Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19].[CH3:20][S:21](Cl)(=[O:23])=[O:22]>N1C=CC=CC=1>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:21]([CH3:20])(=[O:23])=[O:22])=[C:3]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])[CH:4]=1)(=[O:10])[CH3:9]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)c1ccc(N)c(Nc2ccc(F)cc2F)c1
Solvent: c1ccncc1
Product: CC(=O)c1ccc(NS(C)(=O)=O)c(Nc2ccc(F)cc2F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.9 %

Procedure:
A mixture of 4'-amino-3'-(2,4-difluorophenylamino)acetophenone (1.7 g) and methanesulfonyl chloride (0.9 g) in pyridine (17 ml) was stirred for 4 hours at room temperature. Pyridine was evaporated and the residue was stirred with an aqueous solution of sodium hydroxide (5%) for 30 minutes. The solution was washed with toluene, acidified to pH 3 with hydrochloric acid, and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium bicarbonate, dried, and concentrated under reduced pressure. The syrupy residue (1.8 g) was crystallized from ethanol to give pale yellow crystals of 4'-acetyl-2'-(2,4-difluorophenylamino)methanesulfonanilide (1.3 g).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([C:7]([C:9]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)=O)[N:4]=[CH:3][CH:2]=1.[CH3:17][C:18]1[CH:30]=[CH:29][C:21]2[N:22]=[C:23]([NH:25][C:26]([NH2:28])=[NH:27])[NH:24][C:20]=2[CH:19]=1.[OH-].[Na+]>CO.O>[CH3:17][C:18]1[CH:30]=[CH:29][C:21]2[N:22]=[C:23]([N:25]=[C:26]3[NH:28][C:7]4([C:5]5[CH:6]=[CH:1][CH:2]=[CH:3][N:4]=5)[NH:28][C:26](=[N:25][C:23]5[NH:24][C:20]6[CH:19]=[C:18]([CH3:17])[CH:30]=[CH:29][C:21]=6[N:22]=5)[NH:27][C:9]4([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][N:16]=4)[NH:27]3)[NH:24][C:20]=2[CH:19]=1
Reactant: Cc1ccc2nc(NC(=N)N)[nH]c2c1
Reactant: O=C(C(=O)c1ccccn1)c1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc2nc(N=C3NC4(c5ccccn5)NC(=Nc5nc6ccc(C)cc6[nH]5)NC4(c4ccccn4)N3)[nH]c2c1

Procedure:
A mixture of 2,2′-pyridil (603 mg, 2.84 mmol) and 5-methyl-2-guanidinobenzimidazole (489 mg, 2.58 mmol) in methanol (17 mL) was treated with a solution of sodium hydroxide (113.6 mg, 2.84 mmol) in 2.8 mL of water. The title compound was isolated as a grey powder (450 mg, 63% yield). mp: 290-291° C. (dec); HPLC retention time 7.1 min (reversed phase, Beckman ultrasphere ODS 4.6 mm×25 cm column, 20 min gradient elution with 20:80 to 60:40 acetonitrile:water containing 0.1% TFA@2 mL/min); 1H NMR (300 MHz, d6-DMSO) δ11.3 (br s, NH, 2 H), 10.0 (br s, NH, 2 H), 8.5 (br s, NH, 2 H), 8.32 (d, J=4.2 Hz, 2 H), 7.54 (t, J=7.6 Hz, 2 H), 7.31 (d, J=7.6 Hz, 2 H), 7.16 (d, J=7.8 Hz, 2 H), 7.16-7.09 (m, 2 H), 7.09 (s, 2 H), 7.14 (br s, 2 H), 6.86 (d, J=7.8, Hz, 2 H), 2.34 (s, 6 H); MS (ESI) m/z 555 [M+H]+.
Reaction SMILES: [Br-].[CH2:2]([O:4][C:5]([CH2:7][CH2:8][CH2:9][P+](CC)(CC)CC)=[O:6])[CH3:3].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CC(C)([O-])C.[K+]>CC(OC)(C)C>[C:18]1(/[CH:17]=[CH:9]\[CH2:8][CH2:7][C:5]([O:4][CH2:2][CH3:3])=[O:6])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)CCC[P+](CC)(CC)CC
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: COC(C)(C)C
Product: CCOC(=O)CC/C=C\c1ccccc1
Reaction time: 8 h

