Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:9])(C)[NH:3][Si:4](C)(C)C.[Cl-].[Al+3].[Cl-].[Cl-].Cl[Si](Cl)(C)C.Cl[Si](C)(C)C.[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25]>>[CH2:24]([N:26]([Si:2]([CH3:9])([CH3:1])[NH:3][SiH3:4])[CH2:27][CH3:28])[CH3:25]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: CCNCC
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(Cl)Cl
Agent: [Al+3]
Product: CCN(CC)[Si](C)(C)N[SiH3]
Temperature: 25 °C
Yield: 75 %

Procedure:
250 g (1.55 mol) of hexamethyldisilazane (((CH3)3Si)2NH) and 10 g (0.075 mol) of aluminum chloride (AlCl3) were put into 2000 mL of a flame-dried Schlenk flask under anhydrous and inert atmosphere while stirring, 499.80 g (3.87 mol) of dichloro dimethylsilane ((CH3)2SiCl2) was slowly added thereto while maintaining temperature of 25° C. and a temperature of the reaction solution was slowly raised to 40° C. The mixed reaction solution was stirred for 3 hours and the produced chlorotrimethylsilane ((CH3)3SiCl) and the excessively added dichloro dimethylsilane ((CH3)2SiCl2) were removed therefrom by simple distillation or distillation under reduced pressure. The recovered chloro dimethyl disilazane (((CH3)2SiCl)2NH)) solution was stirred and then 475.45 g (6.5 mol) of diethylamine ((CH3CH2)2NH) was slowly added thereto while maintaining temperature of −15° C. After the addition was completed, a temperature of the reaction solution was slowly raised to room temperature, and the reaction solution was stirred at room temperature for 6 hours. After the white solid obtained by filtration was removed to obtain a filtrate, solvent was removed from the filtrate under reduced pressure, and 319.90 g (1.16 mol) of diethylamino dimethyl disilazane ((CH3)2SiN(CH2CH3)2)2NH) was obtained by reduced pressure distillation with a yield of 75%.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]1[C:10](=[O:11])[NH:9][C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[S:6]1.[C-:16]#[N:17].[Na+]>CS(C)=O.O>[C:16]([CH2:2][CH2:3][CH2:4][CH:5]1[C:10](=[O:11])[NH:9][C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[S:6]1)#[N:17]
Reactant: [C-]#N
Reactant: O=C1Nc2ccccc2SC1CCCBr
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCCCC1Sc2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.8 %

Procedure:
To a solution of 2.86 g of 2-(3-bromopropyl)-2H-1,4-benzothiazin-3(4H)-one in 10 ml of dimethyl sulfoxide was added 0.54 g of sodium cyanide. The mixture was stirred at room temperature for 3 hours and diluted with water. The resulting crystals were collected by filtration and washed with water. Recrystallization from methanol gave 1.55 g (66.7%) of 2-(3-cyanopropyl)-2H-1,4-benzothiazin-3(4H)-one as prisms, m.p. 107°-108° C.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH3:15])[CH2:3][CH2:4][C:5]([C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1)=[O:6].[CH2:17](O)[CH2:18][OH:19].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:1][C:2]([CH3:16])([CH3:15])[CH2:3][CH2:4][C:5]1([C:7]2[CH:8]=[CH:9][C:10]([C:11]#[N:12])=[CH:13][CH:14]=2)[O:19][CH2:18][CH2:17][O:6]1
Reactant: CC(C)(C)CCC(=O)c1ccc(C#N)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)CCC1(c2ccc(C#N)cc2)OCCO1
Temperature: 135 °C
Yield: 81.9 %

Procedure:
Dissolve 4-(4,4-dimethyl-pentanoyl)-benzonitrile (275 mg, 1.28 mmol) in toluene (10 mL). Add ethylene glycol (0.35 mL, 6.4 mmol) and p-toluenesulfonic acid monohydrate (24 mg, 0.128 mmol). Heat the mixture at 135° C. in a Dean-Stark for 2 h and then at 120° C. overnight. Cool the mixture to room temperature, dilute with EtOAc and wash with saturated aqueous NaHCO3. Dry the organic phase over MgSO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on basic alumina eluting with hexane and hexane/EtOAc (19:1) to give the desired intermediate as an oil (0.272 g, 82%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:5]=[CH:6][C:7]2[C:12]([C:13]=1[C:14]([O:16]CC)=[O:15])=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:2].[OH-].[Na+]>CO>[CH2:1]([O:3][C:4]1[N:5]=[CH:6][C:7]2[C:12]([C:13]=1[C:14]([OH:16])=[O:15])=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:2]
Reactant: CCOC(=O)c1c(OCC)ncc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOc1ncc2ccccc2c1C(=O)O
Temperature: 60 °C
Reaction time: 16 h
Yield: 65.6 %

