)-tert-Butyl 4-(1-cyano-2-(4-iodophenyl)ethylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 15, step (i), 300 mg), potassium acetate (177 mg) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2(3H)-one (Example 33, step (i), 157 mg) in a mixture of acetonitrile (25 mL) and water (10 mL) under a nitrogen atmosphere, was treated with 1,1 bis(di-tert-butylphosphino)ferrocene palladium dichloride (12 mg) and the mixture stirred and heated 90° C. for 18 h. The reaction mixture was cooled to room temperature and diluted with water. The products were extracted into ethyl acetate (2×100 mL) and the combined extracts dried over magnesium sulphate and concentrated to dryness. The residue was purified by chromatography on silica eluting with ethyl acetate to afford the sub-titled compound (160 mg).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7](Cl)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:14][O-:15].[Na+].[NH4+].[Cl-]>CO>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([O:15][CH3:14])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[O-]
Reactant: CC(C)(C)c1ccc(C#N)c(Cl)n1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: COc1nc(C(C)(C)C)ccc1C#N
Yield: 85 %

Procedure:
In a screw cap pressure tube, 6-tert-butyl-2-chloronicotinonitrile (410.0 mg, 2.1 mmol) was dissolved in anhydrous MeOH (3.0 ml) under N2. NaOMe (159.3 mg, 2.9 mmol) was added as a solution in anhydrous MeOH (3.0 ml). The tube was sealed and the mixture refluxed for 20 hours. The mixture was allowed to cool. NH4Cl (sat.) was added and the product extracted with EtOAc. The combined organic extracts were washed with water, dried (MgSO4), filtered and concentrated. Purification was done by flash chromatography (Pet. Ether/EtOAc 95:5) to give the title substance in 85% yield.
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:48])[C:7]1[CH:17]=[C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29]C(=O)C)[C:10]([C:11]([O:13]CC)=[O:12])=[CH:9][C:8]=1[O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][O:44]C(=O)C)C.Cl>O.C(O)C>[OH:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][O:33][C:8]1[CH:9]=[C:10]([C:11]([OH:13])=[O:12])[C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29])=[CH:17][C:7]=1[C:6]([OH:48])=[O:5]
Reactant: CCOC(=O)c1cc(OCCCCCCCCCCOC(C)=O)c(C(=O)OCC)cc1OCCCCCCCCCCOC(C)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc(OCCCCCCCCCCO)c(C(=O)O)cc1OCCCCCCCCCCO

Procedure:
A solution of 20.0 g (303 mmol) 85% aqueous KOH in 200 ml water is added to 38.0 g (58.4 mmol) diethyl-2,5-bis-(10-acetoxydecoxy)terephthalate in 200 ml ethanol and the whole is heated under reflux for 1.5 hours. 28.0 ml conc. HCl are then added dropwise with ice-cooling and stirring until the solution shows an acidic pH. The precipitated, colourless crude product is filtered off, washed neutral and recrystallized from ethanol and methanol/acetone.
Reaction SMILES: N[C:2]1[C:3]([C:10]([NH:12]C=NNC(N)=O)=[O:11])=[N:4][C:5](Cl)=[C:6](N)[N:7]=1.CC1CCC(=O)CC1>CN(C)C=O>[N:4]1[CH:5]=[CH:6][N:7]=[CH:2][C:3]=1[C:10]([NH2:12])=[O:11]
Reactant: NC(=O)NN=CNC(=O)c1nc(Cl)c(N)nc1N
Agent: CC1CCC(=O)CC1
Solvent: CN(C)C=O
Product: NC(=O)c1cnccn1

Procedure:
A solution of 3,5-diamino-6-chloro-N-[[(aminocarbonyl)amino]iminomethyl]-2-pyrazinecarboxamide (0.5 g., 0.0018 mole) and 4-methylcyclohexanone (0.5 ml.) in dimethylformamide (10 ml.) is heated at 95° C. for 20 hours. The reaction mixture is treated with 20 ml. of 2-propanol, filtered, the filtrate distilled at reduced pressure to a volume of 2 ml. and chromatographed on silica gel to give 3,5-diamino-6-chloro-N-(3',4'-dihydro-6'-hydroxy-4-methylspirocyclohexane]1,4']-1,3,5-triazin-2-yl)-2-pyrazinecarboxamide which melts at 274° C.