Procedure:
3-Ethoxycarbonylpropyltriethylphosphonium bromide (5.488 g, 12.00 mmol), benzaldehyde (3.820 g, 36.00 mmol) and potassium tert-butoxide (4.040 g, 36.00 mmol) were taken up in MTBE (300 mL) at room temperature and was stirred overnight. The reaction mixture was washed with water (1×100 mL) and the aqueous phase was extracted with MTBE (3×100 mL). Solvent was removed from the combined organic phase under reduced pressure and the resulting oil purified by column chromatography (0–10% EtOAc/n-hexane, silica) to give (Z)-ethyl 5-phenylpent-4-enoate as a pale yellow oil. 1H NMR (CDCl3): δ 7.36–7.31 (m, 2H), 7.28–7.21 (m, 3H), 6.47 (d, 1H, J=11.6, Ph-CH), 5.63 (dt, 1H, J1=11.6, J2=7.2), 4.14 (q, 2H, J=7.2), 2.66 (dq, 2H, J1=7.3, J2=1.7), 2.43 (t, 2H, J=7.6), 1.24 (t, 3H, J=7.1). Contains ca. 33% (E)-ethyl 5-phenylpent-4-enoate
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O.O>C(Cl)Cl>[Br:32][CH2:11][CH2:10][CH2:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C)c(CCCO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(C)c(CCCBr)c1
Yield: 86.9 %

Procedure:
Compound 62-2 (1.64 g) was dissolved in methylene chloride (33 ml), triphenylphosphine (2.90 g) and N-bromosuccinimide (1.95 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 3.5 hr. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride and washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (1.97 g) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:31]/[O:32][CH3:33])/[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([OH:28])=[O:27])=[C:15]([CH2:18]OC(=O)CC(=O)C)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[CH3:34][C:35]1[CH:40]=[CH:39][N:38]2[N:41]=[N:42][CH:43]=[C:37]2[CH:36]=1>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:31]/[O:32][CH3:33])/[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O-:28])=[O:27])=[C:15]([CH2:18][N:42]4[CH:43]=[C:37]5[CH:36]=[C:35]([CH3:34])[CH:40]=[CH:39][N:38]5[NH2+:41]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(=O)CC(C)=O)CS[C@H]12)c1csc(N)n1
Reactant: Cc1ccn2nncc2c1
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(CN3C=C4C=C(C)C=CN4[NH2+]3)CS[C@H]12)c1csc(N)n1

Procedure:
7β-[2-(2-Aminothiazol-4-yl)-2(Z)-methoxyiminoacetamido]-3-(3-oxobutyryloxymethyl)-3-cephem-4-carboxylic acid and 5-methyl[1,2,3]triazolo[1,5-a]pyridine are treated by the same procedure as that in Example 1, to yield the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][NH:12][CH:13]=2)=[CH:5][CH:4]=1.[H-].[Na+].[CH3:16][Si:17]([CH2:20][CH2:21][O:22][CH2:23]Cl)([CH3:19])[CH3:18]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][N:12]([CH2:23][O:22][CH2:21][CH2:20][Si:17]([CH3:19])([CH3:18])[CH3:16])[CH:13]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2c[nH]cn2)cc1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(-c2cn(COCC[Si](C)(C)C)cn2)cc1
Yield: 61.2 %

Procedure:
Reaction of 4-(4-methoxyphenyl)-1H-imidazole (610 mg, 3.51 mmol), NaH (60%, 136 mg, 3.40 mmol), and SEMCl (656 uL, 3.71 mmol) followed by column chromatography on silica gel (hexane/EtOAC 1:1) gave the title compound (654 mg, 64%) as a yellow solid. 1H NMR (300 MHz, CDCl3) major isomer: δ0.00 (s, 9H), 0.93 (t, 2H, J=7.5 Hz), 3.52 (t, 2H, J=7.5 Hz), 3.83 (s, 3H), 5.28 (s, 2H), 6.94 (d, 2H, J=9.0 Hz), 7.24 (s, 1H), 7.60 (s, 1H), 7.72 (d, 2H, J=9.0 Hz); minor isomer: δ0.00 (s, 9H), 0.92 (t, 2H, J=7.5 Hz), 3.54 (t, 2H, J=7.5 Hz), 3.85 (s, 3H), 5.23 (s, 2H), 6.98 (d, 2H, J=9.0 Hz), 7.09 (s, 1H), 7.47 (d, 2H, J=9.0 Hz), 7.65 (s, 1H). ES-MS m/z 305 (M+H).
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[CH3:20][NH2:21]>C1COCC1.CCN(C(C)C)C(C)C>[CH3:20][NH:21][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Reactant: CN
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CNC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 2N methylamine in THF and DIEA to give 2-methylamino-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 270 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:35])[C@@H:4]([O:32][CH2:33][CH3:34])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:19][CH:18]=2)=[C:8]([Cl:31])[CH:7]=1.[Li+].[OH-]>>[C:23]([C:20]1[CH:19]=[CH:18][C:17]([O:16][CH2:15][CH2:14][CH2:13][O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][C@H:4]([O:32][CH2:33][CH3:34])[C:3]([OH:35])=[O:2])=[CH:7][C:8]=2[Cl:31])=[CH:22][CH:21]=1)(=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCO[C@@H](Cc1ccc(OCCCOc2ccc(C(=O)c3ccccc3)cc2)c(Cl)c1)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OCCCOc2ccc(C(=O)c3ccccc3)cc2)c(Cl)c1)C(=O)O

