Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:27]=2[C:36]2[C:37]([N+:47]([O-])=O)=[N:38][N:39](C3CCCCO3)[CH:40]=2)=[CH:4][C:5]([F:24])=[C:6]([S:8]([N:11]([C:19]2[N:20]=[CH:21][S:22][CH:23]=2)C(=O)OC(C)(C)C)(=[O:10])=[O:9])[CH:7]=1.[Cl-].[NH4+]>C(O)C.[Fe]>[NH2:47][C:37]1[C:36]([C:27]2[CH:28]=[C:29]([C:32]([F:34])([F:35])[F:33])[CH:30]=[CH:31][C:26]=2[O:25][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([S:8]([NH:11][C:19]3[N:20]=[CH:21][S:22][CH:23]=3)(=[O:10])=[O:9])=[C:5]([F:24])[CH:4]=2)=[CH:40][NH:39][N:38]=1
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(Cl)c(Oc2ccc(C(F)(F)F)cc2-c2cn(C3CCCCO3)nc2[N+](=O)[O-])cc1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: Nc1n[nH]cc1-c1cc(C(F)(F)F)ccc1Oc1cc(F)c(S(=O)(=O)Nc2cscn2)cc1Cl

Procedure:
To a solution of tert-butyl [(5-chloro-2-fluoro-4-{2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]-4-(trifluoromethyl)phenoxy}phenyl)sulfonyl]1,3-thiazol-4-ylcarbamate (Preparation 872, 55 g, 74 mmol) in ethanol (800 mL) was added saturated aqueous ammonium chloride solution (200 mL, 3000 mmol) and iron (65 g, 1200 mmol). The reaction solution was heated at 80° C. for two hours at which point iron (10 g, 185 mmol) was added and the mixture heated for an additional hour. The solution was cooled, filtered and adjusted to pH=9 with saturated aqueous sodium bicarbonate solution. The mixture was filtered and then concentrated to remove most of the ethanol. The resulting slurry was extracted with dichloromethane (4×). The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated to provide the free amine as an orange oil. Purification by manual flash column chromatography using 40% then 75% ethyl acetate/hexanes and a 5×31 cm column provided a mix of Boc protected sulphonamide and non-Boc protected sulphonamide free amine as an orange oil. To this mixture was added an HCl(g) saturated methanol solution (400 mL) and the mixture heated at 60° C. for 7 hours. The reaction solution was cooled and concentrated to give a white solid. The solid was redissolved in methanol, heated to reflux and ethyl acetate added until just before a precipitate formed. It was then cooled, washed with ethyl acetate and dichloromethane to provide the title compound as a white solid. This was repeated until no more clean product was obtained. The impure filtrate was purified by prep HPLC, the product fractions concentrated and the TFA salt exchanged for an HCl salt. All product was combined, dissolved in methanol, filtered, concentrated and isolated as a white solid with 1.5 eq of HCl present (30.3 g, 70%) via trituration with dichloromethane.
