Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]([C:10]2[C:15]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:13]=[CH:12][N:11]=2)=[O:9])[CH2:4][CH2:3]1.[BH4-].[Na+]>CO.O>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([CH:8]([C:10]2[C:15]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:13]=[CH:12][N:11]=2)[OH:9])[CH2:6][CH2:7]1
Reactant: CN1CCC(C(=O)c2ncccc2CCc2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN1CCC(C(O)c2ncccc2CCc2ccccc2)CC1
Yield: 87.5 %

Procedure:
To a mixture of 5.0g (16.2 mmole) of (1-methyl-4-piperidinyl)[3-(2-phenylethyl)-2-pyridinyl]methanone (which can be prepared in the same manner as described in Preparative Example 1, Steps A-D) in 70 mL of methanol was added portionwise 0.8 g (21.1 mmole) of sodium borohydride. The next day the solution was concentrated in vacuo to give a slurry which was dissolved in water and extracted with CHCl3. The combined organic portions were dried over MgSO4, filtered, and concentrated in vacuo to provide a liquid which was distilled (bp 190°-195° C. 1 mm Hg) to give 4.4 gms of the title compound as a viscous oil.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:21]1[CH2:25][CH2:24][CH2:23][N:22]1[C:26](=[O:45])[CH2:27][C@@H:28]([O:43][CH3:44])[C@@H:29]([N:34]([CH3:42])[C:35](=[O:41])[C@H:36]([CH:38]([CH3:40])[CH3:39])[NH2:37])[C@@H:30]([CH3:33])[CH2:31][CH3:32])[C@@H:4]([CH3:20])[C:5]([NH:7][C@H:8]([C:16]([O:18][CH3:19])=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6].C1C2C(COC([NH:63][C@@:64]([C:69](O)=[O:70])([CH3:68])[CH:65]([CH3:67])[CH3:66])=O)C3C(=CC=CC=3)C=2C=CC=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(NCC)C>ClCCl>[CH3:66][CH:65]([CH3:67])[C@:64]([C:69]([NH:37][C@H:36]([C:35]([N:34]([C@@H:29]([C@@H:30]([CH3:33])[CH2:31][CH3:32])[C@H:28]([O:43][CH3:44])[CH2:27][C:26]([N:22]1[CH2:23][CH2:24][CH2:25][C@H:21]1[C@H:3]([O:2][CH3:1])[C@@H:4]([CH3:20])[C:5]([NH:7][C@@H:8]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:16]([O:18][CH3:19])=[O:17])=[O:6])=[O:45])[CH3:42])=[O:41])[CH:38]([CH3:39])[CH3:40])=[O:70])([CH3:68])[NH2:63]
Reactant: CC(C)[C@](C)(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](N)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCNCC
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](NC(=O)[C@@](C)(N)C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 68.9 %

Procedure:
A solution of #114 (225 mg, 0.356 mmol, 1.0 eq.) in 2 mL of dichloromethane was added to a solution of N-[(9H-fluoren-9-ylmethoxy)carbonyl]-3-methyl-D-isovaline (126 mg, 0.356 mmol, 1.0 eq.) in 4 mL of dichloromethane. Hunig's base (0.188 mL, 1.07 mmol, 3.0 eq.) was added followed by HATU (167 mg, 0.427 mmol, 1.2 eq). The reaction was allowed to stir at room temperature for 12 hours. The reaction was concentrated in vacuo and then taken up in ethyl acetate before being washed two times with 1M HCl and once with brine. The organic layer was dried over sodium sulfate and decanted. The organic solvent was removed in a genevac. THF (4 mL) was added followed diethylamine (2 mL, 19 mmol, 53.4 eq.). The reaction was allowed to stir for ˜12 hours. Reaction was concentrated using a genevac followed by silica chromatography (Gradient: 0%-30% methanol in ethyl acetate) producing #146 (183 mg, 69%) as a solid. LC-MS (Protocol Q): m/z 746.4 [M+H+] retention time=1.37 minutes. 1H NMR (400 MHz, DMSO-d6), δ 8.55 (d), 8.26-8.36 (m), 7.88-8.03 (m), 7.81 (d), 7.41-7.53 (m), 7.13-7.30 (m), 7.01 (s), 4.71-4.79 (m), 4.44-4.70 (m), 3.96-4.04 (m), 3.70-3.80 (m), 3.62-3.69 (m), 3.40-3.61 (m), 2.76-3.35 (m), 2.67-2.71 (m), 2.56-2.58 (m), 2.06-2.46 (m), 1.61-1.90 (m), 1.14-1.54 (m), 0.72-1.12 (m).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[C:22]([N:25]5[CH:29]=[C:28]([Sn](CCCC)(CCCC)CCCC)[N:27]=[N:26]5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[C:22]([N:25]5[CH:29]=[C:28]([C:44]6[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=6)[N:27]=[N:26]5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2ccc3ncn(-c4ccnc(N[C@@H](C)c5ccccc5)n4)c3c2)nn1
Reactant: Brc1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C[C@H](Nc1nccc(-n2cnc3ccc(-n4cc(-c5ccccn5)nn4)cc32)n1)c1ccccc1
Reaction time: 16 h
Yield: 9.6 %

