Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:31](=[O:32])[N:30]([CH2:33][CH3:34])[C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([N:23]5[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]5)=[CH:19][CH:18]=4)[N:14]=[CH:15][C:10]=3[CH:9]=2)=[C:4]([Cl:35])[CH:3]=1.[S:36]1[CH:40]=[CH:39][CH:38]=[C:37]1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:35][C:4]1[CH:3]=[C:2]([C:37]2[S:36][CH:40]=[CH:39][CH:38]=2)[CH:7]=[CH:6][C:5]=1[C:8]1[C:31](=[O:32])[N:30]([CH2:33][CH3:34])[C:11]2[N:12]=[C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[N:14]=[CH:15][C:10]=2[CH:9]=1
Reactant: OB(O)c1cccs1
Reactant: CCn1c(=O)c(-c2ccc(Br)cc2Cl)cc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Product: CCn1c(=O)c(-c2ccc(-c3cccs3)cc2Cl)cc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc21
Temperature: 140 °C
Yield: 100 %

Procedure:
6-(4-Bromo-2-chlorophenyl)-8-ethyl-2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (12, 50 mg, 0.09 mmol), thiophene-2-boronic acid (35 mg, 0.27 mmol), K3PO4 (57 mg, 0.27 mmol) and PdCl2(dppf) (7 mg, 0.01 mmol) were mixed as solids and placed under argon. Argon was bubbled through a mixture of dimethylformamide:water (20:1, 2.0 mL) for 20 min. The solvent was added to the solid and the suspension was heated under microwave irradiation at 140° C. for 30 min. The reaction mixture was evaporated and the crude product was purified by column chromatography, eluting with dichloromethane:methanol (100:3). The product was triturated with refluxing acetonitrile to yield the title compound as a yellow solid (48 mg, 0.09 mmol, 100%). ESMS m/z 557 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 8.54 (s, 1H), 7.72 (s, 1H), 7.51-7.60 (m, 4H), 7.40 (d, J=8.0 Hz, 1H), 7.30-7.36 (m, 2H), 7.27 (s, 1H), 7.08-7.13 (m, 1H), 6.97 (d, J=8.8 Hz, 2H), 4.50 (q, J=7.0 Hz, 2H), 3.16-3.28 (m, 4H), 2.54-2.69 (m, 4H), 1.39 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CO/[CH:19]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22].P(Cl)(Cl)(Cl)=O>C(OCC)(=O)C.O.C(O)(=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](/[CH:19]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22])=[C:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CO/C=C/C(=O)OC
Reactant: Cn1c(-c2ccccc2)cc2ccccc21
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)/C=C/c1c(-c2ccccc2)n(C)c2ccccc12
Reaction time: 7 h
Yield: 75.9 %

