Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1([O:12][CH3:13])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5].C([O-])([O-])=O.[K+].[K+].[C:20]([O:24][C:25]([N:27]1[CH2:33][CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].C([BH3-])#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-].O>[CH3:13][O:12][C:6]1([C:4]([O:3][CH3:2])=[O:5])[CH2:7][CH2:8][N:9]([CH:30]2[CH2:31][CH2:32][CH2:33][N:27]([C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])[CH2:28][CH2:29]2)[CH2:10][CH2:11]1
Reactant: COC(=O)C1(OC)CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Solvent: O
Solvent: CO
Product: COC(=O)C1(OC)CCN(C2CCCN(C(=O)OC(C)(C)C)CC2)CC1
Temperature: 50 °C
Reaction time: 3 h
Yield: 18.5 %

Procedure:
4-Methoxypiperidine-4-carboxylic acid methyl ester hydrochloride (0.50 g, 2.38 mmol) was dissolved in methanol (10 mL) and treated with K2CO3 (0.328 g, 2.38 mmol) in a minimum of water to de-salt. The reaction mixture was concentrated in vacuo and azeotroped to dryness with toluene. The residue and 4-oxoazepane-1-carboxylic acid tert-butyl ester (0.745 g, 2.38 mmol) were dissolved in methanol (20 mL) at rt and treated with zinc chloride (0.975 g, 7.15 mmol). The reaction mixture was stirred at 50° C. for 3 h. The solution was cooled to room temperature, sodium cyanoborohydride (0.299 g, 4.77 mmol) was added and the reaction mixture was stirred at 50° C. overnight under nitrogen. The solvents were removed in vacuo, and the residue was partitioned between DCM and sat. NaHCO3 sol. The aqueous phase was extracted with DCM (2×20 mL). The organics were combined, washed with sat. NaCl sol. and dried by passing through a Biotage Phase Separator cartridge. The solvents were removed in vacuo and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 25 g, 40-63 μm, 60 Å, 50 mL per min, gradient 1% to 10% MeOH in DCM]) to give tert-butyl 4-[4-methoxy-4-(methoxycarbonyl)piperidin-1-yl]azepane-1-carboxylate (0.163 g, 15.5%) as a colourless oil.
Reaction SMILES: C(OC1C=CC=CC=1CN(CC1C=CC=CN=1)CCCCCCC1CCC(C2C=CC=CC=2OC)CC1)(C)(C)C.Br[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][N:48]([CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=1[O:63][C:64]([CH3:67])([CH3:66])[CH3:65])[CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=1.[CH3:68][O:69][C:70]1[CH:71]=[C:72]2[C:76](=[CH:77][C:78]=1[O:79][CH3:80])[CH2:75][NH:74][CH2:73]2>>[C:64]([O:63][C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][C:57]=1[CH2:56][N:48]([CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=1)[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][N:74]1[CH2:75][C:76]2[C:72](=[CH:71][C:70]([O:69][CH3:68])=[C:78]([O:79][CH3:80])[CH:77]=2)[CH2:73]1)([CH3:67])([CH3:66])[CH3:65]
Reactant: CC(C)(C)Oc1ccccc1CN(CCCCCCBr)Cc1ccccn1
Reactant: COc1cc2c(cc1OC)CNC2
Agent: COc1ccccc1C1CCC(CCCCCCN(Cc2ccccn2)Cc2ccccc2OC(C)(C)C)CC1
Product: COc1cc2c(cc1OC)CN(CCCCCCN(Cc1ccccn1)Cc1ccccc1OC(C)(C)C)C2
Yield: 60 %