Procedure:
The title compound of Step B (492 mg, 2 mmol) dissolved in MeOH (15 mL) was added NaOH(aq) 2M (2.5 mL). The reaction mixture was stirred at 60° C. for 16 h and then NaOH(aq) 4M (2 mL) was added and the mixture was stirred at 70° C. for 4 h. MeOH was evaporated and the aqueous phase was cooled to 0° C. and acidified with the addition of HCl(aq) 6N. The solid was filtered, washed with cold water and dried to afford the title compound (285 mg, 65%). MS (ESI) mass calcd. for C12H11NO3, 217.1; m/z found 218.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 13.36 (s, 1H), 9.15 (s, 1H), 8.13-8.06 (m, 1H), 7.82-7.70 (m, 2H), 7.54-7.47 (m, 1H), 4.50 (q, J=7.0 Hz, 2H), 1.35 (t, J=7.0 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]([NH2:13])[NH:11][N:12]=1.[C:14](OCC)(=[O:19])[CH2:15][C:16]([CH3:18])=O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]2[N:13]=[C:16]([CH3:18])[CH:15]=[C:14]([OH:19])[N:11]2[N:12]=1
Reactant: Nc1cc(-c2ccccc2Cl)n[nH]1
Reactant: CCOC(=O)CC(C)=O
Solvent: CC(=O)O
Product: Cc1cc(O)n2nc(-c3ccccc3Cl)cc2n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 75 %

Procedure:
To a solution of 5-(2-chlorophenyl)-2H-pyrazol-3-ylamine (I-1A-1a; 1.51 g, 7.80 mmol) in acetic acid (10 ml) was added ethyl acetoacetate (1.1 ml, 8.6 mmol). The reaction was heated at reflux for 17 hours. Upon cooling to room temperature a solid precipitate formed which, after standing for 2 days, was isolated by vacuum filtration and washed with additional acetic acid. The solids were stirred in ether and then isolated by vacuum filtration to afford I-1A-3f as a colorless solid (1.52 g, 75%): +ESI MS (M+1) 260.2; 1H NMR (400 MHz, DMSO-d6) δ 12.18 (br s, 1H), 7.85–7.81 (m, 1H), 7.57–7.54 (m, 1H), 7.46–7.41 (m, 2H), 6.49 (s, 1H), 5.61 (s, 1H), 2.29 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH:7]=[C:8]2[NH:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])=[CH:5][CH:4]=1>[OH-].[Na+].[Ni]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8]2[NH:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])=[CH:15][CH:16]=1
Reactant: COc1ccc(C=C2NC(=O)NC2=O)cc1
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(CC2NC(=O)NC2=O)cc1
Yield: 82 %

Procedure:
218.2 g (1 mole) of 5-(4-methoxy-benzylidene)-hydantoin are dissolved in 2 l of a N sodium hydroxide solution and 50 g of wet Raney-nickel are added. The reaction mixture is worked up according to Example 6. Thus 180.6 g of the desired compound are obtained, yield 82 %. Mp.: 174° C.
Reaction SMILES: [C:1]1([C:7]2[C:12]([C:13]([O:15]C)=[O:14])=[CH:11][N:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].CO.[ClH:21]>C(OCC)(=O)C>[ClH:21].[C:1]1([C:7]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cnccc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(O)c1cnccc1-c1ccccc1
Reaction time: 1 h

Procedure:
Methyl 4-phenylnicotinate [cp. Heterocycles 22, 151-157 (1984)](53 g, 0.25 mol), 5N aqueous NaOH solution (100 ml) and methanol (100 ml) are refluxed together with stirring for 1 h. The reaction solution is allowed to cool, acidified with concentrated HCl to pH 4 and evaporated to dryness in vacuo. The residue is slurried in hot ethanol (75 ml), filtered, and the filtrates are evaporated to dryness in vacuo. The residue obtained is slurried in cold ethyl acetate (30 ml), filtered and dried to give 4-phenylnicotinic acid hydrochloride, m.p. 239°-241°.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.C(N(CC)C(C)C)(C)C.[NH2:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[N:36]([CH3:40])[C:35](=[O:41])[CH2:34]2.COCC(O)C>>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:6]2[C:7]([CH:8]=[N:9][C:4]([NH:30][C:31]3[CH:32]=[C:33]4[C:37](=[CH:38][CH:39]=3)[N:36]([CH3:40])[C:35](=[O:41])[CH2:34]4)=[N:5]2)=[CH:10][CH:11]=1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Reactant: CN1C(=O)Cc2cc(N)ccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc4c(c3)CC(=O)N4C)nn12