Procedure:
1.04 g of 1-methyl-2-phenyl-1H-indol, 0.64 g of methyl trans-3-methoxyacrylate, 94.5 mg of water and 6 mL of glacial acetic acid were mixed, 124 mg of phosphorus oxychloride was added into the mixture at an inner temperature of 25° C., the added mixture was stirred for 7 hours at the same temperature to cause a reaction. After completion of the reaction, 30 mL of water was added dropwise into the reaction liquid, 50 mL of ethyl acetate was added and extraction treatment was conducted, and the resulting organic layer was subjected to concentration treatment. The resultant concentrated residue was purified by flash chromatography, to obtain 1.11 g of methyl trans-3-(1-methyl-2-phenyl-1H-indol-3-yl)acrylate (yellow solid). Yield: 76%.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[O:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl[C:19](=[O:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21].Cl>C(Cl)Cl>[CH2:23]([O:22][C:20](=[O:21])[C:19]([C:9]1[CH:10]=[CH:11][C:6]([O:5][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:7][CH:8]=1)=[O:25])[CH3:24]
Reactant: CCOC(=O)C(=O)Cl
Reactant: c1ccc(Oc2ccccc2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
To 301 g (2.26 mol) of AlCl3 in CH2Cl2 (750 ml) a mixture of 383 g (2.25 ml) of 4-phenoxybenzene and 205 g (1.50 mol) of ethyl chloroglyoxylate in CH2Cl2 (750 ml) is added dropwise at ice-bath temperature during one hour. Thereafter, the mixture is gradually warmed up to room temperature and stirred overnight. Then, the reaction mixture is poured onto ice. The aq. solution is acidified to pH 3 with aqueous HCl solution, followed by an extraction with CH2Cl2. The extract is dried over anhydrous MgSO4. The desired product is purified by silica gel column chromatography using CH2Cl2-hexane mixture as eluent. 338 g of colorless oily 4-phenoxyphenyl glyoxylic acid ethyl ester is obtained (83%).
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][CH2:5][N:6]([CH3:32])[C:7]([C:9]1[CH:10]=[N:11][N:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:22][CH2:21][CH2:20][C@@H:19]3[C:23]3[C:24]([O:30]C)=[N:25][CH:26]=[C:27]([F:29])[CH:28]=3)=[N:14][C:13]=12)=[O:8]>C(#N)C>[Cl:2][CH2:3][CH2:4][CH2:5][N:6]([CH3:32])[C:7]([C:9]1[CH:10]=[N:11][N:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:22][CH2:21][CH2:20][C@@H:19]3[C:23]3[C:24](=[O:30])[NH:25][CH:26]=[C:27]([F:29])[CH:28]=3)=[N:14][C:13]=12)=[O:8]
Reactant: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)N(C)CCCCl)c2n1
Agent: Cl
Solvent: CC#N
Product: CN(CCCCl)C(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)c[nH]c3=O)nc12
Temperature: 90 °C
Yield: 150 %

Procedure:
A mixture of HCl (4 N dioxane, 4 mL, 16.0 mmol) and (R)-N-(3-chloropropyl)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)-N-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide (100 mg, 0.224 mmol) was sealed in a pressure tube and heated at 90° C. for 90 minutes. The reaction mixture was then diluted with acetonitrile and concentrated to yield the crude product, which was carried to the next step without further purification (145 mg, 150% yield). MS (apci) m/z=433.0 (M+H).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:23]1(CN)CCCC[CH2:24]1>>[CH:5]1([CH2:1][NH:6][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH2:4][CH2:3][CH2:2][CH2:24][CH2:23]1
Reactant: NCC1CCCCC1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Product: Cc1nc(NCc2ccccn2)nc(NCC2CCCCC2)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using 1-cyclohexylmethanamine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.66-0.73 (m, 2H), 1.00 (bs, 3H), 1.35 (bs, 1H), 1.42-1.58 (m, 5H), 1.86 (s, 3H), 2.18 (s, 3H), 3.06 (bs, 2H), 4.58 (bs, 2H), 7.26 (bs, 2H), 7.40-7.46 (m, 1H), 7.68-7.74 (m, 1H), 8.49 (bs, 1H); MS (ESI) m/z 326.5 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][CH2:9][C:8]3([CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[C:5]2=[N:6][CH:7]=1.Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=2)[N:20]=[C:19]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[C:18]=1[CH3:34].Cl.O1CCOCC1>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]([C:17]3[C:26]4[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=4)[N:20]=[C:19]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[C:18]=3[CH3:34])[CH2:9][C:8]3([CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[C:5]2=[N:6][CH:7]=1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Reactant: Brc1cnc2c(c1)NCC21CCOCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC2(CCOCC2)c2ncc(Br)cc21
Temperature: 150 °C

Procedure:
Prepared according to procedure L using 6′-bromo-1′,2,2′,3,5,6-hexahydrospiro-[pyran-4,3′-pyrrolo[3,2-b]pyridine] (89 mg, 0.33 mmol), 4-chloro-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (90 mg, 0.33 mmol) and hydrochloric acid in 1,4-dioxane (83 μL, 0.330 mmol) in NMP (2.0 mL) and heating in the microwave at 150° C. for 2 h. After purification 6′-bromo-1′-(7-fluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-yl)-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine] was obtained as a yellow film. Mass Spectrum (ESI) m/e=505 [(M+1) (79Br)] and 507 [(M+1) (81Br)].
Reaction SMILES: [C:1]([C:3]12[CH2:10][C:7]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5][CH2:4]2)#[CH:2].Cl[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>C(#N)C.C(OCC)(=O)C.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.[Cu]I>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:2]#[C:1][C:3]12[CH2:10][C:7]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])([CH2:8][CH2:9]1)[CH2:6][CH2:5][CH2:4]2
Reactant: C#CC12CCCC(NC(=O)OC(C)(C)C)(CC1)C2
Reactant: Clc1ccccn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC12CCCC(C#Cc3ccccn3)(CC1)C2
Temperature: 70 °C
Yield: 76.3 %