Procedure:
The same procedure as described for compound 11 was applied to starting material 10 (0.428 g, 0.988 mmol) and 5,6-dimethoxyisoindoline (0.175 g, 0.975 mmol). Purification was carried out on a silica gel TLC plate that was developed in with a 5% methanolic NH3 (7 M NH3 in methanol/95% CH2Cl2. The product was isolated as pale yellow oil (60%). 1H NMR (CDCl3) δ 8.446 (dd, 1H, Ar), 7.72 (m, 3H, Ar), 7.062 (m, 2H, Ar), 6.981 (ddd, 2H, Ar), 6.888 (s, 2H, Ar), 3.816 (s, 4H, —CH2—CH2—), 3.792 (s, 6H, —OCH3—), 3.714 (s, 2H, —CH2—), 3.637 (s, 2H, —CH2—), 2.611 (t, 2H, —CH2—), 2.436 (t, 2H, —CH2—), 1.503 (m, 4H, —CH2—CH2—), 1.319 (s, 9H, —C(CH3)3), 1.275 (m, 4H, —CH2—CH2—). Mass Spec.=531.73 (M+H)+.
Reaction SMILES: CCN(C(C)C)C(C)C.OC(C(F)(F)F)=O.[O:17]=[C:18]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)[CH2:19][NH:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:25][CH:24]=1)=[O:22].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[F:63][C:64]1[CH:72]=[CH:71][CH:70]=[CH:69][C:65]=1[C:66](O)=[O:67]>CN(C=O)C.O>[F:63][C:64]1[CH:72]=[CH:71][CH:70]=[CH:69][C:65]=1[C:66]([N:38]1[CH2:39][CH2:40][N:35]([C:18](=[O:17])[CH2:19][NH:20][C:21]([C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:27][CH:28]=2)=[O:22])[CH2:36][CH2:37]1)=[O:67]
Reactant: O=C(O)c1ccccc1F
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2F)CC1)c1ccc(-c2ccccc2)cc1
Reaction time: 8 h
Yield: 42.2 %

Procedure:
DIPEA (77.35 mg, 0.598 mmol) was added to a stirred solution of biphenyl-4-carboxylicacid (2-oxo-2-piperazin-1-yl-ethyl)-amide TFA salt (70 mg, 0.16 mmol) in DMF (2 mL). HOBT (19.8 mg, 0.15 mmol) and EDCI.HCl (63.74 mg, 0.33 mmol) were then added. After 2 minutes 2-fluorobenzoic acid (18.6 mg, 0.133 mmol) was added and the resulting mixture was stirred overnight. The reaction mixture was diluted with cold water and the product was precipitated and isolated by filtration to afford crude product, which was purified by column chromotography (using silica gel of 160-120 mesh and 50% EtOAc in hexane as eluent) to afford 25 mg (41.4% yield) of Biphenyl-4-carboxylicacid {2-[4-(2-fluoro-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LC-MS purity: 94.8%, 1H NMR: (CDCl3) δ 7.9 (d, 2H), 7.6 (dd, 4H), 7.4 (m, 4H), 7.2 (s, 1H), 7.1 (t, 1H), 4.4 (dd, 2H), 3.8 (t, 2H), 3.6 (t, 4H), 3.4 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:19])=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]3[N:16]=[C:15]([CH3:17])[O:14][N:13]=3)[C:6]=2[CH:18]=1.[C:20]1(=O)[O:25][C:23](=[O:24])[C:22]2[CH2:26][CH2:27][CH2:28][CH2:29][C:21]1=2>C(O)(=O)C>[F:19][C:3]1[C:2]([N:1]2[C:23](=[O:24])[C:22]3[CH2:26][CH2:27][CH2:28][CH2:29][C:21]=3[C:20]2=[O:25])=[CH:18][C:6]2[N:7]([CH2:11][C:12]3[N:16]=[C:15]([CH3:17])[O:14][N:13]=3)[C:8](=[O:10])[S:9][C:5]=2[CH:4]=1
Reactant: Cc1nc(Cn2c(=O)sc3cc(F)c(N)cc32)no1
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: CC(=O)O
Product: Cc1nc(Cn2c(=O)sc3cc(F)c(N4C(=O)C5=C(CCCC5)C4=O)cc32)no1
Reaction time: 0.5 h
Yield: 70 %