Procedure:
The title compound was prepared from 30.5 mg of 2-[(S)-1-phenylethylamino]-4-[6-(4-tributylstannyl-triazol-1-yl)benzimidazol-1-yl]pyrimidine, 36.3 mg 2-bromopyridine and 0.5 mg Pd(PPh3)4 using the procedure described in EXAMPLE 273 except that the the reaction mixture was stirred for 16 hours. The residue was purified by flash chromatography eluting with acetone in hexanes to give 2.0 mg of the title compound. 1H NMR (500 MHz, 1:1 CD3OD/CDCl3): δ 1.64 (d, J=6.8 Hz, 3H), 5.28 (m, 1H), 7.0-7.35 (m, 5H), 7.40 (br s, 6.4 Hz, 1H), 7.54 (t, J=7.1 Hz, 1H), 7.84 (m, 1H), 7.93 (d, J=8.4 Hz, 1H), 8.11 (t, J=7.5 Hz, 1H), 8.32 (d, J=8.3 Hz, 1H), 8.36 (m, 1H), 8.65 (d, J=4.6 Hz, 1H), 8.83-9.2 (m, 3H). Mass Spectrum (CH3CN-TFA-NH4HCO2-ESI): 460.2 (M+1).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH:6]1[CH2:8][CH2:7]1)[OH:5].O.[NH2:11][NH2:12]>CO>[CH:6]1([CH:4]([OH:5])[C:3]([NH:11][NH2:12])=[O:2])[CH2:8][CH2:7]1
Reactant: NN
Reactant: COC(=O)C(O)C1CC1
Solvent: O
Solvent: CO
Product: NNC(=O)C(O)C1CC1
Yield: 69 %

Procedure:
As described for example 112a, (rac.)-2-cyclopropyl-2-hydroxy-acetic acid methyl ester (Newall, Christopher Earle; Foxton, Michael Walter; Hartley, Charles David; Looker, Brian Edgar. Cephalosporin antibiotics. Eur. Pat. Appl. (1985), 57 pp) in methanol was reacted with hydrazine hydrate (1.0 equivalent) at rt for 76 h. All volatiles were evaporated and the residue was triturated with hexane to afford the title compound as a white solid (yield: 69%). MS: m/e=112.2 [M−H2O]+.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]([C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH2:21][CH2:22][N:23](CC2C=CC=CC=2)[CH3:24])=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3].CO>[Pd].CN(C)C=O>[ClH:19].[NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:20][CH2:21][CH2:22][NH:23][CH3:24])=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3]
Reactant: CN(CCOc1ccc(Cl)cc1-c1cc(C(N)=O)c(NC(N)=O)[nH]1)Cc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Product: CNCCOc1ccccc1-c1cc(C(N)=O)c(NC(N)=O)[nH]1
Product: Cl
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 110.2 %