Procedure:
The title compound was prepared from (S)-3-{4-[3-(4-benzoyl-phenoxy)-propoxy]-3-chloro-phenyl}-2-ethoxy-propionic acid methyl ester by the standard hydrolysis procedure C (LiOH). 1H-NMR (200.15 MHz, CDCl3): δ 7.82–7.72 (m, 4H), 7.56–7.43 (m, 3H), 7.07 (dd, 1H, J=8.8, 2.0), 6.97 (d, 2H, J=8.9), 6.86 (d, 2H, J=8.3), 4.31 (t, 2H, J=6.0), 4.21 (t, 2H, J=6.0), 4.10–4.02 (m, 1H), 3.66–3.44 (m, 2H), 3.10–2.87 (m, 2H), 2.33 (qn, 2H, J=6.2), 1.20 (t, 3H, J=7.0).
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1[CH:13]=[CH:12][C:11]([N:14]([C:22]2[CH:38]=[CH:37][C:25]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:24][CH:23]=2)C(OC(C)(C)C)=O)=[CH:10][CH:9]=1>ClCCl>[N:8]1[CH:13]=[CH:12][C:11]([NH:14][C:22]2[CH:23]=[CH:24][C:25]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:37][CH:38]=2)=[CH:10][CH:9]=1
Reactant: CCOC(=O)CCCCCOc1ccc(N(C(=O)OC(C)(C)C)c2ccncc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CCCCCOc1ccc(Nc2ccncc2)cc1

Procedure:
Trifluoroacetic acid (3 ml) was added to a stirred solution of ethyl 6-[4-[N-(4-pyridyl)-N-tertiary-butyloxycarbonylamino]phenoxy]hexanoate (260 mg) dissolved in dichloromethane (3 ml). After 18 hours the solvents were removed in vacuo and the residual gum dissolved in dichloromethane. This solution was treated with a saturated solution of sodium hydrogen carbonate. The organic phase was washed with water, dried and evaporated. Trituration of the residue with hexane gave the title compound, 120 mg, as a white solid: m.p. 104°-106° C.; NMR (CDCl3) δ8.22 (2H, d), 7.12 (2H, d), 6.90 (2H, d), 6.64 (2H, dd), 5.82 (1H, s), 4.13 (2H, q), 3.97 (2H, t), 2.34 (2H, t), 1.80 (2H, m), 1.70 (2H, m), 1.53 (2H, m), 1.27 (3H, t); m/e 329 (M+H)+ ; calculated for C19H24N2O3.0.25H2O:C, 68.6; H, 7.4; N, 8.4. found: C, 68.8; H, 7.3; N, 8.2%.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][C:27]=1[O:28][CH3:29])[NH:24][C:23](=[O:30])[CH2:22]2>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=[C:22]1[C:21]2[C:25](=[CH:26][C:27]([O:28][CH3:29])=[C:19]([O:18][CH3:17])[CH:20]=2)[NH:24][C:23]1=[O:30])([CH3:3])[CH3:2]
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Reactant: COc1cc2c(cc1OC)NC(=O)C2
Product: COc1cc2c(cc1OC)C(=Cc1cc(C(C)C)c(OC)c(C(C)C)c1)C(=O)N2