Procedure:
A mixture of 5-amino-6-fluoro-3-(5-methyl-1,2,4-oxadiazol-3-ylmethyl)-2(3H)-benzothiazolone (2.8 g) and acetic acid (20 ml) was admixed with 3,4,5,6-tetrahydrophthalic anhydride (1.6 g), stirred at a temperature of 20° to 30° C. for 30 minutes, and then heated under refluxing for 2 hours. The reaction mixture was distilled under a reduced pressure to remove the acetic acid therefrom, and the residue was worked up by chromatography, wherein a silica gel column was used together with an eluant. comprising a tetrahydrofuran/toluene mixture (a 1:3 mixture), so that the aimed compound, i.e. 6-fluoro-3-(5-methyl-1,2,4-oxadiazol-3-ylmethyl)-5-(4,5,6,7-tetrahydro-2H-isoindole-1,3-dion-2-yl)-2(3H)-benzothiazolone (2.9 g) was obtained. m.p. 198°-199° C.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:24][CH2:23][CH2:22][C:21]([C:30]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([S:39][CH2:40][C:41]5[N:45]([CH2:46][CH2:47][CH3:48])[CH:44]=[N:43][C:42]=5[CH3:49])=[C:35]([CH3:50])[CH:34]=4)=[O:31])=[CH:20][C:19]=3[CH:51]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:60])C=1>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:24][CH2:23][CH2:22][C:21]([C:30]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([S:39]([CH2:40][C:41]5[N:45]([CH2:46][CH2:47][CH3:48])[CH:44]=[N:43][C:42]=5[CH3:49])=[O:60])=[C:35]([CH3:50])[CH:34]=4)=[O:31])=[CH:20][C:19]=3[CH:51]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4c(C)ncn4CCC)c(C)c2)CCCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4c(C)ncn4CCC)c(C)c2)CCCN3CC(C)C)cc1
Reaction time: 1 h
Yield: 78.2 %

Procedure:
To a solution of 8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[3-methyl-4-[[[4-methyl-1-propylimidazol-5-yl]methyl]sulfanyl]phenyl]-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxamide (290 mg) in dichloromethane (10 ml) was added dropwise a 70% solution of 3-chloro-perbenzoic acid (111 mg) in dichloromethane (10 ml) at −78° C. After stirring as such for 1 hour, the dry ice-acetone bath was removed, and an aqueous sodium thiosulfate solution was added under vigorous stirring. The mixture was returned to room temperature and stirred for 30 minutes, after which water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous saturated sodium bicarbonate solution and saturated brine, and was dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was separated and purified with basic silica gel column chromatography (ethyl acetate→methanol:ethyl acetate=1:30) and recrystallized from hexane-ethyl acetate to give 8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[3-methyl-4-[[[4-methyl-1-propylimidazol-5-yl]methyl]sulfinyl]phenyl]-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxamide (232 mg) as yellow crystals (Compound 41).
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[C:5]([CH2:9]Br)[C:6]=1[CH2:7]Br.Cl.[NH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[S:3][CH:4]=[C:5]2[CH2:9][N:12]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:7][C:6]=12
Reactant: CCOC(=O)CN
Reactant: Clc1scc(CBr)c1CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1Cc2csc(Cl)c2C1
Temperature: 5 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
A solution of 12.58 g (0.041 mol) of 2-chloro-3,4-bis(bromomethyl)thiophene in 40 ml of dimethylformamide is poured dropwise onto a mixture of 17.77 g of ethyl 2-aminoacetate hydrochloride, 45.5 g of finely powdered potassium carbonate and 80 ml of dimethylformamide, cooled to 5° C. The mixture is stirred at room temperature for 2 h, then poured onto 400 g of a water/ice mixture and stirred for a further 15 min. The mixture is extracted with 5 times 100 ml of diethyl ether, the ether phase is washed with twice 100 ml of salt solution, dried over magnesium sulphate and concentrated. 9.49 g of an oily product are obtained.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[CH:9]1[S:10][CH:11]=[C:12]2[C:18]=1[C:17]([N:19]1[CH2:24][CH2:23][N:22]([CH2:25]CO)[CH2:21][CH2:20]1)=[N:16][C:15]1[CH:28]=[CH:29][CH:30]=[CH:31][C:14]=1[S:13]2.C1SC=C2C=1C(N1CCN(CCO)CC1)=NC1C=CC=CC=1S2.CN1CCNCC1.C([O-])(=O)/C=C/C([O-])=O>C1(C)C=CC=CC=1>[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[CH3:25][N:22]1[CH2:23][CH2:24][N:19]([C:17]2[C:18]3[C:12](=[CH:11][S:10][CH:9]=3)[S:13][C:14]3[CH:31]=[CH:30][CH:29]=[CH:28][C:15]=3[N:16]=2)[CH2:20][CH2:21]1
Reactant: OCCN1CCN(C2=Nc3ccccc3Sc3cscc32)CC1
Agent: CN1CCNCC1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: Cc1ccccc1
Product: CN1CCN(C2=Nc3ccccc3Sc3cscc32)CC1