Procedure:
Palladium on activated carbon (10 mg) was added to a solution of 2-aminocarbonylamino-5-[2-[2-(N-benzyl-N-methylamino)ethyloxy]-5-chlorophenyl]pyrrole-3-carboxamide (Compound No. 8-21, 26 mg, 0.059 mmol) in the mixed solvent (methanol:N,N-dimethylformamide=10:1, 2.2 mL) and the mixture was stirred at room temperature for 2.5 hours under hydrogen gas atmosphere. After the reaction solution was filtered, the filtrate was concentrated in vacuo. The obtained solid was washed with a mixed solvent (6 mL), which consists of chloroform and diethyl ether (1:1), and dried under reduced pressure to give the target compound (23 mg) quantitatively as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1([NH:22][C:23]2[N:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25]N=2)[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7][C:8]([C:10]1[C:15]([C:16]2[N:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:9].[CH3:33]C1(NC2C=CC(C(F)(F)F)=CN=2)CCCC1N.N1C=CC=NC=1C1C(C(O)=O)=NC=CC=1.C(N(CC)CC)C>>[CH3:1][C:2]1([NH:22][C:23]2[CH:33]=[CH:25][C:26]([C:29]([F:30])([F:32])[F:31])=[CH:27][N:28]=2)[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7][C:8]([C:10]1[C:15]([C:16]2[N:17]=[CH:18][CH:19]=[CH:20][N:21]=2)=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:9]
Reactant: CC1(Nc2ccc(C(F)(F)F)cn2)CCCC1N
Reactant: CC1(Nc2ncc(C(F)(F)F)cn2)CCCC1NC(=O)c1ncccc1-c1ncccn1
Agent: O=C(O)c1ncccc1-c1ncccn1
Solvent: CCN(CC)CC
Product: CC1(Nc2ccc(C(F)(F)F)cn2)CCCC1NC(=O)c1ncccc1-c1ncccn1

Procedure:
Prepared according to the procedure for N-(2-methyl-2-{[5-(trifluoromethyl)pyrimidin-2-yl]amino}cyclopentyl)-3-(pyrimidin-2-yl)pyridine-2-carboxamide (Example 153) from 1-methyl-1-N-[5-(trifluoromethyl)pyridin-2-yl]cyclopentane-1,2-diamine (Intermediate 51; 91 mg, 0.35 mmol), 3-(pyrimidin-2-yl)pyridine-2-carboxylic acid (CAS number 1228431-21-7; 85 mg, 0.42 mmol) and triethylamine (0.147 ml, 1.06 mmol) except after work-up the organics were loaded directly on to a cation/anion mixed mode cartridge, eluted with DCM then with 2M ammonia in methanol and concentrated in vacuo. The resulting residue was purified by reverse phase chromatography (C18 silica, 5-100% water (0.05% ammonia)/acetonitrile) then recrystallised from MTBE/heptane to afford the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[CH3:29][NH:30][C:31]1[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=1>>[C:35]([C:34]1[CH:37]=[CH:38][C:31]([N:30]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[C:10]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=3)=[CH:5][CH:4]=2)[CH3:29])=[CH:32][CH:33]=1)#[N:36]
Reactant: CNc1ccc(C#N)cc1
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1C(F)(F)F
Product: CN(Cc1ccc(-c2nccnc2NS(=O)(=O)c2ccccc2C(F)(F)F)cc1)c1ccc(C#N)cc1
Yield: 71 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzene sulfonamide (Intermediate 9), and 4-(N-methylamino)benzonitrile, the title compound was isolated as a yellow solid in 71% yield (94% purity by HPLC).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH2:8])=[CH:3][CH:2]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10].[I:16][CH3:17]>CO>[I-:16].[NH:8]([CH2:7][C:4]1[CH:5]=[CH:6][N+:1]([CH3:17])=[CH:2][CH:3]=1)[C:9]([CH3:10])=[O:11]
Reactant: CC(=O)OC(C)=O
Reactant: CI
Reactant: NCc1ccncc1
Solvent: CO
Product: CC(=O)NCc1cc[n+](C)cc1
Product: [I-]
Temperature: 0 °C
Reaction time: 8 h
Yield: 70.7 %

Procedure:
To a cold (ice-water bath) solution of 4-picolylamine (1070 gr, 9.9 mol) in methanol (3 l) was added dropwise acetic anhydride (1400 gr, 13.7 mol). During addition the reaction temperature was kept between 10 and 30° C. When the addition of the reagent was complete the reaction mixture was left overnight at room temperature. Iodomethane (800 ml, 24.8 mol) was added to the reaction mixture which was cooled with water bath, under nitrogen atmosphere. During addition the reaction temperature was kept below 25° C. When the addition was complete, the reaction mixture was protected from light and left at room temperature overnight The excess iodomethane was evaporated, crystallization was induced, the reaction mixture was cooled (ice bath) and isopropanol (1.5 l) was added. The reaction mixture was left at −30° C. overnight, the precipitate was filtered off, washed with isopropanol and dried. 4-(Acetaminomethyl)-1-methyl-pyridinium iodide (2043 gr, 7 mol) was obtained as yellow powder (71% yield). 1H-NMR (D2O) δ 2.10 (s, CH3CO), 4.32 (s, CH3N+), 4.63 (s, CH2NHCO), 7.89 (d, j=6.6 Hz, 2H), 8.67 (d, j=6.6 Hz, 2H) ppm.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@@H:9]1[C:14]([NH:16][CH:17]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:18]([OH:22])[C:19](O)=[O:20])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:31]([O:33][NH2:34])[CH3:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@@H:9]1[C:14]([NH:16][CH:17]([CH:18]([OH:22])[C:19]([NH:34][O:33][CH2:31][CH3:32])=[O:20])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1
Reactant: CCON
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCONC(=O)C(O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1