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 5,6-dimethoxy-2-oxindole to give 0.4 g of 3-(3,5-diisopropyl-4-methoxybenzylidene)-5,6-dimethoxy-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [C:1]([C:3]1[C:4](=N)[O:5][C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].Cl.C[OH:22]>>[C:1]([C:3]1[C:4](=[O:22])[O:5][C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2]
Reactant: CO
Reactant: N#Cc1c(-c2ccccc2)c2ccccc2oc1=N
Agent: Cl
Product: N#Cc1c(-c2ccccc2)c2ccccc2oc1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 39 %

Procedure:
To a solution of 3-cyano-2-imino-4-phenyl-2H-chromene (90 mg, 0.37 mmol) in methanol (10 mL) was added 37% HCl (0.037 ml, 0.37 mmol). The mixture was stirred at room temperature for 2 h. The solvent was evaporated and the residue was purified by chromatography on silica gel with ethyl acetate and hexane (1:2) as eluant, yielding 35 mg (39%) of the title compound. 1H NMR (CDCl3): 7.80-7.74 (m, 1H), 7.66-7.60 (m, 3H), 7.57-7.54 (m, 1H), 7.47-7.44 (m, 2H), 7.41-7.32 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH3:11].[OH-].[NH4+:14]>C(O)C>[NH2:14][C:5]1[N:4]=[N:3][C:2]([Cl:1])=[C:7]([CH2:8][CH2:9][CH2:10][CH3:11])[CH:6]=1
Reactant: CCCCc1cc(Cl)nnc1Cl
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1cc(N)nnc1Cl
Yield: 36 %

Procedure:
A mixture of 3,6-dichloro-4-n-butylpyridazine (7.1 g, 34 mmol), ethanol (70 ml) and 25% aqueous ammonium hydroxide (70 ml) was heated to 135 deg in a sealed pressure resistant reaction vessel (Parr: achieving a pressure of 90 psi) for 24 hours. After this time the mixture was cooled and concentrated under reduced pressure. The residue was partitioned between dichloromethane (250 ml) and water (250 ml) and the aqueous layer re -extracted with dichloromethane (200 ml). The combined organic extracts were dried over magnesium sulfate and concentrated under reduced pressure to give the crude product as a mixture of isomers. Purification by flash chromotography (10-100% ethyl acetate/hexane) gave 3-amino-5-n-butyl-6-chloropyridazine as a white solid (2.3 g, 36%). 1H-NMR (CDCl3) 6.55 (1H, s, 4-H), 4.98 (2H, bs, NH2), 2.57 (2H, t, Bu), 1.58 (2H, m, Bu), 1.37 (2H, m, Bu), 0.91 (3H, t, Bu)
Reaction SMILES: [NH2:1][C:2]1[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([N+:26]([O-])=O)[CH:20]=2)[CH2:14][CH2:13]1)=[O:9])=[O:5]>[Pd].CO>[NH2:1][C:2]1[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([NH2:26])[CH:20]=2)[CH2:14][CH2:13]1)=[O:9])=[O:5]
Reactant: Cc1ccc(CN2CCC(CNC(=O)CNC(=O)c3cc(F)c(F)cc3N)CC2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(CN2CCC(CNC(=O)CNC(=O)c3cc(F)c(F)cc3N)CC2)cc1N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4-[{N-(2-amino-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(4-methyl-3-nitrobenzyl)piperidine prepared above, 5% palladium-activated carbon (15 mg), and methanol (2 mL) was stirred under a hydrogen atmosphere at room temperature for 4 h. The Pd catalyst was filtered off through Celite and the filtrate was concentrated. Preparative TLC (SiO2, ethyl acetate/MeOH=3/1) gave 4-{(N-(2-amino-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(3-amino-4-methylbenzyl)piperidine (Compound No. 2114) (2.9 mg, 13%): The purity was determined by RPLC/MS (100%); ESI/MS m/e 446.1 (M++H, C23, H29F2N5O2).
Reaction SMILES: C([Li])CCC.C(OP([CH2:14][C:15]([OH:17])=[O:16])(OCC)=O)C.[CH3:18]/[C:19](/[CH:27]=O)=[CH:20]\[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>O1CCCC1>[CH3:18][C:19](=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:27]=[CH:14][C:15]([OH:17])=[O:16]
Reactant: CCOP(=O)(CC(=O)O)OCC
Reactant: C/C(C=O)=C\c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C=CC(=O)O)=Cc1ccccc1
Temperature: -65 °C
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
Butyllithium (135 mL of 2.5 N solution) was added to 600 mL of anhydrous tetrahydrofuran (THF) at −65° C. A solution of diethylphosphonoacetic acid (30.5 g) in 220 mL of anhydrous THF was added dropwise to the stirred solution at −65° C. over a period of 60 minutes. The resulting solution was stirred at −65° C. for an additional 30 minutes and then a solution of α-methyl-trans-cinnamaldehyde (23.2 g) in 100 mL of anhydrous THF was added to the reaction at −65° C. over a period of 70 minutes. The reaction was stirred for one hour, allowed to warm to room temperature and then stirred overnight. The reaction was then acidified with 5% hydrochloric acid (125 mL) to a pH of 2.8. The aqueous layer was extracted with 100 mL of ether twice and with 100 mL of ethyl acetate once. The combined organic extract was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude material was dissolved in 100 mL of hot methanol and then refrigerated overnight. The crystals formed were filtered and dried under vacuum to afford 25.8 g of the desired 4-methyl-5-phenyl-2,4-pentadienoic acid. 1H NMR (acetone-d6, 300 MHz), δ(ppm) 7.53 (d, 1H), 7.43 (m, 4H), 7.37 (dd, 1H), 6.97 (broad s, 1H), 6.02 (d, 1H), 2.07 (s, 3H)
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[F:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][CH2:27][NH2:28])=[CH:24][CH:23]=1.[BH4-].[Na+]>CO>[F:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][CH2:27][NH:28][CH2:1][C:3]2[CH:18]=[CH:17][C:6]([O:7][C:8]3[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=3)=[C:5]([O:19][CH3:20])[CH:4]=2)=[CH:24][CH:23]=1
Reactant: COc1cc(C=O)ccc1Oc1cnc(C(N)=O)cn1
Reactant: NCCc1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(CNCCc2ccc(F)cc2)ccc1Oc1cnc(C(N)=O)cn1
Reaction time: 8 h
Yield: 53.7 %