Procedure:
10-Chloro-thieno[3,4-b][1,5]benzothiazepine (Example 14) is reacted with N-methylpiperazine in toluene giving the base compound, which is then converted to the fumarate, m.p. 186°-188° C.
Reaction SMILES: [N:1]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5][O:4][CH2:3][C@H:2]1[C:7]([O:9]C)=O.[NH2:18][CH2:19][CH2:20][OH:21]>CO>[OH:21][CH2:20][CH2:19][NH:18][C:7]([C@@H:2]1[CH2:3][O:4][CH2:5][CH2:6][N:1]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:9]
Reactant: NCCO
Reactant: COC(=O)[C@@H]1COCCN1C(=O)OC(C)(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCOC[C@H]1C(=O)NCCO
Temperature: 80 °C
Reaction time: 7 h
Yield: 76.7 %

Procedure:
A mixture of (S)-4-tert-butyl 3-methyl morpholine-3,4-dicarboxylate (0.93 g, 3.8 mmol) and 2-aminoethanol (5 g, 81.9 mmol) in methanol (2 mL) was stirred at 80° C. for 7 hours under N2. The mixture was concentrated in vacuo, diluted with EtOAc (100 mL) and acetic acid (5 mL). The organic layer was washed with brine (80 mL×6), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to give the title compound as a white solid (0.8 g, 77%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]#[C:12][C:13]3[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=3)=[CH:9][N:8]([CH:23]3[CH2:26][N:25]([C:27](=[O:32])[CH:28]=[CH:29][CH2:30]Br)[CH2:24]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[NH:33]1[CH2:36][CH2:35][CH2:34]1>C1COCC1>[NH2:1][C:2]1[C:3]2[C:10]([C:11]#[C:12][C:13]3[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=3)=[CH:9][N:8]([CH:23]3[CH2:26][N:25]([C:27](=[O:32])[CH:28]=[CH:29][CH2:30][N:33]4[CH2:36][CH2:35][CH2:34]4)[CH2:24]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C1CNC1
Reactant: COc1cc(C#Cc2cn(C3CN(C(=O)C=CCBr)C3)c3ncnc(N)c23)cc(OC)c1
Solvent: C1CCOC1
Product: COc1cc(C#Cc2cn(C3CN(C(=O)C=CCN4CCC4)C3)c3ncnc(N)c23)cc(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The crude product of 1-(3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidin-1-yl)-4-bromobut-2-en-1-one (10 mg) obtained in Step 1 above was suspended in THF (0.5 ml). Azetidine (7 μl) was added thereto, and the resulting mixture was stirred for 1 hour at room temperature. After concentrating under reduced pressure, the resulting residue was purified by reversed-phase HPLC purification (water/acetonitrile (0.1% formic acid)) to obtain the title compound as a colorless, amorphous substance (1.6 mg). Table 1 shows the physical properties thereof.
Reaction SMILES: [F:1][C:2]1[C:7]([N:8]2[C:12](OS(C(F)(F)F)(=O)=O)=[CH:11][C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([SH:34])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C>[F:1][C:2]1[C:7]([N:8]2[C:12]([S:34][C:31]3[CH:32]=[CH:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=3)=[CH:11][C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cc(OS(=O)(=O)C(F)(F)F)n(-c2cccnc2F)n1
Reactant: COc1ccc(S)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(Sc2ccc(OC)cc2)n(-c2cccnc2F)n1
Temperature: 110 °C
Reaction time: 13 h

Procedure:
A solution of ethyl 1-(2-fluoropyridin-3-yl)-5-{[(trifluoromethyl)sulfonyl]oxy}-1H-pyrazole-3-carboxylate (351 mg), 4-methoxybenzenethiol (141 mg) and sodium carbonate (146 mg) in toluene (5 ml) was sufficiently deaerated, tris(dibenzylideneacetone)dipalladium(0) (17 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (21 mg) were added, and the mixture was further deaerated. Under an argon atmosphere at 110° C., the mixture was stirred for 13 hr, and allowed to cool to room temperature. Ethyl acetate was added, and the mixture was filtered through a silica gel pad. The organic layer of the filtrate was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=9:1→2:1) to give the title compound as a crude yellow oil.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].CC(C)=O.C1(O)C=CC=CC=1.[CH3:18][C:19]1[N:24]=[C:23]2[N:25]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([CH2:38][CH2:39][CH3:40])[CH:32]=3)[C:26]([CH2:28][CH3:29])=[N:27][C:22]2=[C:21]([CH3:41])[CH:20]=1.Br[CH:43]([C:48]1[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=1)[C:44]([O:46][CH3:47])=[O:45]>>[C:44]([CH:43]([C:48]1[CH:49]=[CH:50][C:51]([Cl:54])=[CH:52][CH:53]=1)[O:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][N:25]2[C:23]3=[N:24][C:19]([CH3:18])=[CH:20][C:21]([CH3:41])=[C:22]3[N:27]=[C:26]2[CH2:28][CH3:29])=[CH:32][C:33]=1[CH2:38][CH2:39][CH3:40])([O:46][CH3:47])=[O:45]
Reactant: CCCc1cc(Cn2c(CC)nc3c(C)cc(C)nc32)ccc1O
Reactant: COC(=O)C(Br)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: Oc1ccccc1
Product: CCCc1cc(Cn2c(CC)nc3c(C)cc(C)nc32)ccc1OC(C(=O)OC)c1ccc(Cl)cc1
Yield: 50 %

