Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(C(C)C)CC)(C)C.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]2[CH2:21][NH:22][CH2:23][C:16]=12>C(Cl)Cl>[CH3:1][S:2]([N:22]1[CH2:21][C:17]2[C:16](=[N:15][CH:20]=[CH:19][CH:18]=2)[CH2:23]1)(=[O:4])=[O:3]
Reactant: c1cnc2c(c1)CNC2
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)N1Cc2cccnc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methanesulfonyl chloride (0.97 mL, 12.4 mmol) was added dropwise to a −10° C. solution of diisopropyl-ethylamine (5.16 mL, 31.1 mmol) and 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (2.0 g, 10.0 mmol) in CH2Cl2 (20 mL). The mixture was stirred overnight at rt diluted with CH2Cl2 (300 mL) and washed with saturated aqueous sodium bicarbonate. The organic phase was separated, dried (MgSO4) and filtered through a short silica gel pad with EtOAc rinse. The filtrate was concentrated to yield 2.15 g (quantitative) of Ex 10-Step 1 product as a solid which was used without further purification: LCMS m/z 199.2 (M+1); 1H NMR (400 MHz, CDCl3) δ 8.54 (d, J=4.9, 1H), 7.61 (d, J=7.8, 1H), 7.25 (dd, J=7.8, 5.1, 1H), 4.75 (AB quartet, JAB=2.1, ΔvAB=7.8, 4H), 2.94 (s, 3H).
Reaction SMILES: [O:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]([OH:14])=O)[C:2]1=[O:3].S(Cl)([Cl:17])=O>ClCCl>[O:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]([Cl:17])=[O:14])[C:2]1=[O:3]
Reactant: O=C(O)c1cc2ccccc2oc1=O
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)c1cc2ccccc2oc1=O

Procedure:
Coumarin-3-carboxylic acid (2.1 g, 10 m mole) was suspended in dry dichloromethane (10 ml) and heated at reflux for 2 h with thionyl chloride (5 ml). After this time a small amount of insoluble material was filtered off and petroleum ether 60°-80° C. (35 ml) was added to the filtrate. The acid chloride was filtered, washed with ether and dried (1.63 g, 71%), mp 138°-41° C.; νmax (CHCl3) 1790, 1740, 1610, 1570 cm-1 ; δ (CDCl3) 7.30-8.10 (4H, m, phenyls), 8.95 (1H, s, coumarin 4-H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19]C(C)(C)C)=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.[N:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=2)=[CH:29][CH:28]=1>>[Cl:26][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:24][CH:25]=2)[CH3:12])=[O:9])[C:2]([O:39][C:36]2[CH:35]=[CH:34][C:33]([C:30]3[CH:29]=[CH:28][N:27]=[CH:32][CH:31]=3)=[CH:38][CH:37]=2)=[N:3][CH:4]=1
Reactant: Oc1ccc(-c2ccncc2)cc1
Reactant: C[C@H](NC(=O)c1cc(Cl)cnc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Product: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1ccc(-c2ccncc2)cc1)c1ccc(C(=O)O)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from tert-butyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 45) and 4-pyridin-4-ylphenol (J. Med. Chem. 2003, 46, 3709): 1H-NMR (CDCl3) δ 8.68 (2H, d, J=6.0 Hz), 8.57 (1H, d, J=2.6 Hz), 8.16 (1H, d, J=2.6 Hz), 8.10 (1H, d, J=7.9 Hz), 7.96 (2H, d, J=8.2 Hz), 7.73 (2H, d, J=8.7 Hz), 7.52 (2H, d, J=6.0 Hz), 7.41 (2H, d, J=8.2 Hz), 7.29 (2H, d, J=8.7 Hz), 5.38 (1H, m), 1.60 (3H, d, J=7.5 Hz), 1.57 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH2:8]C2CCNCC2)=[CH:4][C:3]=1[N+:17]([O-])=O.O.O.[Sn](Cl)Cl.[CH3:25][CH2:26]O>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH2:8][N:17]2[CH2:26][CH2:25][CH2:16][CH2:2][CH2:3]2)=[CH:4][C:3]=1[NH2:17]
Reactant: CCO
Reactant: O=[N+]([O-])c1cc(OCCC2CCNCC2)ccc1Cl
Agent: Cl[Sn]Cl
Solvent: O
Product: Nc1cc(OCCN2CCCCC2)ccc1Cl
Temperature: 60 °C
Reaction time: 19 h
Yield: 92 %