Procedure:
Place 5-(4-formyl-2-methoxyphenoxy)pyrazine-2-carboxamide (Example 719, Part A) (0.700 g, 2.56 mmol), 4-fluorophenethylamine (0.374 g, 2.69 mmol) and 3 Å molecular sieves in a vial. Add methanol (12.8 mL), cap and stir overnight. Add NaBH4 (0.0969 g, 2.56 mmol) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 5% to 20% (2.0 M NH3 in methanol) in ethyl acetate over 45 minutes. Concentrate the fraction containing the product then add EtOAc (100 mL). Wash the organic solution with 1.0 N NaOH (2×25 mL), dry it over Na2SO4, filter and concentrate. Dissolve the product in ether:dichloromethane (5:1) (25 mL), add hexanes (20 mL), and then concentrate to about a quarter of the volume. Filter the precipitate to give the title compound (0.545 g, 53.4%): TOF MS ES+ 397.2 (M+H)+, HRMS calcd for C21H22N4O3F 397.1676 (M+H)+, found 397.1689, time 0.38 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=11.2 min, 100% purity.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:15]3([CH2:16][O:17][CH2:18][CH2:19][C:20]([NH2:22])=[N:21]3)[C:14]3[CH:13]=[C:12]([Cl:23])[N:11]=[CH:10][C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[F:24][C:25]1[C:30](B(O)O)=[CH:29][CH:28]=[CH:27][N:26]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[Cl:23][C:12]1[N:11]=[CH:10][C:9]2[O:8][C:5]3[C:4]([C:15]4([CH2:16][O:17][CH2:18][CH2:19][C:20]([NH2:22])=[N:21]4)[C:14]=2[CH:13]=1)=[CH:3][C:2]([C:30]1[C:25]([F:24])=[N:26][CH:27]=[CH:28][CH:29]=1)=[CH:7][CH:6]=3
Reactant: OB(O)c1cccnc1F
Reactant: NC1=NC2(COCC1)c1cc(Br)ccc1Oc1cnc(Cl)cc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: NC1=NC2(COCC1)c1cc(-c3cccnc3F)ccc1Oc1cnc(Cl)cc12
Temperature: 90 °C