Procedure:
The reaction was carried out in analogy to reaction step 20.3 of Example 20 by reacting 3-((R)-1-benzyl-5-oxopyrrolidine-2-carboxamido)-2-hydroxy-4-phenylbutanoic acid with O-ethylhydroxylamine hydrochloride using HATU (1.2 equivalents) as coupling reagent and DIPEA (6.8 equivalents) as base. ESI-MS [M+H]+=440.2
Reaction SMILES: C(Cl)CCl.[Br:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([Br:15])[CH:14]=1)[C:9]([OH:11])=[O:10].[C:16](O)([CH3:19])([CH3:18])[CH3:17]>CN(C1C=CN=CC=1)C.C(Cl)Cl.N1C=CC=CC=1>[Br:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([Br:15])[CH:14]=1)[C:9]([O:11][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:10]
Reactant: CC(C)(C)O
Reactant: O=C(O)c1cc(Br)cc(Br)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cc(Br)cc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
EDC (14.0 g, 73.0 mmol) and DMAP (4.0 g) are added to a solution of 3,5-dibromobenzoic acid (10.0 g, 36.0 mmol) and tert-butanol (3.4 g, 46.8 mmol) in absolute CH2Cl2 (100 ml) and absolute pyridine (30 ml), and the mixture is stirred at RT for 1 h and then at 50° C. for 2 h. The reaction solution is diluted with CH2Cl2 (100 ml) and extracted with a semisaturated aqueous NH4Cl solution (200 ml) (2×), dried over MgSO4, filtered off and concentrated under reduced pressure. Further purification by chromatography [toluene/acetone (95:5)] on a silica gel column gives the title compound (7.7 g) as slightly yellow crystals. TLC, silica gel, glass plates, [toluene/acetone (7.5:2.5)], Rf=0.78.
Reaction SMILES: [N:1]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][C@@H:3]2[CH2:6][NH:7][CH2:8][C@H:2]12.[CH3:23][C:24]([CH3:26])=O.C([BH3-])#N.[Na+]>CO.[OH-].[Na+]>[CH:24]([N:7]1[CH2:6][C@@H:3]2[C@@H:2]([N:1]([C:9]3[CH:10]=[CH:11][C:12]([C:15]4[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=4)=[CH:13][CH:14]=3)[CH2:5][CH2:4]2)[CH2:8]1)([CH3:26])[CH3:23]
Reactant: N#Cc1ccc(-c2ccc(N3CC[C@@H]4CNC[C@@H]43)cc2)cc1
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)N1C[C@H]2CCN(c3ccc(-c4ccc(C#N)cc4)cc3)[C@H]2C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of the product of Example 1E (26 mg, 0.09 mmole) in methanol (2 ml) was added acetone (132 μl, 1.8 mmole), and the mixture was stirred at room temperature for 1.5 hour. Sodium cyanoborohydride (28 mg, 0.44 mmole) was added and the mixture stirred overnight. The mixture was diluted with 2 ml 1N NaOH and extracted with dichloromethane (with 5% methanol) (3×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluting with a mixture of 0.35% ammonium hydroxide and 3.5% methanol in dichloromethane) to provide the title compound. 1H NMR (CDCl3) δ ppm 7.63 (d, J=3.74 Hz, 4H) 7.50 (d, J=9.05 Hz, 2H) 6.64 (d, J=8.73 Hz, 2H) 4.16-4.22 (m, 1H) 3.48-3.55 (m, 1H) 3.31-3.38 (m, 1H) 2.90-3.01 (m, 2H) 2.74 (t, J=7.96 Hz, 1H) 2.46-2.52 (m, 2H) 2.31-2.39 (m, 1H) 2.10-2.20 (m, 1H) 1.90-1.99 (m, 1H) 1.06 (dd, J=6.24, 1.87 Hz, 6H); MS (M+H)+=332.
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[O:12][CH3:13].[CH3:14][O:15][CH2:16][CH2:17][O:18][CH2:19]Cl.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH2:26][C:27]#[N:28]>>[CH3:13][O:12][C:3]1[CH:4]=[C:5](/[CH:6]=[C:26](/[C:25]2[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:23]([O:22][CH3:21])[CH:24]=2)\[C:27]#[N:28])[CH:8]=[C:9]([O:10][CH3:11])[C:2]=1[O:1][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19]
Reactant: COc1cc(C=O)cc(OC)c1O
Reactant: COCCOCCl
Reactant: COc1ccc(CC#N)cc1OC
Product: COCCOCOc1c(OC)cc(/C=C(\C#N)c2ccc(OC)c(OC)c2)cc1OC
Yield: 65.3 %