Procedure:
4-(2-(4-chloro-3-nitrophenoxy)ethyl)piperidine (2.3 g, 8.1 mmol, 1 eq.) and tin (II) chloride dihydrate (9.1 g, 40.4 mmol, 5 eq.) were placed in EtOH (81 mL). The reaction mixture was heated at 60° C. and stirred for 19 hours. The reaction mixture was then concentrated under reduced pressure and the resulting residue was diluted with ethyl acetate. The organic phase was washed with a 1N NaOH aqueous solution, dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to afford 2-chloro-5-(2-piperidinoethoxy)aniline (1.9 g, 92%).
Reaction SMILES: [NH2:1][C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][O:12][CH:13]([O:24][CH3:25])[C:14]1[CH:23]=CC2C(=NC=CC=2)N=1>>[CH3:11][O:12][CH:13]([O:24][CH3:25])[C:14]1[CH:23]=[CH:4][C:3]2[C:2](=[N:9][C:8]([CH3:10])=[CH:7][CH:6]=2)[N:1]=1
Reactant: COC(OC)c1ccc2cccnc2n1
Reactant: Cc1ccc(C=O)c(N)n1
Product: COC(OC)c1ccc2ccc(C)nc2n1

Procedure:
From 2-amino-6-methylnicotinaldehyde, synthesized in an analogous manner to intermediate 5, the title compound was obtained as a white solid. (UPLC-MS 6) tR 0.62; ESI-MS 219.2 [M+H]+.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:27]([OH:29])=O)[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].O[N:31]=[C:32]([CH:34]1[CH2:36][CH2:35]1)[NH2:33]>>[CH:34]1([C:32]2[N:33]=[C:27]([CH:13]3[CH2:14][CH:15]([C:17]4[CH:18]=[CH:19][C:20]([C:23]([F:24])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:16][N:11]([C:9]([N:6]4[CH2:5][CH2:4][CH:3]([C:1]#[N:2])[CH2:8][CH2:7]4)=[O:10])[CH2:12]3)[O:29][N:31]=2)[CH2:36][CH2:35]1
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)CC1
Reactant: NC(=NO)C1CC1
Product: N#CC1CCN(C(=O)N2CC(c3ccc(C(F)(F)F)cc3)CC(c3nc(C4CC4)no3)C2)CC1

Procedure:
100 mg (0.244 mmol) of 1-[(4-cyanopiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 100A) and 26.9 mg (0.269 mmol) of N′-hydroxycyclopropanecarboximidamide (Example 78A) were reacted according to the General Method 1. Yield: 78.3 mg (66% of theory).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]2[N:14]=[C:15]3[CH:21]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([N:28]5[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]5)=[CH:24][CH:23]=4)[NH:19][C:16]3=[N:17][CH:18]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[Br:35]N1C(=O)CCC1=O>C(Cl)Cl>[Br:35][C:21]1[C:15]2[C:16](=[N:17][CH:18]=[C:13]([CH2:12][CH2:11][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=3)[N:14]=2)[NH:19][C:20]=1[C:22]1[CH:23]=[CH:24][C:25]([N:28]2[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]2)=[CH:26][CH:27]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(CCc2cnc3[nH]c(-c4ccc(N5CCN(C)CC5)cc4)cc3n2)cc(OC)c1
Solvent: ClCCl
Product: COc1cc(CCc2cnc3[nH]c(-c4ccc(N5CCN(C)CC5)cc4)c(Br)c3n2)cc(OC)c1
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
To a stirred solution of 2-[2-(3,5-dimethoxyphenyl)ethyl]-6-[4-(4-methylpiperazin-1-yl)phenyl]-5H-pyrrolo[2,3-b]pyrazine (from Example 1, Step 5, 120 mg, 0.262 mmol) in methylene chloride (2 mL), a solution of N-bromosuccinimide (46.7 mg, 0.262 mmol) in methylene chloride (1 mL) was added dropwise at 0° C. After 30 minutes, the reaction was quenched with saturated aqueous NaHCO3, then extracted with methylene chloride. The combined organic layers were dried over MgSO4, and then concentrated. The residue was purified on silica gel (eluting with 0 to 10% MeOH in dichloromethane (DCM)) to give the desired product (110 mg, 78%). LCMS calculated for C27H31BrN5O2 (M+H)+: m/z=536.2. Found: 536.2.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:7][C:8]#[C:9][CH2:10][OH:11]>C1(C)C=CC=CC=1>[N:1]1([CH2:7][C:8]#[C:9][CH2:10][OH:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCC#CCCl
Reactant: C1CCNC1
Solvent: Cc1ccccc1
Product: OCC#CCN1CCCC1
Temperature: 60 °C
Yield: 68.6 %