Procedure:
A vial was charged with (E)-7-bromo-3-chloro-6′,7′-dihydro-2′H-spiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazepin]-5′-amine (280.9 mg, 0.712 mmol), 2-fluoropyridin-3-ylboronic acid (150 mg, 1.068 mmol), Pd(AmPhos)2Cl2 (25.2 mg, 0.036 mmol), and potassium phosphate (453 mg, 2.135 mmol). The vial was flushed with Ar (g), then 1,4-dioxane (2669 μL) and water (890 μL) were added in sequence. The vial was sealed and heated in a microwave reactor for 20 min at 90° C. The mixture was extracted with EtOAc (3×), and the combined organic extracts were concentrated. The crude product was purified by chromatography on silica gel (0-10% MeOH/DCM) to give (E)-3-chloro-7-(2-fluoropyridin-3-yl)-6′,7′-dihydro-2′H-spiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazepin]-5′-amine as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C(N(CC)CC)C.[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](Cl)=[O:24]>O1CCCC1>[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2)=[O:24]
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: O=C(Cl)c1ccco1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc2[nH]ccc2c1)c1ccco1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 50.4 %

Procedure:
To a solution of 2.09 gm (15.8 mMol) 5-amino-1H-indole in 20 mL tetrahydrofuran were added 2.6 mL (18.97 mMol) triethylamine and the solution was cooled in an ice bath. To the reaction mixture were then added dropwise 1.71 ml (17.4 mMol) 2-furoyl chloride. When this addition was complete the cooling bath was removed and the reaction mixture was stirred 1.5 hours at ambient temperature. At this point the reaction was diluted with water and extracted well with ethyl acetate. The organic solutions were combined and washed sequentially with water, 2N sodium hydroxide, water and saturated aqueous sodium chloride. The remaining organics were then dried over sodium sulfate and concentrated under reduced pressure to give a dark purple solid. The solid was subjected to flash chromatography, eluting with a gradient of dichloromethane containing 0-2% methanol. The recovered solid was crystallized from ethyl acetate to give 1.8 gm (50.3%) of 5-(2-furoyl)amino-1H-indole as pale purple crystals.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].S(=O)(=O)(O)O.[CH3:19]O>>[CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][CH3:19])=[O:10])=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CO
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(S(C)(=O)=O)cc1

Procedure:
250 ml of a desiccated methanol solution containing 50 g (0.25 mol) of p-methylsulfonylbenzoic acid and 10 ml of concentrated sulfuric acid was refluxed by heating for 8 hours. The reaction mixture was then cooled with ice and the crystals thus precipitated were collected by filtration and washed with methanol to obtain 48.2 g (0.225 mol) of the above described compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([N+]([O-])=O)[C:4]=1[C:5]#[N:6].[OH-:18].[K+]>FC(F)(F)CO.O>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([O:18][CH2:9][C:11]([F:14])([F:13])[F:12])[C:4]=1[C:5]#[N:6]
Reactant: COc1cc(C(F)(F)F)cc([N+](=O)[O-])c1C#N
Reactant: [OH-]
Agent: [K+]
Solvent: OCC(F)(F)F
Solvent: O
Product: COc1cc(C(F)(F)F)cc(OCC(F)(F)F)c1C#N
Temperature: 25 °C
Yield: 93.1 %

Procedure:
To a solution of 200 mg (0.804 mmol) 2-methoxy-6-nitro-4-trifluoromethyl-benzonitrile in 2.4 ml 2,2,2-trifluoroethanol under argon at 0° C. was added dropwise a solution of 81.3 mg (1.246 mmol) potassium hydroxide in 600 ul water. The mixture was refluxed for 2 days then cooled to room temperature and poured into ice/water. The resulting suspension was filtered and dried in vacuo to provide 112 mg (47%) of the title compound as a white solid. MS (m/e): 317.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[CH2:10]([Mg]Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(OCC)C>O1CCCC1>[CH2:10]([C:6]1[N:7]=[C:2]([Cl:1])[N:3]=[C:4]([Cl:9])[CH:5]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: Clc1cc(Cl)nc(Cl)n1
Solvent: CCOCC
Solvent: C1CCOC1
Product: Clc1cc(Cc2ccccc2)nc(Cl)n1
Temperature: 20 °C
Yield: 65 %

Procedure:
To a solution of 2,4,6-trichloropyrimidine (936 mg, 5.0 mmol) in tetrahydrofuran (50 mL) was added at −78° C. under an atmosphere of nitrogen and stirring drop wise 1 M benzylmagnesium chloride solution in diethyl ether (5 mL, 5.0 mmol). The reaction was let to warm up to 20° C. over 16 h. The solvent was removed under reduced pressure and the residue was dissolved in water. The aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed once with brine, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel using heptane and then heptane/ethyl acetate (9:1 v/v) as eluent to yield the title compound (778 mg, 65%) as a pale-yellow viscous oil.