Procedure:
2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (125.0 mg, 0.0004350 mol), N,N-Diisopropylethylamine (0.250 mL, 0.00144 mol) and 5-Amino-1-methyl-1,3-dihydro-indol-2-one (0.141 g, 0.000870 mol) were dissolved in 1-Methoxy-2-propanol (0.500 mL, 0.00512 mol) and the reaction was irradiated at 300 watts, 180° C. for 40 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 5-[7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-1-methyl-1,3-dihydro-indol-2-one as a lyophilized powder. (M+H)=386.1. 1H NMR (400 MHz, DMSO, d6) δ 9.33 (s, 1H), 8.93 (s, 1H), 7.78 (m, 2H), 7.50 (m, 2H), 7.24 (d, 1H, J=8.28 Hz), 7.15 (t, 1H, J=7.61 Hz), 6.91 (m, 2H), 6.82 (d, 1H, J=8.28 Hz), 3.78 (s, 3H), 3.46 (s, 2H), 3.08 (s, 3H).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][N:14]3[C@H:18]([CH:19]([CH3:21])[CH3:20])[CH2:17][O:16][C:15]3=[O:22])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.Cl.[NH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.O.CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[N:6]3[N:7]=[C:8]([NH:11][CH2:12][CH2:13][N:14]4[C@H:18]([CH:19]([CH3:21])[CH3:20])[CH2:17][O:16][C:15]4=[O:22])[CH:9]=[CH:10][C:5]3=[N:4][CH:3]=2)=[CH:28][CH:27]=1
Reactant: NCc1ccc(B(O)O)cc1
Reactant: CC(C)[C@@H]1COC(=O)N1CCNc1ccc2ncc(Br)n2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: CC(C)[C@@H]1COC(=O)N1CCNc1ccc2ncc(-c3ccc(CN)cc3)n2n1
Temperature: 150 °C

Procedure:
A mixture of (R)-3-[2-(3-bromo-imidazo[1,2-b]pyridazin-6-ylamino)-ethyl]-4-isopropyl-oxazolidin-2-one (95 mg, 0.26 mmol), (4-aminomethylphenyl)boronic acid hydrochloride (63.7 mg, 0.34 mmol), K2CO3 (108 mg, 0.78 mmol) and dichlorobis(triphenylphosphine)palladium(II) (9.1 mg, 0.013 mmol) in MeCN/water (3.2 ml/0.8 ml) was heated in a microwave at 150° C. for 15 min. The reaction mixture was diluted with MeCN and filtered. The filtrate was subjected to preparative HPLC to give the titled compound as HCOOH salt (86.3 mg). 1H NMR (400 MHz, METHANOL-d4) ppm 0.84 (dd, J=6.95, 0.88 Hz, 6H) 2.09 (td, J=6.95, 3.54 Hz, 1H) 3.26-3.31 (m, 1H) 3.59-3.71 (m, 2H) 3.85 (dt, J=13.96, 6.79 Hz, 1H) 3.95 (ddd, J=8.65, 5.24, 3.54 Hz, 1H) 4.11-4.19 (m, 4H) 6.74 (d, J=9.60 Hz, 1H) 7.58 (d, J=8.34 Hz, 2H) 7.68 (d, J=9.85 Hz, 1H) 7.81 (s, 1H) 8.21-8.26 (m, 2H) 8.52 (s, 1H). LRMS (ESI) m/z 395.3 [(M+H)]+, calc'd for C21H26N6O2: 394.48.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:15]=[C:14]([NH:16][C@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]2[NH:23]C(OC(C)(C)C)=O)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:31])[CH:12]=2)[N:7]=1)=[O:5])[CH3:2].C(OCC)(=O)C.[ClH:38]>C(OCC)(=O)C>[ClH:38].[ClH:38].[CH2:1]([O:3][C:4]([C:6]1[N:15]=[C:14]([NH:16][C@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]2[NH2:23])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:31])[CH:12]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(N[C@H]2CCCC[C@H]2NC(=O)OC(C)(C)C)c2cc(C)ccc2n1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(N[C@H]2CCCC[C@H]2N)c2cc(C)ccc2n1
Temperature: 25 °C
Reaction time: 11 h