Procedure:
Pyrrolidine (7.8 ml, 94 mmol) was added dropwise to a solution of 4-chlorobut-2-yn-1-ol (4.74 g, 45 mmol) in toluene (40 ml) and the mixture stirred and heated at 60° C. for 1 hour. The volatiles were removed by evaporation and the residue was purified by chromatography eluting with methylene chloride/methanol (96/4) to give 4-(pyrrolidin-1-yl)but-2-yn-1-ol (4.3 g, 69%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C@H:11]1[N:19]([C:20](=[O:39])[C@@H:21]([NH:25][C:26](=[O:38])[C@@H:27]([N:29](C)[C:30](=O)OC(C)(C)C)[CH3:28])[CH:22]([CH3:24])[CH3:23])[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[CH2:12]1)=[O:10].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C@H:11]1[N:19]([C:20](=[O:39])[C@@H:21]([NH:25][C:26](=[O:38])[C@@H:27]([NH:29][CH3:30])[CH3:28])[CH:22]([CH3:23])[CH3:24])[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[CH2:12]1)=[O:10]
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1c2ncccc2C[C@H]1C(=O)Nc1ccccc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H](C)C(=O)N[C@H](C(=O)N1c2ncccc2C[C@H]1C(=O)Nc1ccccc1F)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
In a 50 mL round-bottomed flask, tert-butyl (S)-1-((S)-1-((S)-2-(2-fluorophenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-3-methyl-1-oxobutan-2-ylamino)-1-oxopropan-2-yl(methyl)carbamate (39 mg, 72.0 μmol, Eq: 1.00) was combined with DCM (3.00 mL) to give a colorless solution. TFA (1.00 mL, 13.0 mmol, Eq: 180) was added the reaction was stirred at rt for 30 min and then concentrated in vacuo. The residue was taken up in DCM, washed with saturated aqueous NaHCO3, dried over Na2SO4 and concentrated in vacuo to give (S)—N-(2-fluorophenyl)-1-((S)-3-methyl-2-((S)-2-(methylamino)propanamido)butanoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide as an off-white solid (25 mg), m/z=442 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8]O)=[CH:6][CH:5]=[C:4]([C:10]([F:13])([F:12])[F:11])[N:3]=1.C1C=CC(OP(OC2C=CC=CC=2)([N:23]=[N+:24]=[N-:25])=O)=CC=1.N12CCCN=C1CCCCC2>C1COCC1>[N:23]([CH2:8][C:7]1[C:2]([CH3:1])=[N:3][C:4]([C:10]([F:13])([F:12])[F:11])=[CH:5][CH:6]=1)=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: Cc1nc(C(F)(F)F)ccc1CO
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Cc1nc(C(F)(F)F)ccc1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.8 %