Reaction SMILES: CS(O[CH2:6][CH:7]1[O:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[O:9][CH2:8]1)(=O)=O.[CH3:17][O:18][C:19]1[C:20]([O:38][CH3:39])=[C:21]([O:36][CH3:37])[C:22]2[S:26][C:25]([NH:27][CH2:28][CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[N:24][C:23]=2[CH:35]=1.[C:40](=[O:43])([O-:42])[O-].[Na+].[Na+].CN(C)C(=O)C>O>[C:10]([OH:18])(=[O:9])/[CH:11]=[CH:13]/[C:40]([OH:42])=[O:43].[O:12]1[C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[O:9][CH2:8][CH:7]1[CH2:6][N:32]1[CH2:33][CH2:34][CH:29]([CH2:28][NH:27][C:25]2[S:26][C:22]3[C:21]([O:36][CH3:37])=[C:20]([O:38][CH3:39])[C:19]([O:18][CH3:17])=[CH:35][C:23]=3[N:24]=2)[CH2:30][CH2:31]1
Reactant: COc1cc2nc(NCC3CCNCC3)sc2c(OC)c1OC
Reactant: CS(=O)(=O)OCC1COc2ccccc2O1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc2nc(NCC3CCN(CC4COc5ccccc5O4)CC3)sc2c(OC)c1OC
Product: O=C(O)/C=C/C(=O)O
Temperature: 75 °C
Reaction time: 8 h
Yield: 48.5 %

Procedure:
A mixture of 2.8 parts of 2,3-dihydro-1,4-benzodioxin-2-methanol methanesulfonate (ester), 3.4 parts of 5,6,7-trimethoxy-N-(4-piperidinylmethyl)-2-benzothiazolamine, 3 parts of sodium carbonate and 67.5 parts of N,N-dimethylacetamide was stirred overnight at about 75° C. Water was added. The product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the (E)-2-butenedioate salt in ethanol and 2-propanone. The salt was filtered off and dried, yielding 3.2 parts (48.5%) of N-[[1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-4-piperidinyl]methyl]-5,6,7-trimethoxy-2-benzothiazolamine (E)-2-butenedioate (2:3); mp. 171.6° C. (compound 26).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH:14]=O)=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[N:16]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO>C(Cl)Cl.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][N:19]2[CH2:18][CH2:17][N:16]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20]2)=[CH:6][CH:7]=1
Reactant: O=Cc1ccccc1-c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2-c2ccc(Cl)cc2)CC1

Procedure:
4′-Chlorobiphenyl-2-carboxaldehyde (4.1 g), tert-butyl piperazine-1-carboxylate (4.23 g) and sodium triacetoxyborohydride (5.61 g) in CH2Cl2 (60 mL) were stirred for 24 hours. The mixture was treated with methanol and poured into ether. The extract was washed with water and brine and concentrated. The concentrate was chromatographed on silica gel with 2-25% ethyl acetate/hexanes.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[C@@H:14]3[CH2:15][C@@H:11]([CH:12]=[CH:13]3)[C@@H:10]2[C:16]([NH2:18])=[O:17])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[C:34]([O:35][CH3:36])=[CH:33][C:24]2[CH2:25][CH2:26][N:27]([CH2:30][CH2:31][OH:32])[CH2:28][CH2:29][C:23]=2[CH:22]=1>>[Cl:19][C:5]1[C:6]([NH:8][C@@H:9]2[C@@H:14]3[CH2:15][C@@H:11]([CH:12]=[CH:13]3)[C@@H:10]2[C:16]([NH2:18])=[O:17])=[N:7][C:2]([NH:20][C:21]2[C:34]([O:35][CH3:36])=[CH:33][C:24]3[CH2:25][CH2:26][N:27]([CH2:30][CH2:31][OH:32])[CH2:28][CH2:29][C:23]=3[CH:22]=2)=[N:3][CH:4]=1
Reactant: COc1cc2c(cc1N)CCN(CCO)CC2
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)n1)CCN(CCO)CC2
Yield: 42 %

Procedure:
In an analogous manner to Example 1503, the product was prepared from (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-ethanol. Product was isolated as a white foam (35 mg, 42%). MS (ESI+): 499 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.22 (s, 1H), 7.91 (s, 1H), 7.42 (s, 1H), 6.66 (s, 1H), 6.57 (s, 1H), 6.51 (s, 1H), 6.33 (s, 2H), 5.60 (s, 1H), 5.35 (s, 1H), 5.32 (s, 1H), 4.47 (t, J=8 Hz, 1H), 3.89 (s, 3H), 3.84 (s, 2H), 3.63 (d, 5H), 3.09 (s, 1H), 2.89-2.69 (m, 20H), 2.53 (d, J=9 Hz, 1H), 2.28 (d, J=9 Hz, 1H), 1.67 (d, J=9 Hz, 1H).