Procedure:
To a solution of 14.5 g of 4-({(1S,2R)-2-[(tert-butoxycarbonyl)amino]cyclohexyl}amino)-6-methylquinazoline-2-carboxylic acid ethyl ester in 600 ml of ethyl acetate, 68 ml of a 4N-hydrogen chloride-ethyl acetate solution was added under ice cooling, and then the mixture was stirred at room temperature for 11 hours. The deposited crystals were collected by filtration, washed with ethyl acetate and then dried to obtain 11.7 g of the desirable compound as a pink powder.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2)[CH3:2].[Cl-].[Br:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[CH:17]=[N+:18]([CH3:20])[CH3:19].BrC1C=C(C=CC=1)C=O.CNC>>[Br:13][C:14]1[CH:15]=[C:16]([CH:17]([N:18]([CH3:20])[CH3:19])[C:8]2[C:7]3[C:11](=[C:3]([CH2:1][CH3:2])[CH:4]=[CH:5][CH:6]=3)[NH:10][CH:9]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: CCc1cccc2cc[nH]c12
Reactant: C[N+](C)=Cc1cccc(Br)c1
Agent: CNC
Agent: O=Cc1cccc(Br)c1
Agent: [Cl-]
Product: CCc1cccc2c(C(c3cccc(Br)c3)N(C)C)c[nH]c12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 7-ethylindole and (3-bromo-benzylidene)-dimethyl-ammonium chloride, which had been prepared in accordance with example 24 from 3-bromo-benzaldehyde and dimethylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][N:12]=[C:11]([CH3:14])[C:10]=2[NH2:15])=[CH:5][CH:4]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](Cl)=[O:22]>>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([NH:15][C:10]1[C:11]([CH3:14])=[N:12][NH:13][C:9]=1[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)=[O:22]
Reactant: COc1ccc(-c2[nH]nc(C)c2N)cc1
Reactant: COc1cccc(C(=O)Cl)c1
Product: COc1ccc(-c2[nH]nc(C)c2NC(=O)c2cccc(OC)c2)cc1

Procedure:
The preparation took place in analogy with Example 15a), starting with 300 mg of 5-(4-methoxyphenyl)-3-methyl-1H-pyrazol-4-ylamine (50) and 277 mg of 3-methoxybenzoyl chloride. The following was obtained: 59.
Reaction SMILES: [CH2:1]([C:13]1[N:14]=[N:15][N:16]([CH:18]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:19]([OH:21])=O)[N:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(C1N=NN(CC(O)=O)N=1)CCCCCCCCC.[CH3:46][O:47][C:48]1[CH:54]=[C:53]([O:55][CH3:56])[CH:52]=[C:51]([O:57][CH3:58])[C:49]=1[NH2:50].C(C1C=CC=C(C(C)C)C=1N)(C)C>>[CH2:1]([C:13]1[N:14]=[N:15][N:16]([CH:18]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:19]([NH:50][C:49]2[C:51]([O:57][CH3:58])=[CH:52][C:53]([O:55][CH3:56])=[CH:54][C:48]=2[O:47][CH3:46])=[O:21])[N:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1nnn(C(CCCCC)C(=O)O)n1
Reactant: COc1cc(OC)c(N)c(OC)c1
Agent: CC(C)c1cccc(C(C)C)c1N
Agent: CCCCCCCCCCc1nnn(CC(=O)O)n1
Product: CCCCCCCCCCCCc1nnn(C(CCCCC)C(=O)Nc2c(OC)cc(OC)cc2OC)n1

Procedure:
When in the general procedure of Example 88 an appropriate amount of (±)-5-dodecyl-α-pentyl-2H-tetrazole-2-acetic acid was substituted for 5-decyl-2H-tetrazole-2-acetic acid and 2,4,6-trimethoxyaniline was substituted for 2,6-diisopropylaniline, the title compound was obtained, mp 152°-155° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[N:7]=[CH:6][C:5]=1[CH2:11][C:12]#[N:13].Br[CH2:15][CH2:16]Cl>C1COCC1>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[N:7]=[CH:6][C:5]=1[C:11]1([C:12]#[N:13])[CH2:16][CH2:15]1
Reactant: ClCCBr
Reactant: N#CCc1cnc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC1(c2cnc(Cl)cc2Cl)CC1