Procedure:
A 25 mL flask was charged with (2-methyl-6-(trifluoromethyl)pyridin-3-yl)methanol (287 mg, 1.50 mmol), tetrahydrofuran (5 mL) and diphenylphosphonic azide (356 μL, 1.65 mmol), purged with nitrogen, and cooled in ice. A solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (236 μL, 1.57 mmol) in THF (1 mL) was added dropwise to the resultant mixture, and after 1.5 h, the mixture was warmed to room temperature and stirred overnight. Additional diphenylphosphonic azide (100 μL, 0.3 equiv.) was added followed by additional 1,8-diazabicyclo[5.4.0]undec-7-ene (90 μL, 0.4 equiv.), and the mixture was again stirred overnight. The reaction was quenched with 1M NaOH (20 mL), and poured into chloroform (20 mL). The organic layer was washed with 1M Na2HPO4 (pH 8, 2×15 mL), dried (Na2SO4), filtered and concentrated to a yellow oil which was purified by silica gel column (0-25% ethyl acetate/hexane) to yield a colorless oil (301 mg, 93%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:32])=[C:6]([CH:31]=1)[O:7][CH2:8][C:9]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=2[O:26][CH3:27])=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([CH3:30])=[CH:12][C:13]([CH3:29])([CH3:28])[NH:14]2.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:32])=[C:6]([CH:31]=1)[O:7][CH2:8][C:9]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([O:25][S:34]([CH3:33])(=[O:36])=[O:35])=[CH:21][C:20]=2[O:26][CH3:27])=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([CH3:30])=[CH:12][C:13]([CH3:28])([CH3:29])[NH:14]2
Reactant: COc1cc(O)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)C(C)=CC(C)(C)N2
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(OS(C)(=O)=O)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)C(C)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
5-(5-Fluoro-2-methylphenoxymethyl)-6-(4-hydroxy-2-methoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 3-1, 61.0 mg, 0.141 mmol) was dissolved in methylene dichloride (2 mL), methanesulfonyl chloride (26 μL, 0.34 mmol) and triethylamine (92 μL, 0.66 mmol) were added thereto, and then the mixture was stirred at room temperature overnight. The reaction mixture was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (58.0 mg) as a pale pink solid. (Yield 82%)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH2:10][CH:9]1[CH2:22][OH:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH2:10][CH:9]1[CH2:22][O:23][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2ccc(F)cc2F)CC1CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCC2CC(Oc3ccc(F)cc3F)CN2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Yield: 75.1 %