Procedure:
The hydroxyl group of 4-hydroxy-3,5-dimethoxybenzaldehyde (2.44 g) was protected by use of 2-methoxyethoxymethyl chloride (1.67 g) in accordance with (production process 1), to thereby produce an MEM form (3.40 g, yield: 94%). The resultant MEM form (3.40 g) and 3,4-dimethoxybenzyl cyanide (2.23 g) were subjected to condensation in accordance with process A of (production process 2), to thereby produce (Z)-3-[3,5-dimethoxy-4-(2-methoxyethoxymethoxy)-phenyl]-2-(3,4-dimethoxy-phenyl)-acrylonitrile (3.53 g, yield: 65%). The thus-produced (Z)-3-[3,5-dimethoxy-4-(2-methoxyethoxymethoxy)-phenyl]-2-(3,4-dimethoxy-phenyl)-acrylonitrile (0.35 g) was subjected to deprotection in accordance with (production process 3), to thereby produce the target product (0.25 g, yield: 90%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:23]=[C:22]3[C:18]([CH2:19][CH2:20][N:21]3[C:24](=[O:26])[CH3:25])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:36]1([C@@H:42]2[CH2:44][C@H:43]2[C:45](Cl)=[O:46])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(#N)C>[C:24]([N:21]1[C:22]2[C:18](=[CH:17][CH:16]=[C:15]([N:14]([CH:11]3[CH2:12][CH2:13][N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:9][CH2:10]3)[C:45]([C@@H:43]3[CH2:44][C@H:42]3[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:46])[CH:23]=2)[CH2:19][CH2:20]1)(=[O:26])[CH3:25]
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Reactant: CC(=O)N1CCc2ccc(NC3CCN(Cc4ccccc4)CC3)cc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(=O)N1CCc2ccc(N(C(=O)[C@@H]3C[C@H]3c3ccccc3)C3CCN(Cc4ccccc4)CC3)cc21
Reaction time: 8 h
Yield: 60.2 %

Procedure:
To a solution of 1-[6-(1-benzyl-piperidin-4-ylamino)-2,3-dihydro-indol-1-yl]-ethanone (0.353 g, 1.01 mmol) in 50 mL of acetonitrile was added diisopropylethylamine (0.193 mL, 1.11 mmol) and trans-2-phenyl-1-cyclopropanecarbonyl chloride (90%, 0.174 mL, 1.01 mmol). The reaction mixture was stirred overnight, and then was filtered through diatomaceous earth. The filtrate was evaporated and the residue was chromatographed over silica gel (acetone/MeOH/CH2Cl2) to provide the desired product as a tan solid (0.30 g, 61%). 1H NMR (400 MHz, CDCl3): 8.04 (s, 1H), 7.38-6.98 (m, 9H), 6.97-6.82 (m, 2H), 6.76 (dd, J=12.5, 6.2 Hz, 1H), 4.65 (br t, J=12.7 Hz, 1H), 4.12 (t, J=9.5 Hz, 1H), 4.09-3.87 (m, 1H), 3.44 (s, 2H), 3.26-3.07 (m, 2H), 2.97-2.79 (m, 2H), 2.51-2.47 (m, 1H), 2.29-1.98 (m, 5H), 1.92-1.66 (m, 2H), 1.65-1.29 (m, 4H), 1.08-0.96 (m, 1H). MS: exact mass calculated for C32H35N3O2, 493.27; m/z found, 494.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:22]([C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27])#[CH:23]>C(O)(C)C>[CH3:16][O:15][CH2:14][CH2:13][O:12][C:9]1[CH:10]=[C:11]2[C:2]([NH:27][C:26]3[CH:28]=[CH:29][CH:30]=[C:24]([C:22]#[CH:23])[CH:25]=3)=[N:3][CH:4]=[N:5][C:6]2=[CH:7][C:8]=1[O:17][CH2:18][CH2:19][O:20][CH3:21].[ClH:1]
Reactant: C#Cc1cccc(N)c1
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OCCOC
Solvent: CC(C)O
Product: C#Cc1cccc(Nc2ncnc3cc(OCCOC)c(OCCOC)cc23)c1
Product: Cl
Temperature: 27.5 °C
Yield: 86.6 %