Reaction SMILES: [NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([NH:18][NH2:19])=[O:17])[N:11]=2)[N:9]=1)[NH2:3].S(O)(O)(=O)=O.CS[C:27](=[NH:29])[NH2:28].C(OCC)(=O)C>CS(C)=O>[NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16](=[O:17])[NH:18][NH:19][C:27]([NH2:29])=[NH:28])[N:11]=2)[N:9]=1)[NH2:3]
Reactant: CSC(=N)N
Reactant: NNC(=O)c1cccc(-c2csc(N=C(N)N)n2)n1
Agent: O=S(=O)(O)O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N=C(N)NNC(=O)c1cccc(-c2csc(N=C(N)N)n2)n1
Temperature: 100 °C
Reaction time: 6 h
Yield: 81.2 %

Procedure:
A mixture of 2-(diaminomethyleneamino)-4-(6-hydrazinocarbonylpyridin-2-yl)thiazole (3.0 g) and 2-methyl-2-thiopseudourea sulfate (1.8 g) in dimethylsulfoxide (30 ml) was stirred for 6 hours at 100° C., and then the mixture was cooled to ambient temperature. To the mixture was added ethyl acetate (30 ml) under stirring. The isolated precipitate was collected by filtration and the precipitate was added to a mixture of water and ethyl acetate. The mixture was adjusted to pH 10 with 4N-sodium hydroxide and precipitate was collected by filtration to give 2-(diaminomethyleneamino)-4-(6-guanidinocarbamoylpyridin-2-yl)thiazole (2.48 g).
Reaction SMILES: CO[C:3]([C:5]1[S:9][N:8]=[C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:6]=1)=[O:4].[CH2:24]([CH2:26][NH2:27])[OH:25]>>[CH:13]([NH2:14])([CH3:18])[CH3:12].[OH:25][CH2:24][CH2:26][NH:27][C:3]([C:5]1[S:9][N:8]=[C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(OCc2c(-c3ccccn3)noc2C)ns1
Reactant: NCCO
Product: CC(C)N
Product: Cc1onc(-c2ccccn2)c1COc1cc(C(=O)NCCO)sn1
Yield: 156.1 %

Procedure:
As described for example 36b, 3-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-isothiazole-5-carboxylic acid methyl ester (100 mg, 0.32 mmol), was converted, using ethanolamine (23 mg, 0.38 mmol), instead of isopropyl amine, to the title compound (90 mg, 82%) which was obtained as a white solid after purification by chromatography (silica, dichloromethane:methanol=1:0 to 9:1). MS: m/e=345.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[O:6][CH2:5][CH2:4][O:3]1.CCN(CC)CC.C(Cl)(=O)C(C)(C)C.[O:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33].[Li]CCCC.[Li]>C(OCC)(=O)C.C1COCC1>[CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([N:30]2[CH2:31][CH2:32][O:28][C:29]2=[O:33])=[O:13])[O:3][CH2:4][CH2:5][O:6]1
Reactant: O=C1NCCO1
Reactant: CC1(CCCCC(=O)O)OCCO1
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]
Agent: [Li]CCCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(CCCCC(=O)N2CCOC2=O)OCCO1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 2-2 (16.0 g, 85.5 mmol), NEt3 (13.1 ml, 94.1 mmol) and THF (400 mL) at −78° C. was added pivaloyl chloride (11.6 ml, 94.1 mmol). The mixture was warmed to 0° C. for 1.0 h and then recooled to −78° C. To a stirred solution of 2-oxazolidinone (9.3 g, 106.9 mmol) and THF (200 ml) at −78° C. was added nBuLi (43.0 ml, 106.9 mmol, 2.5M in hexanes) dropwise over 10 minutes. After 20 minutes, the lithium reagent was transferred to the mixed anhydride via cannula. After 10 minutes, the reaction was warmed to 0° C. for 1.0 h. The mixture was diluted with ethyl acetate, washed with sat. NaHCO3, brine, and dried over MgSO4. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 40%-50% EtOAc/hexanes) to give 2-3 as a colorless foam.