Procedure:
Sodium hydride (60% in mineral oil, 0.128 g, 3.21 mmol) was suspended in 0.5 ml THF. At 0° C. a solution of 2-(4,6-dichloro-3-pyridyl)acetonitrile (0.200 g, 1.07 mmol) in 1.7 ml THF was added drop wise. The reaction mixture was stirred until no gas evolution was detectable. It was then a red suspension. At 0° C. 1-Bromo-2-chloro-ethane (0.355 mL, 4.28 mmol) was added drop wise. The reaction mixture was stirred 30 min at 0° C. then overnight at rt. It was quenched with aq NH4Cl. The organic layer was separated and dried with Na2SO4 then filtrated. The filtrate was concentrated. The residue was a brown gum (260 mg). The crude product was purified by flash chromatography (Solvent: Cyclohexane/EtOAc 3/1). The desired product was isolated as a white solid (135 mg).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21](=[O:30])[C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])[CH2:17][CH2:16]2)=[CH:10][CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]2[CH2:16][CH2:17][N:18]([C:21]([C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])=[O:30])[CH2:19][CH2:20]2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC2CCN(C(=O)c3c(Cl)cccc3Cl)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(OC2CCN(C(=O)c3c(Cl)cccc3Cl)CC2)cc1
Temperature: 22 °C
Reaction time: 0.25 h
Yield: 92 %

Procedure:
The above white solid, {4-[1-(2,6-dichloro-benzoyl)-piperidin-4-yloxy]-phenyl}-carbamic acid tert-butyl ester, is suspended in a solution of trifluoroacetic acid in dichloromethane (25% v/v, 20 mL). The reaction mixture is stirred at 22° C. for 15 min. After removal of the solvent, the oily residue is neutralized with 0.5 N aqueous sodium hydroxide solution (50 mL) and extracted with dichloromethane (5×50 mL). The combined organic phases are dried over anhydrous sodium sulfate and concentrated to yield a yellow solid (440.2 mg, 92.0% yield, ES+(m/z) 365.1 [M+H]).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:26][C:27]([C:29]2[C:30](=[O:42])[N:31]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:32]([CH3:35])[C:33]=2[CH3:34])=[O:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH2:20][CH2:21][C:22]3([OH:25])[CH2:24][CH2:23]3)=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.[C:43]([NH:50][CH2:51][C:52](O)=[O:53])([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.ClCCl>[C:46]([O:45][C:43]([NH:50][CH2:51][C:52]([O:25][C:22]1([CH2:21][CH2:20][O:19][C:15]2[CH:14]=[C:13]3[C:18]([C:9]([O:8][C:7]4[CH:6]=[CH:5][C:4]([NH:26][C:27]([C:29]5[C:30](=[O:42])[N:31]([C:36]6[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=6)[N:32]([CH3:35])[C:33]=5[CH3:34])=[O:28])=[CH:3][C:2]=4[F:1])=[CH:10][CH:11]=[N:12]3)=[CH:17][CH:16]=2)[CH2:23][CH2:24]1)=[O:53])=[O:44])([CH3:49])([CH3:48])[CH3:47]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OCCC5(O)CC5)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OCCC5(OC(=O)CNC(=O)OC(C)(C)C)CC5)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.2 %