Procedure:
To a stirred solution of tert-butyl 5-ethynylbicyclo[3.2.1]octan-1-ylcarbamate (5.8 g, 23.3 mmol) and 2-chloropyridine (3.18 g, 28 mmol) in TEA (30 mL) and acetonitrile (150 mL) under N2 was added Pd(PPh3)4 (266 mg, 0.23 mmol), followed by CuI (266 mg, 1.4 mmol). The reaction mixture was heated at 70° C. for three hours. After cooled to room temperature, the reaction mixture was diluted with ethyl acetate (250 mL), washed with water (150 mL) and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5/1) to give 5.8 g (76%) of the title compound, tert-butyl 5-(pyridin-2-ylethynyl)bicyclo[3.2.1]octan-1-ylcarbamate, as a white solid. ESI-MS m/z: 298 (M-55)+.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]2[CH2:14]O)=[CH:4][CH:3]=1.C(N(CC)CC)C.CS([Cl:29])(=O)=O.C(=O)([O-])O.[Na+]>ClCCl>[Cl:29][C@@H:12]1[CH2:11][CH2:10][CH2:14][CH2:9][N:8]([CH2:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:17][CH:16]=2)[CH2:13]1
Reactant: CS(=O)(=O)Cl
Reactant: OC[C@H]1CCCCN1CCc1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Clc1ccc(CCN2CCCC[C@@H](Cl)C2)cc1
Reaction time: 14 h

Procedure:
(R)-1-(4-chlorophenethyl)-2-hydroxymethylpiperidine (354 mg) was dissolved in 10 ml of dichloromethane. Triethylamine (184 mg, 1.82 mmol) and methanesulfonyl chloride (208 mg, 1.82 mmol) were added to the obtained solution under stirring under cooling on ice. They were stirred under cooling on ice for 1 hour and then at room temperature for 14 hours. The reaction liquid was distributed in dichloromethane and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain (R)-3-chloro-1-(4-chlorophenethyl) homopiperidine in the form of a light yellow oil (380 mg, 100%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH:11]=[C:12]([CH:27]=[CH:28][CH:29]=2)[CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([O:25]C)=[O:24])=[CH:17][CH:16]=2)=[CH:2]1.[OH-].[K+]>O1CCCC1.C(O)C.C(OCC)(=O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH:11]=[C:12]([CH:27]=[CH:28][CH:29]=2)[CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:17][CH:16]=2)=[CH:2]1
Reactant: COC(=O)CCc1ccc(OCc2cccc(-c3csc4ccccc34)c2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(O)CCc1ccc(OCc2cccc(-c3csc4ccccc34)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.5 %