Reaction SMILES: [CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH2:20][C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[Br:31]Br.O>C(O)(=O)C>[CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:20]([Br:31])[C:21]([N:23]([CH3:24])[CH3:25])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrBr
Reactant: CN(C)C(=O)Cc1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CN(C)C(=O)C(Br)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture 2-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-N,N-dimethylacetamide (1.1 g, 1 eq.) and sodium acetate (761 mg, 3 eq.) in acetic acid (15 ml), was added bromine (158 ul, 1 eq.) and the reaction was stirred at room temperature for 4 h. Water was added and the product extracted into ethyl acetate. The ethyl acetate layer was washed several times with water, saturated sodium bicarbonate, saturated sodium chloride, dried over magnesium sulfate, filtered, and concentrated to give 2-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-bromo-N,N-dimethylacetamide (1.44 g) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:13][C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2[O:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19]([CH3:24])=[CH:18]3)[CH:6]=1)=[O:4].C1CCN2[C:28](=[N:29][CH2:30]CC2)CC1.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=[O:38].CN.C([O-])(O)=O.[Na+]>CCOC(C)=O.C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:13][C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2[O:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([C:30](=[O:38])[NH:29][CH3:28])[C:19]([CH3:24])=[CH:18]3)[CH:6]=1)=[O:4]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: C1CCC2=NCCCN2CC1
Reactant: COC(=O)c1cc2nccc(Oc3ccc4[nH]c(C)cc4c3)c2s1
Agent: CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CNC(=O)n1c(C)cc2cc(Oc3ccnc4cc(C(=O)OC)sc34)ccc21
Temperature: 0 °C
Reaction time: 24 h
Yield: 48.6 %

Procedure:
To a solution of methylene chloride (2 mL) was added 7-(2-Methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridine-2-carboxylic acid methyl ester (0.4 g, 1.82 mmol), DBU (0.5 mL, 3.5 mmol), 4-nitrophenyl chloroformate (0.72 g, 3.5 mmol) then stirred at 0° C. for 24 h. Next was added 2.4 mL of methyl amine (2.0 M in THF) via syringe and stirred an addition 1 h. To the reaction mixture was added 50 mL of EtOAc worked-up by portioning between 50/50 NaHCO3 and concentrated. Purification was through silica (30 mL) eluting with EtOAc/CH2Cl2/MeOH (2:1:0.1) combined purified fraction to afford 7-(2-Methyl-1-methylcarbamoyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridine-2-carboxylic acid methyl ester as yellow solid (0.35 g, 74%). HPLC: Rt 3.96 min. (100% area). 1H NMR (CDCl3-d3, 400 MHz) δ: 8.40 (1H, d, J=5.6 Hz), 8.09 (1H, s), 7.64 (1H, d, J=8.8 Hz), 6.92 (1H, dd, J=7.4, 2.2 Hz), 6.84 (1H, d, J=9.1 Hz), 6.49 (1H, d, J=5.3 Hz), 6.23 (1H, s), 5.98 (1H, d, J=4.5 Hz), 3.89 (3H, s), 3.04 (3H, d, 4.5 Hz), 2.52 (3H, s). LCMS (ACPI) M+H+ m/z: 396.2.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[C:15]([Cl:21])[CH:14]=2)=[O:10])[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[NH:31]1[CH:35]=[C:34]([CH2:36][CH2:37][C:38](Cl)=[O:39])[N:33]=[N:32]1>C(Cl)Cl>[NH:31]1[CH:35]=[C:34]([CH2:36][CH2:37][C:38]([NH:2][CH:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[C:15]([Cl:21])[CH:14]=3)=[O:10])[CH2:5][CH2:4]2)=[O:39])[N:33]=[N:32]1