Procedure:
To a mixture of N-(3-fluoro-4-(7-(2-(1-hydroxycyclopropyl)ethoxy)quinolin-4-yloxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (218 mg, 0.384 mmol), N-Boc-glycine (133.4 mg, 0.768 mmol, Alfa), and DMAP (7.03 mg, 0.058 mmol, Aladdin) in 10 mL of dichloromethane was added DCC solid (323.4 mg, 1.54 mmol, Aldrich) slowly at 0° C. The reaction was then warmed up to rt and continued to stir at rt overnight. The reaction mixture was filtered and the solid was washed with dichloromethane (10 mL×2). The combined organic phases were washed with 20 mL of saturated NaNCO3 solution followed by 20 mL of brine, dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on a silica gel column (PE: EA=1:6) to give the desired compound as a yellow solid (190 mg, 70%).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].C(N(CC)CC)C.[Br:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](Cl)=[O:17].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([NH:4][CH2:1][CH2:2][CH3:3])=[O:17]
Reactant: CCCN
Reactant: O=C(Cl)c1cccc(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCNC(=O)c1cccc(Br)c1
Temperature: -5 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
A mixture of N-propyl amine (0.33 mL, 4.1 mmol) and triethylamine (0.83 mL, 5.8 mmol) in methylene chloride was cooled to −5° C., treated with 3-bromobenzoyl chloride (1 g, 4.5 mmol), warmed to room temperature, stirred at room temperature for 1 h, poured into aqueous sodium bicarbonate and extracted with methylene chloride. The extracts were combined, washed sequentially with water and brine, dried over magnesium sulfate and concentrated under reduced pressure. The resultant residue was purified by flash chromatography on silica gel, 2:1 hexane/ethyl acetate as eluent, to give 3-bromo-N-propyl-benzamide as a white solid, 0.74 g (67% yield); 1H NMR (DMSO-d6) δ 0.8 (t, 3H); 1.5 (m, 2H); 3.2 (t, 2H); 7.4 (t, 1H); 7.6 (d, 1H), 7.8 (d, 1H); 7.9 (s, 1H); 8.5 (b, 1H); MS [(+)ESI] m/z 242[M−H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9]/[C:10](=[C:17]2\[C:18](=[O:26])[NH:19][C:20]3[C:25]\2=[CH:24][CH:23]=[CH:22][CH:21]=3)/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].Cl.[CH3:28][NH2:29]>CO>[CH3:28][NH:29][C:1]([C:3]1[CH:4]=[C:5]([NH:9]/[C:10](=[C:17]2\[C:18](=[O:26])[NH:19][C:20]3[C:25]\2=[CH:24][CH:23]=[CH:22][CH:21]=3)/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1)=[NH:2]
Reactant: N#Cc1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1
Reactant: CN
Agent: Cl
Solvent: CO
Product: CNC(=N)c1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1

Procedure:
Prepared analogously to Example 62 from (Z)-3-[1-(3-cyanophenylamino)-1-phenyl-methylidene]-2-indolinone, methanolic hydrochloric acid and methylamine in methanol.
Reaction SMILES: CO[C:3](=[O:20])[C:4]1[C:9]([F:10])=[CH:8][C:7]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:6][C:5]=1[F:19].[CH3:21][C@@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1[CH2:27][C@@H:28]1[CH2:32][CH2:31][CH2:30][NH:29]1>>[F:10][C:9]1[CH:8]=[C:7]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:6]=[C:5]([F:19])[C:4]=1[C:3]([N:29]1[CH2:30][CH2:31][CH2:32][C@H:28]1[CH2:27][N:23]1[CH2:24][CH2:25][CH2:26][C@H:22]1[CH3:21])=[O:20]
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1
Reactant: COC(=O)c1c(F)cc(OCc2ccccn2)cc1F
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1c(F)cc(OCc2ccccn2)cc1F

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure F from 2,6-Difluoro-4-(pyridin-2-ylmethoxy)-benzoic acid methyl ester and 2-(R)-Methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine. MS (ES+) 416.2
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[CH:25]=[CH:24][C:23]3[NH:22][C:21]4[CH2:26][CH2:27][N:28](C(OCC5C=CC=CC=5)=O)[CH2:29][C:20]=4[C:19]=3[CH:18]=2)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[CH2:29]1[C:20]2[C:19]3[CH:18]=[C:17]([C:15]([NH:14][CH:11]4[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][CH2:12]4)=[O:16])[CH:25]=[CH:24][C:23]=3[NH:22][C:21]=2[CH2:26][CH2:27][NH:28]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccc3[nH]c4c(c3c2)CN(C(=O)OCc2ccccc2)CC4)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccc3[nH]c4c(c3c2)CNCC4)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of benzyl 8-(1-(tert-butoxycarbonyl)piperidin-4-ylcarbamoyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (8 in Scheme 1(m), 1.0 g, 1.9 mmol) and Pd/C (10% wt., 0.2 g) in MeOH (20 mL) was allowed to stir at room temperature overnight. The palladium was then removed by filtration and washed with MeOH; and the resulting clear solution was concentrated to give tert-butyl 4-(2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamido)piperidine-1-carboxylate as an-off white solid (0.745 g, 100%). MS (ES) 399 (M+H).