Procedure:
Using the K2CO3 /acetone conditions for phenol alkylation described in Step A of Example 4; 5,7-dimethyl-2-ethyl-3-[4-hydroxy-3-propylphenyl methyl]-3H-imidazo[4,5-b]pyridine (Step A, Example 8) was alkylated with methyl 2-bromo-2-(4-chlorophenyl)acetate. Standard workup and purification by flash chromatography afforded a 50% yield of the title compound.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1Cl)=[O:13])[CH2:8]2.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:13])[CH2:8]2
Reactant: C1CCNCC1
Reactant: CC(C)(C)n1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1Cl
Product: CC(C)(C)n1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1N1CCCCC1

Procedure:
Heating a mixture of 1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Example 36, 101 mg; 0.30 mmol) and piperidine (0.30 mL; 3.0 mmol) under microwave irradiation according to the procedure described in Example 37, Step 5 provided after purification by reverse phase HPLC, 1-tert-butyl-5-piperidin-1-yl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (19 mg, 16%) as an off-white powder. ES-HRMS m/e calcd for C23H37N4O (M+H+) 385.2962, found 385.2958.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][C:14]=3[O:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][C:19]=3[F:27])[CH:9]=2)=[CH:6][N:5]=[CH:4]1)[CH3:2].[BH4-].[Na+]>CO.C1COCC1.Cl[Ni]Cl>[CH2:1]([N:3]1[C:7]([C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][C:14]=3[O:17][C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=3[F:27])[CH:9]=2)=[CH:6][N:5]=[CH:4]1)[CH3:2]
Reactant: CCn1cncc1-c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCn1cncc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Reaction time: 1 h
Yield: 71.2 %

Procedure:
To a solution of the nitro compound 119 (3.05 g, 7.93 mmol) in MeOH/THF (50 ml/50 mL) was added NiCl2×6H2O (3.77 g, 15.86 mmol) and NaBH4 (1.18 g, 31.73 mmol). The reaction mixture was allowed to stir for 1 hr, concentrated to dryness and the resultant solid was dissolved in 2 M HCl. The acidic solution was then made basic with aqueous ammonium hydroxide solution and extracted with EtOAc. The organic extract was dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography (eluents DCM-MeOH, 98:2, 95:5, 9:1) to afford title compound 120 (2.00 g, 71% yield) as a yellow solid. MS (m/z): 355.1 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@H:10]([C:14]([OH:17])([CH3:16])[CH3:15])[C:11](O)=[O:12])=[C:5]([CH3:18])[C:4]=1[C:19]([F:22])([F:21])[F:20])#[N:2].[C:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([NH:31][NH2:32])=[O:30])=[CH:27][CH:26]=1)#[N:24].OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>C1COCC1.C(OCC)(=O)C>[C:23]([C:25]1[CH:26]=[CH:27][C:28]([C:29]([NH:31][NH:32][C:11](=[O:12])[C@H:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([C:19]([F:22])([F:21])[F:20])[C:5]=2[CH3:18])[C:14]([OH:17])([CH3:16])[CH3:15])=[O:30])=[CH:33][CH:34]=1)#[N:24]
Reactant: N#Cc1ccc(C(=O)NN)cc1
Reactant: Cc1c(N[C@@H](C(=O)O)C(C)(C)O)ccc(C#N)c1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(C#N)cc2)C(C)(C)O)ccc(C#N)c1C(F)(F)F
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 108.8 %