Reactant: O=C(Cl)CCc1c[nH]nn1
Reactant: N#Cc1cc(Cl)cc(COC(=O)N2CCC(N)CC2)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(Cl)cc(COC(=O)N2CCC(NC(=O)CCc3c[nH]nn3)CC2)c1
Reaction time: 1 h

Procedure:
To a suspension of 3-chloro-5-cyanobenzyl 4-aminopiperidine-1-carboxylate HCl salt (Example 64, step 3) (234 mg, 0.709 mmol) in DCM (5 mL) at RT under nitrogen was added Huenig's Base (0.248 mL, 1.418 mmol). 3-(1H-1,2,3-Triazol-4-yl)propanoyl chloride (113 mg, 0.709 mmol) in DCM (2 mL) was then added and the mixture stirred for 1 hour. The reaction mixture was diluted with DCM and washed with a 10% solution of citric acid, a saturated solution of brine and then the organic portion was dried over MgSO4, filtered and concentrated under reduced pressure. Purification was carried out by chromatography on silica using 0-10% MeOH in DCM as eluent to afford the title product;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:45]=[CH:44][C:6]([CH2:7][N:8]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([C:32](=O)[CH3:33])[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:30][CH3:31])=[C:27]([F:29])[CH:28]=3)[N:10]=2)=[CH:5][CH:4]=1.[NH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1.[C:52]([Al](CC)CC)#[N:53].C([O-])(O)=O.[Na+]>C(Cl)Cl.C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C.CCOC(C)=O>[CH3:43][O:42][C:39]1[CH:40]=[CH:41][C:36]([CH2:35][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:45][CH:44]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([C:32]([N:46]4[CH2:51][CH2:50][O:49][CH2:48][CH2:47]4)([CH3:33])[C:52]#[N:53])[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:30][CH3:31])=[C:27]([F:29])[CH:28]=3)[N:10]=2)=[CH:37][CH:38]=1
Reactant: C1COCCN1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)=O)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Reactant: CC[Al](C#N)CC
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)(C#N)N4CCOCC4)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Reaction time: 8 h
Yield: 99.6 %

Procedure:
A solution of 1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)ethanone (Example 271, 0.564 g, 0.925 mmol) and morpholine (0.201 mL, 2.313 mmol) in DCM (4.5 mL) was treated with tetraisopropoxytitanium (0.678 mL, 2.313 mmol). The reaction was sealed and stirred rapidly overnight. Cyanodiethylaluminum (1.0 M in toluene; 2.313 mL, 2.313 mmol) was added and the reaction was resealed and stirred overnight. EtOAc was added followed by sat'd NaHCO3 (cautiously). An exotherm and effervescence was observed, so the reaction was poured onto ice and treated with EtOAc and sat'd aq. NaHCO3. The aqueous layer was extracted with EtOAc (2×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give 2-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-2-morpholinopropanenitrile (0.650 g, 0.921 mmol, 100% yield) as a yellow solid. m/z (ESI, +ve ion) 706 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 11.99 (br. s., 1H); 9.00 (d, J=2.5 Hz, 1H); 8.50 (d, J=2.5 Hz, 1H); 8.03 (dd, J=12.1, 2.2 Hz, 1H); 7.97 (d, J=2.2 Hz, 1H); 7.17-7.26 (m, 4H); 6.82-6.93 (m, 4H); 4.73-5.01 (m, 4H); 4.03 (s, 3H); 3.82 (s, 3H); 3.79 (s, 3H); 3.61-3.71 (m, 4H); 2.64-2.76 (m, 2H); 2.60 (s, 3H); 2.44-2.54 (m, 2H); 1.75 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[O:17][CH3:18])=[O:6].CO[C:21](OC)([CH3:23])[CH3:22].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C=O>[CH3:18][O:17][C:8]1[CH:9]=[CH:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]=1[C:5]([N:4]1[CH2:3][CH2:2][O:1][C:21]1([CH3:23])[CH3:22])=[O:6]