Procedure:
Methyl 3-(4-{[3-(1-benzothiophen-3-yl)benzyl]oxy}phenyl)propanoate (0.80 g, 1.99 mmol) was dissolved in a mixed solvent of tetrahydrofuran (10 mL) and ethanol (10 mL). An aqueous solution (5 mL) of 85% potassium hydroxide (0.28 g, 4.24 mmol) was added to the solution, and the mixture was stirred at room temperature for 18 hr. The reaction solution was diluted with ethyl acetate, and the mixture washed successively with aqueous citric acid solution, water and aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were washed with diethyl ether-hexane to give the title compound (0.70 g, yield 91%) as colorless prism crystals. MS: m/z 371 (M−OH), 1H NMR (CDCl3) δ: 2.65 (2H, t, J=7.4 Hz), 2.92 (2H, t, J=7.4 Hz), 5.13 (2H, s), 6.93 (2H, d, J=8.8 Hz), 7.14 (2H, d, J=8.8 Hz), 7.34-7.98 (9H, m).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([N:11]2[C:15]3[CH:16]=[C:17]([CH2:20][N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)=[N:8][C:7]=1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=1)=[O:5])C.[OH-].[Li+]>O1CCCC1.O>[Cl:34][C:30]1[CH:29]=[C:28]([C:7]2[N:8]=[C:9]([N:11]3[C:15]4[CH:16]=[C:17]([CH2:20][N:21]5[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]5)[CH:18]=[CH:19][C:14]=4[N:13]=[CH:12]3)[S:10][C:6]=2[C:4]([OH:5])=[O:3])[CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)c1sc(-n2cnc3ccc(CN4CCN(C)CC4)cc32)nc1-c1cccc(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCN(Cc2ccc3ncn(-c4nc(-c5cccc(Cl)c5)c(C(=O)O)s4)c3c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
To a solution of 0.250 g (0.5 mmole) of 4-(3-chloro-phenyl)-2-[6-(4-methyl-piperazin-1-ylmethyl)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid ethyl ester (I.2d) in 10 mL of tetrahydrofuran and 10 mL of water was added 0.12 g (5 mmole) of lithium hydroxide. The mixture was stirred at ambient temperature for 1 hour. The mixture was concentrated under reduced pressure, 40 mL of water was added and the pH adjusted to 6-7 by the addition of 1M hydrochloric acid. The precipitate was collected by filtration to give 0.145 g of 4-(3-chloro-phenyl)-2-[6-(4-methyl-piperazin-1-ylmethyl)-benzoimidazol-1-yl]-thiazole-5 carboxylic acid (I.2f) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[CH2:10]2)[N:3]=1.[F:17][C:18]1[C:19]([C:27]2[N:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](O)=[O:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][N:13]([C:21]([C:20]4[CH:24]=[CH:25][CH:26]=[C:18]([F:17])[C:19]=4[C:27]4[N:28]=[CH:29][CH:30]=[CH:31][N:32]=4)=[O:22])[CH2:14]3)[CH2:10]2)[N:3]=1
Reactant: O=C(O)c1cccc(F)c1-c1ncccn1
Reactant: Cc1cc(C)nc(N2CC3CNCC3C2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C)nc(N2CC3CN(C(=O)c4cccc(F)c4-c4ncccn4)CC3C2)n1
Reaction time: 1 h
Yield: 44.1 %

Procedure:
To a mixture of 2-(4,6-dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole (1.4 g, 6.5 mmol), 3-fluoro-2-(pyrimidin-2-yl)benzoic acid (1.4 g, 6.5 mmol), and TEA (1.3 mL, 9.7 mmol) in DMF (32.0 mL) was added HATU (2.7 g, 7.1 mmol). After 1 h, the reaction mixture was diluted with EtOAc and washed with water. The aqueous layer was then extracted with EtOAc (1×). The combined organic phases were dried (Na2SO4), filtered and concentrated to dryness. The crude product was purified using silica gel chromatography (0-5% MeOH in EtOAc) to yield pure title compound (1.2 g, 44%). MS (ESI) mass calcd. For C23H23FN6O, 418.48; m/z found 419.2 [M+H]+. 1H NMR (CDCl3): 8.91-8.56 (m, 2H), 7.47-7.42 (m, 1H), 7.24-7.14 (m, 3H), 6.30 (s, 1H), 3.81 (dd, J=11.6, 7.2 Hz, 1H), 3.72 (ddd, J=9.0, 7.2, 2.2 Hz, 2H), 3.68-3.47 (m, 4H), 3.31 (dd, J=11.0, 4.8 Hz, 1H), 3.05-2.89 (m, 2H), 2.31 (s, 6H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH:9][C:10]([C:12]2[S:16][C:15]([C:17]([O:19]C)=O)=[CH:14][CH:13]=2)=[O:11])=[CH:3][CH:2]=1.CO.O.[NH2:24][NH2:25]>O1CCCC1>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH:9][C:10]([C:12]2[S:16][C:15]([C:17]([NH:24][NH2:25])=[O:19])=[CH:14][CH:13]=2)=[O:11])=[CH:3][CH:2]=1
Reactant: NN
Reactant: COC(=O)c1ccc(C(=O)NCCc2ccncc2)s1
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: NNC(=O)c1ccc(C(=O)NCCc2ccncc2)s1
Reaction time: 24 h
Yield: 82 %