Procedure:
(R)-2-(4-cyano-2-methyl-3-(trifluoromethyl)phenylamino)-3-hydroxy-3-methylbutanoic acid (500 mg, 1.58 mmol) and 4-cyanobenzohydrazide (301 mg, 1.87 mmol) were mixed together in THF (20 mL) and cooled to −15° C. under N2 atmosphere. To the pre-cooled reaction mixture were added hydroxybenzotriazole (HOBT) (230 mg, 1.70 mmol), TEA (0.36 mL, 2.55 mmol) followed by N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI) (489 mg, 2.55 mmol). The reaction mixture was allowed to stir at −20° C. for 20 min and then at room temperature overnight. After the reaction was complete, ethyl acetate (50 mL) was added and the solution was washed with 5% citric acid (2×40 mL), 5% NaHCO3 (2×40 mL) followed by water (40 mL) and then dried (Na2SO4) to provide the crude product as a yellow solid (790 mg, 99%): 1H NMR (400 MHz, d6-acetone, δ in ppm) 9.92 (br s, 1H), 9.49 (br s, 1H), 7.99 (d, J=9 Hz, 2H), 7.81 (d, J=9 Hz, 2H), 7.42 (d, J=9 Hz, 1H), 6.61 (d, J=9 Hz, 1H), 6.53 (dd, J=12 and 18 Hz, 1H), 5.99 (d, J=9 Hz, 1H), 5.73 (dd, J=2 and 12 Hz, 2H), 5.64 (dd, J=2 and 18 Hz), 4.29-4.22 (m, 1H), 4.01-3.99 (m, 1H) and 1.20 (d, J=7 Hz, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[C:13]([C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[S:23])=[CH:17][CH:16]=1)#[N:14]>CCOCC>[C:13]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([N:10]2[CH2:9][CH2:8][N:7]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][N:1]=3)[CH2:12][CH2:11]2)=[S:23])=[CH:17][CH:16]=1)#[N:14]
Reactant: c1cnc(N2CCNCC2)cn1
Reactant: N#Cc1ccc(N=C=S)cc1
Solvent: CCOCC
Product: N#Cc1ccc(NC(=S)N2CCN(c3cnccn3)CC2)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 4.92 g. of 1-(2-pyrazinyl)piperazine in 45 ml. of anhydrous ether is added a slurry of 4.8 g. of p-cyanophenyl isothiocyanate in 45 ml. of anhydrous ether, dropwise over 10 minutes. Themixture is stirred for 30 minutes and the resulting solid collected. This solid is dissolved in a mixture of 200 ml. of benzene and 200 ml. of ethanol and then cooled. The resulting solid is collected giving 6.95 g. of the desired product, m.p. 208°-210° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:28]([NH2:29])=[N:27][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1.[H-].[Na+].[C:32]([N:36]=[C:37]=[O:38])([CH3:35])([CH3:34])[CH3:33]>CN(C=O)C>[C:32]([NH:36][C:37]([NH:29][C:28]1[C:9]([C:3]2[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[CH:10][C:11]2[CH:16]=[N:15][C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[N:13][C:12]=2[N:27]=1)=[O:38])([CH3:35])([CH3:34])[CH3:33]
Reactant: Nc1nc2nc(NCCCN3CCOCC3)ncc2cc1-c1c(Cl)cccc1Cl
Reactant: CC(C)(C)N=C=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)Nc1nc2nc(NCCCN3CCOCC3)ncc2cc1-c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
To a solution of 6-(2,6-dichlorophenyl)-N2 -(3-morpholin-4-yl-propyl)-pyrido[2,3-d]pyrimidine-2,7-diamine (1.0 g) from Example 58 in DMF (15 mL) was added one equivalent of 60% sodium hydride suspension (0.92 g). After stirring for approximately 1 hour at room temperature, one equivalent of tert-butyl isocyanate (0.230 g) was added, and the reaction was monitored by thin layer chromatography. After approximately 4 hours, the solvent was removed in vacuo. The residue was partitioned between ethyl acetate and water. The aqueous layer was washed several times with ethyl acetate. The ethyl acetate layers were combined, dried with magnesium sulfate, and concentrated in vacuo. Chromatography of the residue on silica gel using ethyl acetate followed by ethyl acetate:ethanol:triethylamine (18:2:1) gave 0.98 g of the title compound 1-tert-butyl-3-[6-(2,6-dichlorophenyl)-2-(3-morpholin-4-yl-propylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea, CIMS (1% NH3 in CH4): 532=M+ +H, 531=M+, 433, 84 (Base); mp 236-240° C.