Reactant: COc1ccc2ccccc2c1C(=O)NCCO
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2ccccc2c1C(=O)N1CCOC1(C)C
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a solution of Example 175A in anhydrous N,N-dimethyl formamide (10 mL) was added 2,2-dimethoxypropane (0.62 mL, 5.0 mmol) and p-toluenesulfonic acid monohydrate (50 mg, 0.26 mmol). The resulting mixture was stirred under a N2 atmosphere at 60° C. for 16 h. Additional 2,2-dimethoxypropane (0.3 mL, 2.4 mmol) and p-toluenesulfonic acid monohydrate (50 mg, 0.26 mmol) were added, and the mixture was stirred at 60° C. for 6 h. The mixture was partitioned between saturated NaHCO3 (50 mL) and ethyl acetate (3×50 mL), and the combined organic layers were dried over Na2SO4. The crude product was purified by column chromatography on silica gel using a solvent gradient of 50-65% ethyl acetate in hexane. The title compound was obtained as a colorless, crystalline solid (0.44 g, 62% for two steps). 1H NMR (300 MHz, CDCl3) δ 1.83 (s, 3 H), 1.88 (s, 3 H), 3.13 (m, 1 H), 3.40 (m, 1 H), 3.92 (m, 2 H), 3.98 (s, 3 H), 7.28 (m, 1 H), 7.37 (m, 1 H), 7.49 (m, 1 H), 7.71 (m, 1 H), 7.80 (m, 1 H), 7.86 (m, 1 H).
Reaction SMILES: C(N(CC)CC)C.N12CCN(CC1)CC2.[CH2:16]([N:18]=[C:19]=[O:20])[CH3:17].[Cl:21][C:22]1[CH:31]=[C:30]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=2)[CH:29]=[CH:28][C:23]=1[O:24][CH2:25][CH2:26][OH:27]>O1CCCC1>[Cl:21][C:22]1[CH:31]=[C:30]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=2)[CH:29]=[CH:28][C:23]=1[O:24][CH2:25][CH2:26][O:27][C:19]([NH:18][CH2:16][CH3:17])=[O:20]
Reactant: CCN=C=O
Reactant: OCCOc1ccc(Oc2cccc(Cl)c2)cc1Cl
Agent: C1CN2CCN1CC2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCNC(=O)OCCOc1ccc(Oc2cccc(Cl)c2)cc1Cl

Procedure:
0.1 ml of triethylamine, 15 mg of 1,4-diazabicyclo[2.2.2]octane and 1.3 g of ethyl isocyanate are added to a solution of 4.49 g of 2-[2-chloro-4-(3-chlorophenoxy)phenoxy] ethanol in 40 ml of tetrahydrofuran. The reaction mixture is heated at 55° for 18 hours, with stirring, and then evaporated to dryness in vacuo. The residue is purified by chromatography [silica gel; diethyl ether/hexane (2:3)]. This gives the title compound which melts at 73°-74° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[C:10](#[N:14])[CH2:11][C:12]#[N:13].[OH:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[CH:19][N:20]2[CH3:25].N1CCCCC1>C(O)C>[NH2:13][C:12]1[O:15][C:16]2[C:24]([CH:5]([C:4]3[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[CH:3]=3)[C:11]=1[C:10]#[N:14])=[CH:23][CH:22]=[C:21]1[N:20]([CH3:25])[CH:19]=[CH:18][C:17]=21
Reactant: N#CCC#N
Reactant: O=Cc1cccc(F)c1
Reactant: Cn1ccc2c(O)cccc21
Solvent: CCO
Solvent: C1CCNCC1
Product: Cn1ccc2c3c(ccc21)C(c1cccc(F)c1)C(C#N)=C(N)O3
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.5 %

Procedure:
To a mixture of 3-fluorobenzaldehyde (46 mg, 0.37 mmol) and malononitrile (25 mg, 0.37 mmol) in ethanol (1 mL) was added 4-hydroxy-1-methyl-indole (55 mg, 0.37 mmol) followed by piperidine (0.02 mL, 0.19 mmol, 0.5 eq.). Reaction mixture was stirred at room temperature overnight. The desired compound precipitated and was collected, washed with ethanol and dried, yielding 36 mg of a yellow solid. 1H NMR (CDCl3): 7.28-7.23 (m, 1H), 7.05-7.01 (m, 3H), 6.92-6.86 (m, 2H), 6.74 (d, J=8.4 Hz, 1H), 6.56 (d, J=3.1 Hz, 1H), 4.84 (s, 1H), 4.67 (s, 2H), 3.76 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21]O[CH2:19][C@H:18]2[CH:23]([CH3:25])[CH3:24])[N:3]=1.[OH2:26].[NH2:27][NH2:28]>CCO>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:11]([C:12]([NH2:13])=[N:27][NH:28]3)=[CH:14][CH:15]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21][O:26][CH2:19][C@H:18]2[CH:23]([CH3:24])[CH3:25])[N:3]=1
Reactant: O
Reactant: CC(C)[C@@H]1COCCN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: NN
Solvent: CCO
Product: CC(C)[C@@H]1COCCN1c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
To a solution of 4-{2-amino-6-[(3R)-3-(1-methylethyl)-4-morpholinyl]-4-pyrimidinyl}-2-fluorobenzonitrile (355 mg, 1.04 mmol) in EtOH (10 mL) was added hydrazine monohydrate (2 mL) in one portion at room temperature. The mixture was heated in an oil bath at 100° C. under a gentle reflux for 18 hours. LCMS showed conversion complete. The mixture was cooled to room temperature, filtered through celite, and rinsed with EtOH (20 mL). The filtrate was concentrated in vacuo. The residue was suspended in water (10 mL). The suspension was sonicated briefly, and filtered. The solids were washed with water, dried under house vacuum at room temperature for 2 hours, and then under vacuum at room temperature over P2O5 for 20 hours. These solids were washed with hexane (2×3 mL), followed by drying under vacuum at 65° C. for 24 hours to give the title compound (256 mg) as a beige solid. LC-MS (ES) m/z=354 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 0.88 (d, J=6.8 Hz, 3H), 1.10 (d, J=6.6 Hz, 3H), 2.47-2.54 (m, 1H), 3.21-3.30 (m., 1H), 3.51-3.58 (m, 2H), 3.93 (dd, J=11.2, 3.41 Hz, 1H), 4.10 (d, J=11.6 Hz, 1H), 6.46 (s, 1H), 7.47 (dd, J=8.5, 1.4 Hz, 1H), 7.76 (d, J=8.6 Hz, 1H), 7.79 (s, 1H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:9][CH2:8][CH2:7][NH:6][C:4](=[O:5])[CH2:3]1.C(N(CC)CC)C.[C:17]([S:20][CH2:21][CH:22]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:23](Cl)=[O:24])(=[O:19])[CH3:18].Cl>C(#N)C.O>[C:17]([S:20][CH2:21][CH:22]([CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:23]([NH:1][C@H:2]1[CH2:9][CH2:8][CH2:7][NH:6][C:4](=[O:5])[CH2:3]1)=[O:24])(=[O:19])[CH3:18]
Reactant: N[C@H]1CCCNC(=O)C1
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)Cl
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)SCC(Cc1ccccc1)C(=O)N[C@H]1CCCNC(=O)C1
Reaction time: 0.5 h

Procedure:
Combine 3(S)-amino-ε-caprolactam (1.00 g, 7.8 mmol) and triethylamine (0.87 g, 8.6 mmol) in acetonitrile (40ml) and H2O (20 ml). Add dropwise 2-acetylthiomethyl-3-phenylpropionyl chloride. After 30 min, add 1.0N HCl (13 ml), extract with ethyl acetate (EtOAc), dry and concentrate. Chromatograph on silica, eluting with 3%MeOH/CH2Cl2 to obtain the title compound as a foam. MS: M+1=349.