Procedure:
Methyl 5-[2-(pyridin-4-yl)ethylcarbamoyl]thiophene-2-carboxylate (0.40 g, 1.4 mmol) was suspended in a liquid mixture of methanol (4.0 mL) and tetrahydrofuran (2.0 mL) and left at 55° C. until conversion to a homogeneous amber solution was confirmed. After addition of 80% hydrazine monohydrate (0.17 mL, 2.8 mmol), it was left at 55° C. for 24 hours. After addition of 80% hydrazine monohydrate (0.17 mL, 2.8 mmol), it was left at 55° C. for 4.5 hours and then at room temperature for 14 hours. The precipitated solid was recovered by filtration and dried to give the desired product, 5-hydrazinocarbonylthiophene-2-carboxylic acid (2-pyridin-4-yl)ethylamide (yield 82%).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[C:7]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Cl:30])[N:6]=1)(=O)=O.[CH:31]1([CH2:34][OH:35])[CH2:33][CH2:32]1>>[CH:31]1([CH2:34][O:35][C:5]2[N:10]=[C:9]([N:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:8]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[C:7]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[Cl:30])[N:6]=2)[CH2:33][CH2:32]1
Reactant: CS(=O)(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c(N2CCCC2)n1
Reactant: OCC1CC1
Product: Clc1ccc(-c2c(-c3ccc(Cl)cc3Cl)nc(OCC3CC3)nc2N2CCCC2)cc1

Procedure:
2-(Methylsulfonyl)-4-(N-pyrrolidinyl)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine (Example 36, Step A, 48 mg, 0.1 mmol) was treated with cyclopropyl methanol by the same general procedure described in Reference Examples 6 and 7. Workup and flash column chromatography on silica gel (eluted with 70/30 hexanes/ethyl acetate) afforded the title compound. HPLC: Rt=3.46 min. 1H-NMR 500 MHz (CDCl3): δ 0.37 (d, J=4 Hz, 2H), 0.61 (dd, J=8 Hz, J=1 Hz, 2H), 1.38 (m, 1H), 1.80 (bs, 4H), 3.2 (bs, 4H), 4.17 (m, 1H), 4.25 (m, 1H), 6.85 (d, J=8 Hz, 1H), 7.08 (d over bs, J=8 Hz, 3H), 7.12 (d, J=8 Hz, 2H) 7.24 (d, J=2 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@H:10]2[CH2:14][N:13]([CH2:15][C:16](=[O:32])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]4=[O:30])=[CH:20][C:19]=3[F:31])[CH2:12][C@@H:11]2[O:33][CH2:34][C:35]([OH:37])=O)=[O:8])=[CH:4][CH:3]=1.Cl.[CH3:39][NH:40][CH3:41]>>[CH3:39][N:40]([CH3:41])[C:35]([CH2:34][O:33][C@H:11]1[CH2:12][N:13]([CH2:15][C:16](=[O:32])[NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]3=[O:30])=[CH:20][C:19]=2[F:31])[CH2:14][C@@H:10]1[NH:9][C:7]([C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:8])=[O:37]
Reactant: CNC
Reactant: O=C(O)CO[C@H]1CN(CC(=O)Nc2ccc(-n3ccccc3=O)cc2F)C[C@@H]1NC(=O)c1ccc(Cl)s1
Agent: Cl
Product: CN(C)C(=O)CO[C@H]1CN(CC(=O)Nc2ccc(-n3ccccc3=O)cc2F)C[C@@H]1NC(=O)c1ccc(Cl)s1