Procedure:
To a stirred solution of 1-(tert-butoxycarbonyl)-4-(2,4-difluorophenoxy)-2-pyrrolidinylmethanol (500 mg, 1.52 mmol), methyl 4-hydroxybenzoate (277 mg, 1.82 mmol), and Ph3P (477 mg, 1.82 mmol) in THF (10 ml) was added DIAD (358 ul, 1.82 mmol), and the mixture was heated at reflux for 5 h; After cooling to room temperature, the mixture was concentrated in vacuo and the residue was chromatographed on silica gel with CHCl3-EtOAc (20:1) as eluent to give methyl 4-[1-(tert-butoxycarbonyl)-4-(2,4-difluorophenoxy)-2-pyrrolidinylmethoxy]benzoate (529 mg, 75%) as a colorless oil. 1H-NMR (CDCl3) δ 1.46 (s, 9 H), 2.20–2.47 (m, 2 H), 3.64 (m, 2 H), 3.86 (s, 3 H), 4.07–4.43 (m, 3 H), 4.86 (m, 1 H), 6.74–6.87 (m, 3 H), 6.94 (d, 2 H, J=8.5 Hz), 7.95 (d, 2 H, J=8.5 Hz).
Reaction SMILES: Cl[C:2]1([NH:24][C:25]2[CH:30]=[CH:29][C:28]3[O:31][CH2:32][CH2:33][O:34][C:27]=3[CH:26]=2)[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:18](OCC)=[O:19])([CH3:17])[CH3:16])=[CH:11][CH:10]=2)[C:5]([F:23])=[CH:4][NH:3]1.CC(C[AlH]CC(C)C)C>ClCCl>[CH2:33]1[CH2:32][O:31][C:28]2[CH:29]=[CH:30][C:25]([NH:24][C:2]3[N:7]=[C:6]([NH:8][C:9]4[CH:14]=[CH:13][C:12]([C:15]([CH3:16])([CH3:17])[CH2:18][OH:19])=[CH:11][CH:10]=4)[C:5]([F:23])=[CH:4][N:3]=3)=[CH:26][C:27]=2[O:34]1
Reactant: CCOC(=O)C(C)(C)c1ccc(NC2=NC(Cl)(Nc3ccc4c(c3)OCCO4)NC=C2F)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: CC(C)(CO)c1ccc(Nc2nc(Nc3ccc4c(c3)OCCO4)ncc2F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Chloro-5-fluoro-N4-[4-[ethoxycarbonyl(dimethyl)methyl]phenyl]-N2-(3,4-ethylenedioxyphenyl)-2,4-pyrimidinediamine was reduced with 10 eq. DIBALH (1.0 M in toluene) at 0° C. in dichloromethane. Reaction was quenched with methanol, diluted with ethylacetate followed by the addition of aqueous Rochelle's salt solution, stirred at room temperature for 30 minutes followed by the addition of anhydrous sodium sulfate. The solution was filtered through Celite, concentrated and purified the concentrated by silica gel column chromatography to furnish the N2-(3,4-ethylenedioxyphenyl)-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 10.01 (br s, 1H), 9.6 (br s, 1H), 8.13 (d, 1H, J=4.7 Hz), 7.58 (d, 2H, J=8.2 Hz), 7.31 (d, 2H, J=8.8 Hz), 7.18 (d, 1H, J=2.3 Hz), 6.88 (dd, 1H, J=2.3 and 8.8 Hz), 6.73 (d, 1H, J=8.8 Hz), 4.21-4.19 (m, 4H), 3.56 (br s, 2H), 1.20 (s, 6H); LCMS: ret. time: 20.34 min.; purity: 98%; MS (m/e): 411 (MH+).
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH3:14])[C:10](=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.[OH-].[NH4+:17]>>[NH2:17][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH3:14])[C:10](=[O:15])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: CN1CCC(c2ccc(F)nc2)CC1=O
Agent: [OH-]
Product: CN1CCC(c2ccc(N)nc2)CC1=O
Temperature: 150 °C

Procedure:
To a steel bomb, (+/−)-4-(6-fluoropyridin-3-yl)-1-methylpiperidin-2-one (341 mg, 1.638 mmol) was added followed by addition of ammonium hydroxide solution (0.00 mmol)—remaining 40% head space. The reactor was heat at 150° C. for 20 hr (internal pressure built up to 100 psi upon heating). After cooling down, the reaction was completed. The whole solvent (transferred to a flask) was removed in vacuo. Toluene was added and co-evaporated to remove water. The crude product, (+/−)-4-(6-aminopyridin-3-yl)-1-methylpiperidin-2-one, was used for the next step without further purification (87%). LCMS (m/z): 206.1 (MH+), 0.24 min.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6]1)=[O:4].[Cl:20]Cl.O>C(O)(=O)C>[Cl:1][CH2:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:20])=[CH:11][CH:12]=2)[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6]1)=[O:4]
Reactant: ClCl
Reactant: O=C(CCl)N1CC(c2ccccc2)c2ccccc21
Solvent: O
Solvent: CC(=O)O
Product: O=C(CCl)N1CC(c2ccccc2)c2cc(Cl)ccc21
Temperature: 15 °C

Procedure:
2.7 G of N-chloracetyl-3-phenylindoline was added with vigorous stirring to a solution of 0.77 g of chlorine in 10 ml of glacial acetic acid which had been cooled to 15° C. The temperature of the mixture which rose to 33° C. was cooled down to room temperature and the mixture stirred for a further hour. The resulting solution was poured into 100 ml of cold water. The liquid was decanted from the gummy residue, which was subsequently crystallized from ethanol to give 1.9 g of crystalline N-chloracetyl-3-phenyl-5-chloroindoline having a melting point of 107°-9° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][N:7]=2)=[CH:2]1.[CH:14]([Mg]Cl)([CH3:16])[CH3:15]>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:7]=[CH:8][C:9]([CH:10]([OH:11])[CH:14]([CH3:16])[CH3:15])=[CH:12][CH:13]=2)=[CH:2]1
Reactant: CC(C)[Mg]Cl
Reactant: O=Cc1ccc(-c2ccoc2)nc1
Product: CC(C)C(O)c1ccc(-c2ccoc2)nc1