Procedure:
4-Chloro-6,7-bis-(2-methoxyethoxy)-quinazoline (63 gm) and isopropyl alcohol (990 ml) are added to 3-ethynylaniline (23.6 gm) at 25-30° C. under stirring, the contents are heated to reflux and then refluxed for 1 hour 30 minutes to 2 hours. The reaction mass is cooled to 25-30° C. and stirred for 30 minutes. Filtered the material, washed with chilled isopropyl alcohol (400 ml) followed by n-hexane (300 ml) and then dried the material at 50-60° C. under vacuum for 6 hours to give 75 gm of crude erlotinib hydrochloride in polymorph form A [HPLC purity: 97%; Mean particle size (D50): 3.42 μm and 90 volume-% of the particles (D90): 4.53 μm].
Reaction SMILES: Br[CH2:2][O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])=[O:5].[Cl:23]CI>>[Cl:23][CH2:2][O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])=[O:5]
Reactant: O=C(Cc1ccccc1C(=O)OCBr)OCc1ccccc1
Reactant: ClCI
Product: O=C(Cc1ccccc1C(=O)OCCl)OCc1ccccc1

Procedure:
In like manner benzyl 2-(bromomethoxycarbonyl)-phenylacetate is prepared by substituting bromoiodomethane for chloroiodomethane.
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.C([O:19][C:20](=[O:31])[C:21]#[C:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([F:30])[CH:24]=1)C.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[CH2:10]([N:4]1[CH2:3][C:22]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([F:30])[CH:24]=2)=[C:21]([C:20]([OH:31])=[O:19])[CH2:5]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CCOC(=O)C#Cc1ccc(Cl)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1=C(c2ccc(Cl)c(F)c2)CN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
At r.t., a solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methyl amine (61.3 g, 0.26 mol) in CH2Cl2 (120 ml) was added dropwise over 90 minutes to a stirred solution of (4-chloro-3-fluoro-phenyl)-propynoic acid ethyl ester (39.0 g, 0.17 mol) and trifluoroacetic acid (1.30 ml, 0.02 mol) in CH2Cl2 (170 ml). The reaction mixture was stirred at 25° C. for 72 h and afterward evaporated to dryness. The residue was dissolved in dioxane (390 ml). An aqueous solution of NaOH (45.0 ml, 0.48 mol, 2.8 eq.) was added, and the resulting emulsion was stirred at r.t. for 18 h. The low boiling organic solvent was removed under vacuum. Water (100 ml) was added, the aqueous layer was separated and washed with TBME (2 times 100 ml). The aqueous layer was then acidified to a pH value of 2.5 by addition of 25% HCl. The resulting suspension was stirred overnight and the white precipitate was filtered off, washed with water and ethanol and dried under high vacuum to yield 42.0 g (75%) of IId as a white solid.
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[CH3:24])[CH2:4][CH3:5])[CH3:2].[CH3:25][S:26]([OH:29])(=[O:28])=[O:27]>C(OCC)(=O)C>[CH3:25][S:26]([O-:29])(=[O:28])=[O:27].[CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[NH+:10]=[C:9]([O:14][C:15]2[C:16]([CH3:23])=[CH:17][C:18]([CH3:22])=[CH:19][C:20]=2[CH3:21])[C:8]=1[CH3:24])[CH2:4][CH3:5])[CH3:2]
Reactant: CS(=O)(=O)O
Reactant: CCC(CC)Oc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C
Solvent: CCOC(C)=O
Product: CCC(CC)Oc1cc(C)[nH+]c(Oc2c(C)cc(C)cc2C)c1C
Product: CS(=O)(=O)[O-]

Procedure:
4-(1-ethyl-propoxy)-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine (prepared as described in Example 1) was treated with 1 equivalent of methanesulfonic acid in ethyl acetate. The white crystals formed from ethyl acetate, melting point 117-119° C.