Procedure:
According to general procedure D ((3S,4S)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-1-{[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenylcarbamoyl]-methyl}-pyrrolidin-3-yloxy)-acetic acid (example 97) was reacted with dimethylamine hydrochloride to give 5-chloro-thiophene-2-carboxylic acid ((3S,4S)-4-dimethylcarbamoylmethoxy-1-{[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenylcarbamoyl]-methyl}-pyrrolidin-3-yl)-amide. Off-white solid. MS576.3 ([M+H]+)
Reaction SMILES: [CH:1]([OH:3])=[O:2].C([N:11](CC1C=CC=CC=1)[C@@H:12]([CH3:20])[C@H:13]([CH:15]1[CH2:17][C:16]1([CH3:19])[CH3:18])[OH:14])C1C=CC=CC=1>[Pd].C(O)C>[CH3:19][C:16]1([CH3:18])[CH2:17][CH:15]1[CH:13]([OH:14])[C@@H:12]([NH:11][C:1](=[O:3])[O:2][C:15]([CH3:17])([CH3:16])[CH3:13])[CH3:20]
Reactant: O=CO
Reactant: C[C@@H]([C@@H](O)C1CC1(C)C)N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: C[C@H](NC(=O)OC(C)(C)C)C(O)C1CC1(C)C
Temperature: 90 °C
Reaction time: 5 h

Procedure:
Formic acid (2.4 ml) and 10% Pd/C (0.4 g) were added to an ethanol solution (60 ml) containing (1S,2S)-2-(dibenzylamino)-1-(2,2-dimethylcyclopropyl)propan-1-ol (2.4 g) obtained in the 5th step, followed by stirring at 90° C. for 5 hours. The reaction solution was filtered through Celite and the filtrate was distilled away under reduced pressure. Diisopropyl ethylamine (1.5 ml) and di-tert-butyl carbonate (1.75 g) were added to a THF (5 ml) solution containing the obtained residue, followed by stirring at room temperature for 40 minutes. Water and a 10% citric acid aqueous solution were added to the reaction solution, followed by extraction with ethyl acetate. The organic layers were washed with water and saturated saline and dried over anhydrous sodium sulfate. Then, the solvent was distilled away under reduced pressure and the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0 to 1:0.2). A yellow liquid of tert-butyl ((2S)-1-(2,2-dimethylcyclopropyl)-1-hydroxypropan-2-yl)carbamate (0.45 g) was thus obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[NH:5][CH:6]1[CH2:9][C:8]2([CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18](Br)=[CH:17][N:16]=3)[CH2:11][CH2:10]2)[CH2:7]1)[CH3:2].O[C:24]([C:27](O)(C)C)([CH3:26])[CH3:25].CC(C)=CB([O-])[O-].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCCC1>O>[CH2:1]([O:3][C:4](=[O:22])[NH:5][CH:6]1[CH2:9][C:8]2([CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:25]=[C:24]([CH3:27])[CH3:26])=[CH:17][N:16]=3)[CH2:11][CH2:10]2)[CH2:7]1)[CH3:2]
Reactant: CCOC(=O)NC1CC2(CCN(c3ccc(Br)cn3)CC2)C1
Reactant: CC(C)(O)C(C)(C)O
Agent: CC(C)=CB([O-])[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)NC1CC2(CCN(c3ccc(C=C(C)C)cn3)CC2)C1
Yield: 83.5 %

Procedure:
The process is performed according to the method described in Example 2 (step 2.7.). Starting with 0.50 g (1.36 mmol) of ethyl[7-(5-bromopyridin-2-yl)-7-azaspiro[3.5]non-2-yl]carbamate, prepared in the preceding step, 0.33 mL (1.63 mmol) of pinacol 2-methyl-1-propenylboronate (commercial) and 1.33 g (4.07 mmol) of caesium carbonate, suspended in 9 mL of a 9/1 mixture of tetrahydrofuran and water, and 0.11 g (0.14 mmol) of PdCl2dppf.CH2Cl2, and after purifying on a column of silica gel, eluting with a 100/0/0 to 99/1/0.1 mixture of dichloromethane, methanol and 28% aqueous ammonia, 0.39 g of expected product is obtained in the form of a wax.