Procedure:
Synthesized using compound 47b (160 mg, 0.92 mmol) and isopropylmagnesium chloride (0.92 mL, 1.85 mmol, 2 M in THF) according to Method D. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (3:1) as eluent. Yellow solid. Yield: 53 mg, 27%. MS (ESI): m/z=218.30 [M+H]+.
Reaction SMILES: C1(S([CH2:10][C:11]2[N:15]=[C:14]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[NH:13][N:12]=2)(=O)=O)C=CC=CC=1.[CH2:21]([C:25]1[CH:26]=[CH:27][C:28](/[CH:31]=[CH:32]/[C:33]#[N:34])=[N:29][CH:30]=1)[CH2:22][CH2:23][CH3:24]>>[CH2:21]([C:25]1[CH:26]=[CH:27][C:28]([C:31]2[CH:32]=[C:33]([NH2:34])[N:12]3[N:13]=[C:14]([C:16]4[O:17][CH:18]=[CH:19][CH:20]=4)[N:15]=[C:11]3[CH:10]=2)=[N:29][CH:30]=1)[CH2:22][CH2:23][CH3:24]
Reactant: O=S(=O)(Cc1n[nH]c(-c2ccco2)n1)c1ccccc1
Reactant: CCCCc1ccc(/C=C/C#N)nc1
Product: CCCCc1ccc(-c2cc(N)n3nc(-c4ccco4)nc3c2)nc1

Procedure:
The title compound, MS m/e (%): 334 (M+H+, 100), was prepared in accordance with the general method of example 1 from 3-benzenesulfonylmethyl-5-furan-2-yl-1H-[1,2,4]triazole and (E)-3-(5-butyl-pyridin-2-yl)-acrylonitrile.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.[S].[C:10](=[S:12])=[S:11]>>[SH:12][C:10]1[S:11][C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([CH3:8])[C:2]=2[N:1]=1
Reactant: Cc1ccccc1N
Reactant: S=C=S
Agent: [S]
Product: Cc1cccc2sc(S)nc12
Reaction time: 1.5 h
Yield: 46 %

Procedure:
Into a 500 ml reactor were charged o-toluidine (27 g), sulfur (8g), and carbon disulfide (22 g). Seventy minutes of electrically heating the system was required to elevate the temperature to 275°C (240 psig original pressure at 275°C). After 21/2 hours at 275°C (the pressure leveled out at 470 psig in 90 minutes) the heat source was removed and the reactor was cooled. The reaction mixture was mixed with 200 g water containing 16 g sodium hydroxide. Tar-like residue (18.5 g) was removed by decantation. Acidification of decantate with hydrochloric acid and filtration of the resulting mixture gave 21 g (46 percent yield) of crude 2-mercapto-4-methylbenzothiazole (m.p. 161°-173°C).
Reaction SMILES: [F:1][CH:2]([F:32])[C:3]1[CH:4]=[C:5]([N:9]2[C:14]3[CH2:15][CH2:16][C:17](=[O:18])[C:13]=3[CH:12]([C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][C:20]=3[S:27]([CH3:30])(=[O:29])=[O:28])[NH:11][C:10]2=[O:31])[CH:6]=[CH:7][CH:8]=1.[C:33](=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[F:32][CH:2]([F:1])[C:3]1[CH:4]=[C:5]([N:9]2[C:14]3[CH2:15][CH2:16][C:17](=[O:18])[C:13]=3[CH:12]([C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][C:20]=3[S:27]([CH3:30])(=[O:29])=[O:28])[N:11]([CH3:33])[C:10]2=[O:31])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: CS(=O)(=O)c1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)F)c2)C2=C1C(=O)CC2
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN1C(=O)N(c2cccc(C(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl idodide (15 μL, 0.24 mmol) is added to a solution of 4-(1-(3-(difluoromethyl)-phenyl)-2,5-dioxo-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]pyrimidin-4-yl)-3-(methyl-sulfonyl)benzonitrile (example 15.4, 69 mg, 0.15 mmol) and cesium carbonate (98 mg, 0.30 mmol) in N,N-dimethylformamide (1.0 mL). The mixture is stirred at room temperature for 1 h and purified by reversed phase HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 19 mg; ESI mass spectrum [M+H]+=472; Retention time HPLC: 0.97 min (Z018_S04).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([C:16]([F:19])([F:18])[F:17])=[C:11]([C:13]([OH:15])=O)[N:12]=1.[NH2:20][C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH2:31][CH2:30][C@H:29]([OH:32])[CH2:28]2)=[N:25][CH:26]=1>>[OH:32][C@H:29]1[CH2:30][CH2:31][N:27]([C:24]2[N:25]=[CH:26][C:21]([NH:20][C:13]([C:11]3[N:12]=[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Br:1])[O:9][C:10]=3[C:16]([F:19])([F:18])[F:17])=[O:15])=[CH:22][CH:23]=2)[CH2:28]1
Reactant: O=C(O)c1nc(-c2ccccc2Br)oc1C(F)(F)F
Reactant: Nc1ccc(N2CC[C@H](O)C2)nc1
Product: O=C(Nc1ccc(N2CC[C@H](O)C2)nc1)c1nc(-c2ccccc2Br)oc1C(F)(F)F

Procedure:
With a method similar to example 43 above, 2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((S)-3-hydroxy-pyrrolidin-1-yl)-pyridin-3-yl]-amide was prepared from 2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid and (S)-1-(5-Amino-pyridin-2-yl)-pyrrolidin-3-ol. LCMS calcd for C20H16BrF3N4O3 m/e 497, obsd 498.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:38]=[CH:37][C:17]3[C:18]4[N:22]([CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH:21]=[C:20]([C:26]2[N:27]([CH:34]([CH3:36])[CH3:35])[N:28]=[C:29]([CH2:31][O:32][CH3:33])[N:30]=2)[N:19]=4)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>C(Cl)Cl>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[CH:34]([N:27]1[C:26]([C:20]2[N:19]=[C:18]3[N:22]([CH2:23][CH2:24][O:25][C:16]4[CH:15]=[C:14]([CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)[CH:38]=[CH:37][C:17]=43)[CH:21]=2)=[N:30][C:29]([CH2:31][O:32][CH3:33])=[N:28]1)([CH3:36])[CH3:35]
Reactant: COCc1nc(-c2cn3c(n2)-c2ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc2OCC3)n(C(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCc1nc(-c2cn3c(n2)-c2ccc(C4CCNCC4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-[2-(2-isopropyl-5-methoxymethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylic acid tert-butyl ester (158 mg, 0.30 mmol) in DCM (1.5 mL) was added trifluoroacetic acid (1.5 mL, 20.2 mmol) and the reaction mixture stirred at RT for 30 min. The reaction mixture was concentrated in vacuo and the residue azeotroped with ether. The resultant oil was triturated with diethyl ether to give 2-(2-Isopropyl-5-methoxymethyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene trifluoroacetate salt as a solid which was collected by filtration (103 mg, 64%). LCMS RT=3.03 min, [M+H]+=423. 1H NMR 400 MHz (DMSO-d) δ: 8.56 (1H, s), 8.33 (1H, d, J=8.33 Hz), 7.90 (1H, s), 7.00 (1H, dd, J=8.38, 1.78 Hz), 6.85 (1H, d, J=1.73 Hz), 5.81-5.80 (1H, m), 4.46 (4H, d, J=2.51 Hz), 4.33 (2H, s), 3.34 (2H, d, J=12.58 Hz), 3.27 (3H, s), 2.98-2.95 (2H, m), 2.82 (1H, t, J=11.91 Hz), 1.93 (2H, d, J=13.66 Hz), 1.75 (2H, t, J=12.95 Hz), 1.44 (6H, d, J=6.60 Hz)